TW202233668A - 用於治療眼部疾病之雙特異性抗-VEGF及抗-TrkB結合分子 - Google Patents

用於治療眼部疾病之雙特異性抗-VEGF及抗-TrkB結合分子 Download PDF

Info

Publication number
TW202233668A
TW202233668A TW110138827A TW110138827A TW202233668A TW 202233668 A TW202233668 A TW 202233668A TW 110138827 A TW110138827 A TW 110138827A TW 110138827 A TW110138827 A TW 110138827A TW 202233668 A TW202233668 A TW 202233668A
Authority
TW
Taiwan
Prior art keywords
seq
amino acid
acid sequence
heavy chain
light chain
Prior art date
Application number
TW110138827A
Other languages
English (en)
Inventor
彼得 麥可 班士
瑞可 亞力山德 貝克
豪格 富奇斯
菲 韓
珊迪普 庫瑪
莎拉 羅
賈斯汀 Ｍ 謝爾
里歐 湯瑪斯
Original Assignee
德商百靈佳殷格翰國際股份有限公司
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by 德商百靈佳殷格翰國際股份有限公司 filed Critical 德商百靈佳殷格翰國際股份有限公司
Publication of TW202233668A publication Critical patent/TW202233668A/zh

Links

Images

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/02—Ophthalmic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
    • C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
    • C07K16/22—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against growth factors ; against growth regulators
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
    • C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
    • C07K16/28—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants
    • C07K16/2863—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against receptors for growth factors, growth regulators
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K2039/505—Medicinal preparations containing antigens or antibodies comprising antibodies
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/10—Immunoglobulins specific features characterized by their source of isolation or production
    • C07K2317/14—Specific host cells or culture conditions, e.g. components, pH or temperature
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/20—Immunoglobulins specific features characterized by taxonomic origin
    • C07K2317/24—Immunoglobulins specific features characterized by taxonomic origin containing regions, domains or residues from different species, e.g. chimeric, humanized or veneered
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/30—Immunoglobulins specific features characterized by aspects of specificity or valency
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/30—Immunoglobulins specific features characterized by aspects of specificity or valency
    • C07K2317/31—Immunoglobulins specific features characterized by aspects of specificity or valency multispecific
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/30—Immunoglobulins specific features characterized by aspects of specificity or valency
    • C07K2317/35—Valency
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/50—Immunoglobulins specific features characterized by immunoglobulin fragments
    • C07K2317/52—Constant or Fc region; Isotype
    • C07K2317/53—Hinge
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/50—Immunoglobulins specific features characterized by immunoglobulin fragments
    • C07K2317/54—F(ab')2
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/50—Immunoglobulins specific features characterized by immunoglobulin fragments
    • C07K2317/55—Fab or Fab'
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/50—Immunoglobulins specific features characterized by immunoglobulin fragments
    • C07K2317/56—Immunoglobulins specific features characterized by immunoglobulin fragments variable (Fv) region, i.e. VH and/or VL
    • C07K2317/565—Complementarity determining region [CDR]
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/60—Immunoglobulins specific features characterized by non-natural combinations of immunoglobulin fragments
    • C07K2317/62—Immunoglobulins specific features characterized by non-natural combinations of immunoglobulin fragments comprising only variable region components
    • C07K2317/622—Single chain antibody (scFv)
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/60—Immunoglobulins specific features characterized by non-natural combinations of immunoglobulin fragments
    • C07K2317/64—Immunoglobulins specific features characterized by non-natural combinations of immunoglobulin fragments comprising a combination of variable region and constant region components
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/70—Immunoglobulins specific features characterized by effect upon binding to a cell or to an antigen
    • C07K2317/73—Inducing cell death, e.g. apoptosis, necrosis or inhibition of cell proliferation
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/70—Immunoglobulins specific features characterized by effect upon binding to a cell or to an antigen
    • C07K2317/75—Agonist effect on antigen
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/70—Immunoglobulins specific features characterized by effect upon binding to a cell or to an antigen
    • C07K2317/76—Antagonist effect on antigen, e.g. neutralization or inhibition of binding
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/90—Immunoglobulins specific features characterized by (pharmaco)kinetic aspects or by stability of the immunoglobulin
    • C07K2317/92—Affinity (KD), association rate (Ka), dissociation rate (Kd) or EC50 value

Abstract

本發明係關於特異性結合血管內皮生長因子(Vascular Endothelial Growth Factor；VEGF)及肌旋蛋白受體激酶B(Tropomyosin receptor kinase B；TrkB)之結合分子及其在醫藥中之用途；包含其之醫藥組合物；及使用其作為藥劑用於治療及/或預防眼部疾病之方法。

Description

用於治療眼部疾病之雙特異性抗-VEGF及抗-TrkB結合分子
本發明係關於與血管內皮生長因子(Vascular Endothelial Growth Factor；VEGF)及肌旋蛋白受體激酶B (Tropomyosin receptor B；TrkB)結合之結合分子及其在醫藥中之用途；包含其之醫藥組合物；及使用其作為藥劑用於治療及/或預防眼部疾病之方法。
黃斑變性且特定言之老年性黃斑變性(AMD)為已開發國家中失明之主要原因。其晚期階段分成濕性新生血管性AMD及乾性地圖狀萎縮(geographic atrophy；GA)。wAMD之特徵在於眼部新血管形成及血管滲漏增加以及進行性神經退化及感光體損失。抗VEGF治療為此疾病之當前標準照護。療法通常由靶向VEGF之藥劑(阿瓦斯汀(Avastin)、雷珠單抗(Lucentis)、艾力雅(Eylea)及最新Beovu)組成，該等藥劑係藉由注射至眼睛後部給藥。
儘管VEGF清除減少血管滲漏且因此最初改善視力，但視網膜仍處於受損條件下，導致進一步的細胞損失。儘管過去十年間已見到針對wAMD伴隨玻璃體內抗VEGF之突破性治療，但無針對地圖狀萎縮(一種減緩進行性疾病，最終導致失明)之治療選擇。
在wAMD診斷後兩年內且即時成功進行抗VEGF治療，但幾乎三分之一之患者罹患進行性地圖狀萎縮。其為與進行性視覺障礙相關之較晚階段。患者失去其視力及獨立性。其日常生活因為不能駕駛、閱讀、看電視或識別面部而嚴重受影響。wAMD患者通常在現實世界環境中治療不足且需要返回門診以進行頻繁的玻璃體內注射。
目前無治療可用於任何類型之地圖狀萎縮，包括在wAMD期間發展之地圖狀萎縮。此外，一些證據表明，較頻繁的抗VEGF治療可能與較高比率之地圖狀萎縮發展相關。
因此，迫切需要提供可在抗VEGF治療中頻繁使用而同時減輕並行地圖狀萎縮發展之風險的新治療性生物分子。
本發明係基於將與血管內皮生長因子(VEGF)特異性結合之抗原結合位點與同肌旋蛋白受體激酶B (TrkB)特異性結合之抗原結合位點組合在單一結合分子內的概念。
在第一態樣中，本發明係關於一種結合分子，其包含至少一個與血管內皮生長因子(VEGF)特異性結合之抗原結合位點及至少一個與肌旋蛋白受體激酶B (TrkB)特異性結合之抗原結合位點。在關於第一態樣之一個實施例中，結合分子為雙特異性且四價的。在關於根據第一態樣或其實施例中之任一者之結合分子的另一實施例中，該至少一個與VEGF特異性結合之抗原結合位點為免疫球蛋白(Ig)分子。在關於根據第一態樣或其實施例中之任一者之結合分子的另一實施例中，該至少一個與TrkB特異性結合之抗原結合位點與Ig分子之重鏈的C端融合。在關於根據第一態樣或其實施例中之任一者之結合分子的另一實施例中，該至少一個與TrkB特異性結合之抗原結合位點包含一或多個scFv。在關於根據第一態樣或其實施例中之任一者之結合分子的另一實施例中，該至少一個與VEGF特異性結合之抗原結合位點為免疫球蛋白(Ig)分子，且該至少一個與TrkB特異性結合之抗原結合位點包含一或多個scFv。在一相關實施例中，該一或多個scFv自N端至C端具有VL-VH定向。在又一相關實施例中，該一或多個scFv與Ig分子之重鏈的C端融合。在關於根據第一態樣或其實施例中之任一者之結合分子的另一實施例中，Ig分子為單株抗體、人類單株抗體、人源化單株抗體、嵌合抗體、(scFv) 2或抗體之片段，諸如F(ab')2片段。在關於根據第一態樣或其實施例中之任一者之結合分子的另一實施例中，Ig分子為IgG或F(ab')2。在關於根據第一態樣或其實施例中之任一者之結合分子的另一實施例中，該一或多個scFv藉由肽連接子，較佳地長度為約4至20個胺基酸之肽連接子與Ig分子融合。
在關於根據第一態樣或其實施例中之任一者之結合分子的另一實施例中，與TrkB特異性結合之抗原結合位點選自： a)    包含輕鏈CDR之抗原結合位點，該輕鏈CDR包含SEQ ID NO:201 (CDR1)、SEQ ID NO:202 (CDR2)及SEQ ID NO:203 (CDR3)之胺基酸序列，及 包含重鏈CDR之抗原結合位點，該重鏈CDR包含SEQ ID NO:204 (CDR1)、SEQ ID NO:205 (CDR2)及SEQ ID NO:206 (CDR3)之胺基酸序列；或 包含重鏈CDR之抗原結合位點，該重鏈CDR包含SEQ ID NO:207 (CDR1)、SEQ ID NO:208 (CDR2)及SEQ ID NO:209 (CDR3)之胺基酸序列；或 包含重鏈CDR之抗原結合位點，該重鏈CDR包含SEQ ID NO:210 (CDR1)、SEQ ID NO:211 (CDR2)及SEQ ID NO:212 (CDR3)之胺基酸序列。
在關於根據第一態樣或其實施例中之任一者之結合分子的另一實施例中，與TrkB特異性結合之抗原結合位點選自： a)  包含輕鏈可變域及重鏈可變域之抗原結合位點，該輕鏈可變域包含與SEQ ID NO:213或215之胺基酸序列至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或至少99%一致的胺基酸序列，該重鏈可變域包含與SEQ ID NO:214或216之胺基酸序列至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或至少99%一致的胺基酸序列。
在關於根據第一態樣或其實施例中之任一者之結合分子的另一實施例中，結合分子包含SEQ ID NO:222之胺基酸序列、或SEQ ID NO:223之胺基酸序列、或SEQ ID NO:224之胺基酸序列或SEQ ID NO:225之胺基酸序列。
在關於根據第一態樣或其實施例中之任一者之結合分子的另一實施例中，與VEGF特異性結合之抗原結合位點選自由抗原結合位點a)至c)組成之群： a)    包含輕鏈CDR之抗原結合位點，該輕鏈CDR包含SEQ ID NO:145 (CDR1)、SEQ ID NO:146 (CDR2)及SEQ ID NO:147 (CDR3)之胺基酸序列，及 包含重鏈CDR之抗原結合位點，該重鏈CDR包含SEQ ID NO:148 (CDR1)、SEQ ID NO:149 (CDR2)及SEQ ID NO:150 (CDR3)之胺基酸序列；或 包含重鏈CDR之抗原結合位點，該重鏈CDR包含SEQ ID NO:151 (CDR1)、SEQ ID NO:152 (CDR2)及SEQ ID NO:153 (CDR3)之胺基酸序列；或 包含重鏈CDR之抗原結合位點，該重鏈CDR包含SEQ ID NO:154 (CDR1)、SEQ ID NO:155 (CDR2)及SEQ ID NO:156 (CDR3)之胺基酸序列； b)   包含輕鏈CDR之抗原結合位點，該輕鏈CDR包含SEQ ID NO:157 (CDR1)、SEQ ID NO:158 (CDR2)及SEQ ID NO:159 (CDR3)之胺基酸序列，及 包含重鏈CDR之抗原結合位點，該重鏈CDR包含SEQ ID NO:160 (CDR1)、SEQ ID NO:161 (CDR2)及SEQ ID NO:162 (CDR3)之胺基酸序列；或 包含重鏈CDR之抗原結合位點，該重鏈CDR包含SEQ ID NO:163 (CDR1)、SEQ ID NO:164 (CDR2)及SEQ ID NO:165 (CDR3)之胺基酸序列；或 包含重鏈CDR之抗原結合位點，該重鏈CDR包含SEQ ID NO:166 (CDR1)、SEQ ID NO:167 (CDR2)及SEQ ID NO:168 (CDR3)之胺基酸序列； c)    包含輕鏈CDR之抗原結合位點，該輕鏈CDR包含SEQ ID NO:169 (CDR1)、SEQ ID NO:170 (CDR2)及SEQ ID NO:171 (CDR3)之胺基酸序列，及 包含重鏈CDR之抗原結合位點，該重鏈CDR包含SEQ ID NO:172 (CDR1)、SEQ ID NO:173 (CDR2)及SEQ ID NO:174 (CDR3)之胺基酸序列；或 包含重鏈CDR之抗原結合位點，該重鏈CDR包含SEQ ID NO:175 (CDR1)、SEQ ID NO:176 (CDR2)及SEQ ID NO:177 (CDR3)之胺基酸序列；或 包含重鏈CDR之抗原結合位點，該重鏈CDR包含SEQ ID NO:178 (CDR1)、SEQ ID NO:179 (CDR2)及SEQ ID NO:180 (CDR3)之胺基酸序列。
在關於根據第一態樣或其實施例中之任一者之結合分子的另一實施例中，與VEGF特異性結合之抗原結合位點選自由抗原結合位點a)至d)組成之群： a)    包含輕鏈可變域及重鏈可變域之抗原結合位點，該輕鏈可變域包含與SEQ ID NO:181之胺基酸序列至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或至少99%一致的胺基酸序列，該重鏈可變域包含與SEQ ID NO:182之胺基酸序列至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或至少99%一致的胺基酸序列； b)   包含輕鏈可變域及重鏈可變域之抗原結合位點，該輕鏈可變域包含與SEQ ID NO:183之胺基酸序列至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或至少99%一致的胺基酸序列，該重鏈可變域包含與SEQ ID NO:184之胺基酸序列至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或至少99%一致的胺基酸序列； c)    包含輕鏈可變域及重鏈可變域之抗原結合位點，該輕鏈可變域包含與SEQ ID NO:189之胺基酸序列至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或至少99%一致的胺基酸序列，該重鏈可變域包含與SEQ ID NO:190、191、192或194之胺基酸序列至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或至少99%一致的胺基酸序列； d)   包含輕鏈可變域及重鏈可變域之抗原結合位點，該輕鏈可變域包含與SEQ ID NO:193之胺基酸序列至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或至少99%一致的胺基酸序列，該重鏈可變域包含與SEQ ID NO:190、191、192或194之胺基酸序列至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或至少99%一致的胺基酸序列。
在關於根據第一態樣或其實施例中之任一者之結合分子的另一實施例中，與VEGF特異性結合之抗原結合位點選自由抗原結合位點a)至d)組成之群： a)    包含輕鏈及重鏈之抗原結合位點，該輕鏈包含與SEQ ID NO:185之胺基酸序列至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或至少99%一致的胺基酸序列，該重鏈包含與SEQ ID NO:186之胺基酸序列至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或至少99%一致的胺基酸序列； b)   包含輕鏈及重鏈之抗原結合位點，該輕鏈包含與SEQ ID NO:187之胺基酸序列至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或至少99%一致的胺基酸序列，該重鏈包含與SEQ ID NO:188之胺基酸序列至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或至少99%一致的胺基酸序列； c)    包含輕鏈及重鏈之抗原結合位點，該輕鏈包含與SEQ ID NO:195之胺基酸序列至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或至少99%一致的胺基酸序列，該重鏈包含與SEQ ID NO:196、197、198或200之胺基酸序列至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或至少99%一致的胺基酸序列； d)   包含輕鏈及重鏈之抗原結合位點，該輕鏈包含與SEQ ID NO:199之胺基酸序列至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或至少99%一致的胺基酸序列，該重鏈包含與SEQ ID NO:196、197、198或200之胺基酸序列至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或至少99%一致的胺基酸序列。
在第二態樣中，本發明係關於一種結合分子，其包含輕鏈及重鏈，該輕鏈包含與SEQ ID NO:1、3、5、7、9、11、13、15、17、19、21、23、25、27、29、31、33、35、37、39、41、43、45、47、49、51、53、55、57、59、61、63、65、67、69、71、73、75、77、79、81、83、85、87、89、91、93、95、97、99、101、103、105、107、109、111、113、115、117、119、121、123、125、127、129、131、133、135、137、139、141或143之胺基酸序列至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或至少99%一致的胺基酸序列，該重鏈包含與SEQ ID NO:2、4、6、8、10、12、14、16、18、20、22、24、26、28、30、32、34、36、38、40、42、44、46、48、50、52、54、56、58、60、62、64、66、68、70、72、74、76、78、80、82、84、86、88、90、92、94、96、98、100、102、104、106、108、110、112、114、116、118、120、122、124、126、128、130、132、134、136、138、140、142或144之胺基酸序列至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或至少99%一致的胺基酸序列。
在第三態樣中，本發明係關於一種結合分子，其包含：(i)包含SEQ ID NO:41之胺基酸序列的輕鏈及包含SEQ ID NO:42之胺基酸序列的重鏈；或(ii)包含SEQ ID NO:43之胺基酸序列的輕鏈及包含SEQ ID NO:44之胺基酸序列的重鏈；或(iii)包含SEQ ID NO:45之胺基酸序列的輕鏈及包含SEQ ID NO:46之胺基酸序列的重鏈；或(iv)包含SEQ ID NO:47之胺基酸序列的輕鏈及包含SEQ ID NO:48之胺基酸序列的重鏈；或(v)包含SEQ ID NO:49之胺基酸序列的輕鏈及包含SEQ ID NO:50之胺基酸序列的重鏈；或(vi)包含SEQ ID NO:51之胺基酸序列的輕鏈及包含SEQ ID NO:52之胺基酸序列的重鏈；或(vii)包含SEQ ID NO:53之胺基酸序列的輕鏈及包含SEQ ID NO:54之胺基酸序列的重鏈；或(viii)包含SEQ ID NO:55之胺基酸序列的輕鏈及包含SEQ ID NO:56之胺基酸序列的重鏈；或(ix)包含SEQ ID NO:57之胺基酸序列的輕鏈及包含SEQ ID NO:58之胺基酸序列的重鏈；或(x)包含SEQ ID NO:59之胺基酸序列的輕鏈及包含SEQ ID NO:60之胺基酸序列的重鏈；或(xi)包含SEQ ID NO:61之胺基酸序列的輕鏈及包含SEQ ID NO:62之胺基酸序列的重鏈；或(xii)包含SEQ ID NO:63之胺基酸序列的輕鏈及包含SEQ ID NO:64之胺基酸序列的重鏈；或(xiii)包含SEQ ID NO:65之胺基酸序列的輕鏈及包含SEQ ID NO:66之胺基酸序列的重鏈；或(xiv)包含SEQ ID NO:67之胺基酸序列的輕鏈及包含SEQ ID NO:68之胺基酸序列的重鏈；或(xv)包含SEQ ID NO:69之胺基酸序列的輕鏈及包含SEQ ID NO:70之胺基酸序列的重鏈；或(xvi)包含SEQ ID NO:71之胺基酸序列的輕鏈及包含SEQ ID NO:72之胺基酸序列的重鏈；或(xvii)包含SEQ ID NO:73之胺基酸序列的輕鏈及包含SEQ ID NO:74之胺基酸序列的重鏈；或(xviii)包含SEQ ID NO:75之胺基酸序列的輕鏈及包含SEQ ID NO:76之胺基酸序列的重鏈；或(xix)包含SEQ ID NO:77之胺基酸序列的輕鏈及包含SEQ ID NO:78之胺基酸序列的重鏈；或(xx)包含SEQ ID NO:79之胺基酸序列的輕鏈及包含SEQ ID NO:80之胺基酸序列的重鏈；或(xxi)包含SEQ ID NO:81之胺基酸序列的輕鏈及包含SEQ ID NO:82之胺基酸序列的重鏈；或(xxii)包含SEQ ID NO:83之胺基酸序列的輕鏈及包含SEQ ID NO:84之胺基酸序列的重鏈；或(xxiii)包含SEQ ID NO:85之胺基酸序列的輕鏈及包含SEQ ID NO:86之胺基酸序列的重鏈；或(xxiv)包含SEQ ID NO:87之胺基酸序列的輕鏈及包含SEQ ID NO:88之胺基酸序列的重鏈；或(xxv)包含SEQ ID NO:89之胺基酸序列的輕鏈及包含SEQ ID NO:90之胺基酸序列的重鏈；或(xxvi)包含SEQ ID NO:91之胺基酸序列的輕鏈及包含SEQ ID NO:92之胺基酸序列的重鏈；或(xxvii)包含SEQ ID NO:93之胺基酸序列的輕鏈及包含SEQ ID NO:94之胺基酸序列的重鏈；或(xxviii)包含SEQ ID NO:95之胺基酸序列的輕鏈及包含SEQ ID NO:96之胺基酸序列的重鏈；或(xxix)包含SEQ ID NO:97之胺基酸序列的輕鏈及包含SEQ ID NO:98之胺基酸序列的重鏈；或(xxx)包含SEQ ID NO:99之胺基酸序列的輕鏈及包含SEQ ID NO:100之胺基酸序列的重鏈；或(xxxi)包含SEQ ID NO:101之胺基酸序列的輕鏈及包含SEQ ID NO:102之胺基酸序列的重鏈；或(xxxii)包含SEQ ID NO:103之胺基酸序列的輕鏈及包含SEQ ID NO:104之胺基酸序列的重鏈；或(xxxiii)包含SEQ ID NO:105之胺基酸序列的輕鏈及包含SEQ ID NO:106之胺基酸序列的重鏈；或(xxxiv)包含SEQ ID NO:107之胺基酸序列的輕鏈及包含SEQ ID NO:108之胺基酸序列的重鏈；或(xxxv)包含SEQ ID NO:109之胺基酸序列的輕鏈及包含SEQ ID NO:110之胺基酸序列的重鏈；或(xxxvi)包含SEQ ID NO:111之胺基酸序列的輕鏈及包含SEQ ID NO:112之胺基酸序列的重鏈；或(xxxvii)包含SEQ ID NO:113之胺基酸序列的輕鏈及包含SEQ ID NO:114之胺基酸序列的重鏈；或(xxxviii)包含SEQ ID NO:115之胺基酸序列的輕鏈及包含SEQ ID NO:116之胺基酸序列的重鏈；或(xxxix)包含SEQ ID NO:117之胺基酸序列的輕鏈及包含SEQ ID NO:118之胺基酸序列的重鏈；或(xl)包含SEQ ID NO:119之胺基酸序列的輕鏈及包含SEQ ID NO:120之胺基酸序列的重鏈；或(xli)包含SEQ ID NO:121之胺基酸序列的輕鏈及包含SEQ ID NO:122之胺基酸序列的重鏈；或(xlii)包含SEQ ID NO:123之胺基酸序列的輕鏈及包含SEQ ID NO:124之胺基酸序列的重鏈；或(xliii)包含SEQ ID NO:125之胺基酸序列的輕鏈及包含SEQ ID NO:126之胺基酸序列的重鏈；或(xliv)包含SEQ ID NO:127之胺基酸序列的輕鏈及包含SEQ ID NO:128之胺基酸序列的重鏈；或(xlv)包含SEQ ID NO:129之胺基酸序列的輕鏈及包含SEQ ID NO:130之胺基酸序列的重鏈；或(xlvi)包含SEQ ID NO:131之胺基酸序列的輕鏈及包含SEQ ID NO:132之胺基酸序列的重鏈；或(xlvii)包含SEQ ID NO:133之胺基酸序列的輕鏈及包含SEQ ID NO:134之胺基酸序列的重鏈；或(xlviii)包含SEQ ID NO:135之胺基酸序列的輕鏈及包含SEQ ID NO:136之胺基酸序列的重鏈；或(xlix)包含SEQ ID NO:137之胺基酸序列的輕鏈及包含SEQ ID NO:138之胺基酸序列的重鏈；或(l)包含SEQ ID NO:139之胺基酸序列的輕鏈及包含SEQ ID NO:140之胺基酸序列的重鏈；或(li)包含SEQ ID NO:141之胺基酸序列的輕鏈及包含SEQ ID NO:142之胺基酸序列的重鏈；或(lii)包含SEQ ID NO:143之胺基酸序列的輕鏈及包含SEQ ID NO:144的重鏈。
在第四態樣中，本發明係關於一種TrkB結合分子，其包含兩個scFv或由其組成，其中各scFv與TrkB特異性結合。
在關於第四態樣之另一實施例中，TrkB結合分子進一步包含Ig分子。
在關於第四態樣或其實施例中之任一者之另一實施例中，Ig分子為單株抗體；人類單株抗體；人源化單株抗體；嵌合抗體；抗體之片段，諸如Fv、Fab、Fab'或F(ab')2片段；單鏈抗體，諸如單鏈可變片段(single chain variable fragment；scFv)；小模組免疫藥物(Small Modular Immunopharmaceutical；SMIP)；域抗體；奈米抗體；或雙功能抗體。
在關於第四態樣或其實施例中之任一者之另一實施例中，各scFv與Ig分子之重鏈的C端融合。在關於第四態樣或其實施例中之任一者之另一實施例中，Ig分子為IgG、F(ab)、F(ab')2。在關於第四態樣或其實施例中之任一者之另一實施例中，Ig分子包含Fc區或由其組成。在關於第四態樣或其實施例中之任一者之另一實施例中，TrkB結合分子為雙特異性且四價的。
在第五態樣中，本發明係關於一種與TrkB特異性結合之scFv結合，其包含(i)包含SEQ ID NO:213之胺基酸序列的輕鏈可變域及包含SEQ ID NO:214之胺基酸序列的重鏈可變域；或(ii)包含SEQ ID NO:215之胺基酸序列的輕鏈可變域及包含SEQ ID NO:216之胺基酸序列的重鏈可變域。
在關於第五態樣之另一實施例中，scFv包含SEQ ID NO:222之胺基酸序列、或SEQ ID NO:223之胺基酸序列、或SEQ ID NO:224之胺基酸序列或SEQ ID NO:225之胺基酸序列。
在第六態樣中，本發明係關於一種與VEGF特異性結合之抗體分子，其包含： (i)     輕鏈可變域，其包含SEQ ID NO:189之胺基酸序列，及 重鏈可變域，其包含SEQ ID NO:191之胺基酸序列；或 重鏈可變域，其包含SEQ ID NO:192之胺基酸序列；或 重鏈可變域，其包含SEQ ID NO:194之胺基酸序列； (ii)    重鏈可變域，其包含SEQ ID NO:190之胺基酸序列，及 輕鏈可變域，其包含SEQ ID NO:192之胺基酸序列；或 輕鏈可變域，其包含SEQ ID NO:193之胺基酸序列。
在關於第六態樣之另一實施例中，抗體分子包含： 輕鏈，其包含SEQ ID NO:195或199之胺基酸序列，及 重鏈，其包含SEQ ID NO:196、197、198或200之胺基酸序列。
在第七態樣中，本發明係關於一種經分離之核酸分子，其編碼前述態樣及實施例中之任一者之結合分子的(i)重鏈或重鏈可變域及/或(ii)輕鏈或輕鏈可變域。
在第八態樣中，本發明係關於一種經分離之核酸分子，其編碼根據前述態樣及實施例中之任一者之TrkB結合分子的(i)重鏈或重鏈可變域及/或(ii)輕鏈或輕鏈可變域。
在第九態樣中，本發明係關於一種經分離之核酸分子，其編碼根據前述態樣及實施例中之任一者之scFv的(i)重鏈可變域及/或(ii)輕鏈可變域。
在第十態樣中，本發明係關於一種經分離之核酸分子，其編碼根據前述態樣及實施例中之任一者之抗體分子的(i)重鏈或重鏈可變域及/或(ii)輕鏈或輕鏈可變域。
在第十一態樣中，本發明係關於一種病毒載體，其包含根據第七、第八、第九或第十態樣之經分離之核酸分子。
在第十二態樣中，本發明係關於一種表現載體，其包含根據第十一態樣之核酸分子。
在第十三態樣中，本發明係關於一種宿主細胞，其用根據第十二態樣之表現載體轉染。
在第十四態樣中，本發明係關於一種製造根據前述態樣及實施例中之任一者之結合分子、TrkB結合分子、scFv或抗體分子之方法，其包含 (a)    在允許該分子表現之條件下培養第十三態樣之宿主細胞；及 (b)    回收該分子；及視情況 (c)    進一步純化及/或修飾及/或調配該分子。
在第十五態樣中，本發明係關於根據前述態樣及實施例中之任一者之結合分子、TrkB結合分子、scFv或抗體分子，其用於醫藥中。
在關於第十五態樣之一實施例中，本發明係關於根據第十五態樣使用之結合分子、TrkB結合分子、scFv或抗體分子，其中用途為治療眼部或視網膜或神經退化性疾病。
在關於第十五態樣之另一實施例中，本發明係關於根據第十五態樣使用之結合分子、TrkB結合分子、scFv或抗體分子，其中該用途為用於治療神經/神經元眼部或視網膜疾病。
在關於第十五態樣之另一實施例中，本發明係關於根據第十五態樣使用之結合分子、TrkB結合分子、scFv或抗體分子，其中該用途為用於治療黃斑變性、老年性黃斑變性、糖尿病性視網膜病變、糖尿病性黃斑水腫、色素性視網膜炎、遺傳性視網膜營養性萎縮、遺傳性黃斑營養不良、近視變性、地圖狀萎縮、視網膜動脈阻塞、眼內炎、葡萄膜炎、囊樣黃斑水腫、繼發於任何視網膜疾病之脈絡膜新生血管性膜、視神經病、青光眼、視網膜脫落、毒性視網膜病、輻射性視網膜病、及創傷性視網膜病、前驅性及輕度至中度阿茲海默氏症(Alzheimer´s disease)，延遲患有阿茲海默氏病、杭丁頓氏症(Huntington´s disease)、帕金森氏症(Parkinson´s disease)、嚴重抑鬱症、精神分裂症、與精神分裂症相關之認知障礙之患者的疾病進展，預防患有減弱精神病症候群之個體的第一次精神病發作，預防患有精神分裂症、難治性抑鬱、暴食、肥胖症或代謝症候群之患者復發。
在關於第十五態樣之一實施例中，本發明係關於根據第十五態樣使用之結合分子、TrkB結合分子、scFv或抗體分子，其中該用途為用於治療黃斑變性，且特定言之濕性年齡相關之黃斑變性(wet age-related macular degeneration；wAMD)。
在關於第十五態樣之一實施例中，本發明係關於根據第十五態樣使用之結合分子、TrkB結合分子、scFv或抗體分子，其中該用途為用於治療視網膜靜脈阻塞(retinal vein occlusion；RVO)。
在關於第十五態樣之一實施例中，本發明係關於根據第十五態樣使用之結合分子、TrkB結合分子、scFv或抗體分子，其中該用途為用於治療及/或預防地圖狀萎縮。
在第十六態樣中，本發明係關於一種醫藥組合物，其包含醫藥學上可接受之載劑及根據前述態樣及實施例中之任一者之結合分子、TrkB結合分子、scFv或抗體分子。
在第十七態樣中，本發明係關於一種治療或預防眼部疾病或視網膜疾病或神經退化性疾病之方法，其包含向需要其之患者投與治療有效量之根據前述態樣及實施例中之任一者的結合分子、TrkB結合分子、scFv或抗體分子。
在第十八態樣中，本發明係關於一種根據前述態樣及實施例中之任一者之結合分子、TrkB結合分子、scFv或抗體分子的用途，其用於製備治療或預防眼部疾病或視網膜疾病或神經退化性疾病的醫藥組合物。
本發明係基於將與血管內皮生長因子(VEGF)特異性結合之抗原結合位點與同肌旋蛋白受體激酶B (TrkB)特異性結合之抗原結合位點組合在單一結合分子內的概念。
重要的是指出，直至本發明，未曾揭示或甚至略微考慮製備靶向此等兩種抗原之結合分子。因此，本發明人製備之結合分子包括至少一個與VEGF特異性結合之抗原結合位點及至少一個與TrkB特異性結合之抗原結合位點。
本發明人之初始目標為設計一種當相較於其各別個別結合劑，亦即僅與其各別目標結合之個別VEGF或TrkB結合劑時具有相當的功效及/或效能的單一結合分子。此已視為本身具有挑戰性，此係因為未完全瞭解但預期將個別結合劑格式化成單一結合分子將不利地影響單一結合分子內之個別結合劑的初始功效及/或效能。
出人意料地發現，將TrkB活化與VEGF清除組合於單一結合分子中導致TrkB活化之功效以及效能兩者出人意料的增加。根據本發明之單一結合分子顯示完全TrkB促效活性--與個別TrkB結合劑之部分促效劑活性相對。此外，TrkB活化之效能在VEGF與單一結合分子結合之後進一步增強。
不希望受理論所束縛，似乎VEGF誘導之與本發明之單一結合分子聚類可為造成所觀測到之TrkB活化之效能增加的原因。另外，與所提出之VEGF誘導之聚類機制無關，明顯地，本發明之結合分子中之TrkB結合位點的設計支持TrkB結合的最佳空間形成，此導致觀測到的完全TrkB促效活性。有利的是，藉由將VEGF清除(導致抑制血管功能異常及滲漏)與神經保護性TrkB受體之活化(導致神經元死亡減少)組合，患者現獲益於單一注射。此為重要的，因為視網膜專家並不喜歡在同一天向同一眼睛注射超過一次治療。因此，解決wAMD及GA之兩個分開治療將需要每眼兩個分開治療問診。總而言之，根據本發明之結合分子適用於治療及/或預防視覺功能損失且因此改善生活品質。
在一個態樣中，本發明提供一種結合分子，特定言之一種具有至少一個與血管內皮生長因子VEGF，較佳地VEGF-A特異性結合之抗原結合位點及至少一個與肌旋蛋白受體激酶B (TrkB)特異性結合之抗原結合位點的分子，其具有本文下文所描述之特性中的一或多者。
在另一態樣中，本發明之結合分子以高親和力與人類TrkB結合。在關於此態樣之一實施例中，本發明之結合分子以K D＜ 500 nM與人類TrkB結合。在另一實施例中，本發明之結合分子以K D＜ 450 nM與人類TrkB結合。在另一實施例中，本發明之結合分子以K D＜ 400 nM與人類TrkB結合。在另一實施例中，本發明之結合分子以K D＜ 300 nM與人類TrkB結合。在另一實施例中，本發明之結合分子以K D＜ 250 nM與人類TrkB結合。在關於此態樣之一實施例中，本發明之結合分子以K D＜ 200 nM與人類TrkB結合。在另一實施例中，本發明之結合分子以K D＜ 150 nM與人類TrkB結合。在另一實施例中，本發明之結合分子以K D＜ 100 nM與人類TrkB結合。在另一實施例中，本發明之結合分子以K D＜ 50 nM與人類TrkB結合。
在另一態樣中，本發明之結合分子—在包含與200 ng/mL人類VEGF-A一起預培育之條件下—以高效能活化TrkB。在關於此態樣之一實施例中，本發明之結合分子以EC 50＜ 100 nM活化人類TrkB。在又一實施例中，本發明之結合分子以EC 50＜ 90 nm活化人類TrkB。在又一實施例中，本發明之結合分子以EC 50＜ 80 nm活化人類TrkB。在又一實施例中，本發明之結合分子以EC 50＜ 70 nm活化人類TrkB。在又一實施例中，本發明之結合分子以EC 50＜ 60 nm活化人類TrkB。在又一實施例中，本發明之結合分子以EC 50＜ 50 nm活化人類TrkB。在又一實施例中，本發明之結合分子以EC 50＜ 40 nm活化人類TrkB。在又一實施例中，本發明之結合分子以EC 50＜ 30 nm活化人類TrkB。在又一實施例中，本發明之結合分子以EC 50＜ 20 nm活化人類TrkB。在又一實施例中，本發明之結合分子以EC 50＜ 10 nm活化人類TrkB。
在另一態樣中，本發明之結合分子以高親和力與人類VEGF (較佳地VEGF-A)結合。在關於此態樣之一實施例中，本發明之結合分子以K D＜ 1 nM與人類VEGF-A結合。在另一實施例中，本發明之結合分子以K D＜ 900 pM與人類VEGF-A結合。在另一實施例中，本發明之結合分子以K D＜ 800 pM與人類VEGF-A結合。在另一實施例中，本發明之結合分子以K D＜ 700 pM與人類VEGF-A結合。在另一實施例中，本發明之結合分子以K D＜ 600 pM與人類VEGF-A結合。在另一實施例中，本發明之結合分子以K D＜ 500 pM與人類VEGF-A結合。在另一實施例中，本發明之結合分子以K D＜ 400 pM與人類VEGF-A結合。
在另一態樣中，本發明之結合分子以高效能抑制VEGF-A磷酸化(Tyr1175)。在關於此態樣之一實施例中，本發明之結合分子以IC 50＜ 1 nM抑制人類VEGF-A磷酸化(Tyr1175)。在關於此態樣之一實施例中，本發明之結合分子以IC 50＜ 900 pM抑制人類VEGF-A磷酸化(Tyr1175)。在關於此態樣之一實施例中，本發明之結合分子以IC 50＜ 800 pM抑制人類VEGF-A磷酸化(Tyr1175)。在關於此態樣之一實施例中，本發明之結合分子以IC 50＜ 700 pM抑制人類VEGF-A磷酸化(Tyr1175)。在關於此態樣之一實施例中，本發明之結合分子以IC 50＜ 600 pM抑制人類VEGF-A磷酸化(Tyr1175)。在關於此態樣之一實施例中，本發明之結合分子以IC 50＜ 500 pM抑制人類VEGF-A磷酸化(Tyr1175)。在關於此態樣之一實施例中，本發明之結合分子以IC 50＜ 400 pM抑制人類VEGF-A磷酸化(Tyr1175)。在關於此態樣之一實施例中，本發明之結合分子以IC 50＜ 300 pM抑制人類VEGF-A磷酸化(Tyr1175)。
在另一態樣中，與天然TrkB配體BDNF相比，本發明之結合分子更強效地誘導TrkB下游傳訊路徑之活化。在另一態樣中，本發明之結合分子經由TrkB介導之傳訊路徑以與BDNF相當的模式調控基因表現。
在又另一態樣中，本發明之結合分子不降低BDNF誘導之ERK磷酸化。在另一態樣中，本發明之結合分子對TrkB磷酸化及/或活化具有特異性且不會非特異性地磷酸化/活化TrkA或TrkC。
在一個態樣中，根據本發明之結合分子適用於預防疾病相關動物模型中之神經退化及視網膜功能損失。在又一態樣中，本發明之結合分子藉由刺激TrkB依賴性存活傳訊路徑且因此提供神經保護而保護患有例如黃斑變性、老年性黃斑變性、地圖狀萎縮或糖尿病性視網膜病變之患者的視網膜中之神經元、神經膠細胞及/或神經血管單元。
在另一態樣中，在例如黃斑變性、老年性黃斑變性、地圖狀萎縮或糖尿病性視網膜病變中，本發明之結合分子使視網膜中之軸突/樹突及/或突觸在疾病發作之後再生，且由此使得神經再生。在一個態樣中，本發明之結合分子可調配至高濃度以用於玻璃體內注射至眼睛中。
在另一態樣中，就抑制VEGF誘導之傳訊、內皮細胞增殖/出芽及/或抑制VEGF誘導之大鼠視網膜中之高滲透性而言，相較於當前抗VEGF標準照護化合物阿柏西普(aflibercept) (艾力雅)，根據本發明之結合分子顯示優良的VEGF-A清除。
在另一態樣中，相較於例如艾力雅或其他IgG抗體，根據本發明之結合分子在兔PK研究中顯示實質上更長的玻璃體半衰期。因此，根據本發明之結合分子適合於季度注射或甚至更低頻率的注射。
在另一態樣中，根據本發明之結合分子適用於靶向患有wAMD及處於發展地圖狀萎縮風險下之患者的高度未滿足的需求。在一相關實施例中，根據本發明之結合分子尤其適用於治療患有wAMD之患者及預防發展地圖狀萎縮。在另一相關實施例中，延遲發展地圖狀萎縮，或降低疾病之嚴重程度，亦即降低地圖狀萎縮發作及/或其進展速率。就此而言，用根據本發明之結合分子治療患者可在確切診斷出地圖狀萎縮之前起始，亦即對於處於發展地圖狀萎縮風險下之患者。
在另一態樣中，根據本發明之結合分子適用於靶向患有視網膜靜脈阻塞(CRVO)之患者的高度未滿足的需求。
在另一態樣中，當相較於當前標準照護(艾力雅)時，根據本發明之結合分子改善ERG缺陷隱含時間。
在一個態樣中，根據本發明之結合分子與TrkB之結合不會誘導受體內化。在一相關態樣中，當相較於天然配體BDNF時，根據本發明之結合分子與TrkB之結合將導致更少的受體內化。
在一個態樣中，與根據本發明之結合分子結合之VEGF-A增加TrkB活化之效能。
該效能增加可例如藉由在用單一結合分子處理後，測定適當細胞模型，諸如過度表現(人類) TrkB之CHO細胞中之TrkB或Erk1/2磷酸化的EC 50來活體外量測(參見實例)。將在使細胞與適當濃度之人類VEGF-A (hVEGF) (諸如200 ng/mL、50 ng/mL、10 ng/mL或2 ng/mL)一起預培育之情況下，測試單一結合分子。在使細胞與人類VEGF-A一起預培育之後，本發明之單一結合分子將顯示效能增加，如藉由TrkB或Erk1/2磷酸化之EC 50所量測，當相較於未與VEGF-A一起預培育之細胞時，效能增加至少大致2倍、3倍、4倍、5倍、6倍、7倍、8倍、9倍或至少大致10倍。
在另一態樣中，根據本發明之結合分子顯示完全TrkB促效活性。因此，根據本發明之結合分子在活化TrkB上與天然配體BDNF一樣有效。
在另一態樣中，根據本發明之結合分子可同時活化TrkB受體及清除VEGF，較佳地VEGF-A。
定義
未在本文中特別定義之術語應被賦予熟習此項技術者依據本發明及上下文將對其賦予之含義。然而，如本說明書中所使用，除非相反說明，否則以下術語具有指定之含義且將遵守以下慣例。
如本文所用，術語「抗原結合位點」包含來源於抗體之重鏈可變域(VH)及輕鏈可變域(VL)。在此情況下，各可變域包含3個CDR。在一個態樣中，根據本發明之抗原結合位點或該蛋白質之某些部分一般來源於抗體。抗體或免疫球蛋白分子之通用型結構為熟習此項技術者熟知。
「抗體」或「免疫球蛋白分子」(亦稱為免疫球蛋白，縮寫為Ig)為可在脊椎動物之血液或其他體液中發現的γ球蛋白蛋白質，且供免疫系統用於鑑別及中和外來物體，諸如細菌及病毒。其通常由基礎結構單元構成，各結構單元具有兩條大重鏈及兩條小輕鏈，形成例如具有一個單元之單體、具有兩個單元之二聚體或具有五個單元之五聚體。抗體可藉由非共價相互作用與稱為抗原之其他分子或結構結合。在抗體將僅以高親和力與特異性結構結合之意義上，此結合具有特異性。由抗體識別之抗原之獨特部分稱為抗原決定基或抗原決定子。結合於抗原決定基之抗體部分有時稱為互補位且存在於抗體之所謂可變域或可變區(Fv)中。可變域包含三個由構架區(FR)隔開之所謂互補決定區(CDR)。
在本發明之上下文內，對CDR之參考係基於不同定義，諸如CCG，亦稱為IMGT (Lefranc MP, Pommié C, Ruiz M, Giudicelli V, Foulquier E, Truong L, Thouvenin-Contet V, Lefranc G. 「IMGT unique numbering for immunoglobulin and T cell receptor variable domains and Ig superfamily V-like domains.」 Dev Comp Immunol. 2003年1月;27(1):55-77；Giudicelli V, Brochet X, Lefranc MP. 「IMGT/V-QUEST: IMGT standardized analysis of the immunoglobulin (IG) and T cell receptor (TR) nucleotide sequences」. Cold Spring Harb Protoc. 2011;2011(6):695-715。CDR之替代定義係基於Chothia (Chothia及Lesk, J. Mol. Biol. 1987, 196: 901-917)以及Kabat ( E.A. Kabat, T.T. Wu, H. Bilofsky, M. Reid-Miller及H. Perry, Sequence of Proteins of Immunological Interest, National Institutes of Health, Bethesda (1983))。
如本文所用，表述「可變域」或「可變區」或Fv表示輕鏈及重鏈對中之每一者，其直接參與抗體與抗原之結合。輕鏈之可變域縮寫為「VL」，且重鏈之可變域縮寫為「VH」。可變輕鏈及重鏈域具有相同的通式結構，且各域包含四個由三個HVR (或CDR)連接之構架(FR)區，其序列為廣泛保守的。構架區採用β-褶板構形，且CDR可形成連接β-褶板結構之環。各鏈中之CDR藉由構架區保持其三維結構且與來自另一鏈之CDR一起形成抗原結合位點。抗體之重鏈及輕鏈CDR3區在根據本發明之抗體之結合特異性/親和力方面發揮尤其重要作用且因此提供本發明之另一目標。如本申請案中使用之術語「恆定域」或「恆定區」表示抗體除可變區以外之域的總和。此類恆定域及恆定區為目前最佳技術所熟知且例如由Kabat等人(「Sequence of proteins of immunological interest」, US Public Health Services, NIH Bethesda, MD, 公開案第91號)描述。
抗體之「Fc部分」不直接參與抗體與抗原之結合，但展現各種效應功能。「抗體之Fc部分」為熟習此項技術者熟知之術語且基於抗體之番木瓜蛋白酶裂解而定義。視其重鏈之恆定區之胺基酸序列而定，抗體或免疫球蛋白分成以下類別：IgA、IgD、IgE、IgG及IgM。根據重鏈恆定區，不同類別之免疫球蛋白分別稱為α、δ、ε、γ及μ。此等中之若干者可進一步分成子類(同型)，例如IgGl、IgG2、IgG3及IgG4、IgAl及IgA2。基於補體活化、C1q結合及Fc受體結合，抗體之Fc部分直接參與ADCC (抗體依賴性細胞介導之細胞毒性)及CDC (補體依賴性細胞毒性)。補體活化(Complement activation；CDC)藉由補體因子C1q與大部分IgG抗體子類之Fc部分之結合來起始。雖然抗體對於補體系統之影響視某些條件而定，但與C1q之結合係由Fc部分內之界定結合位點造成。此類結合位點在目前最佳技術中已知且例如由以下描述：Boakle等人, Nature 282 (1975) 742-743，Lukas等人, J. Immunol. 127 (1981) 2555-2560，Brunhouse及Cebra, Mol. Immunol. 16 (1979) 907-917，Burton等人, Nature 288 (1980) 338-344，Thommesen等人, Mol. Immunol. 37 (2000) 995-1004，Idusogie等人, J. Immunol.164 (2000) 4178-4184，Hezareh等人, J. Virology 75 (2001) 12161- 12168，Morgan等人, Immunology 86 (1995) 319-324, EP 0307434。此類結合位點為例如L234、L235、D270、N297、E318、K320、K322、P331及P329 (根據Kabat EU索引編號，參見下文)。此等殘基中介導IgG1中C1q及Fcγ受體結合最關鍵的殘基為L234及L235 (Hezareh等人, J. Virology 75 (2001) 12161- 12168)。子類別IgGl及IgG3之抗體通常顯示補充活化及Clq及C3結合，而IgG2及IgG4不活化補體系統且不結合Clq及C3。
此項技術已進一步研發出抗體且使其成為醫藥及技術中之通用工具。因此，在本發明之上下文中，術語「抗體分子」或「抗體」或「Ig分子」(本文中同義使用)不僅包括如可在自然界中發現之包含例如兩條輕鏈及兩條重鏈或如駱駝科物種中僅包含兩條重鏈的抗體，亦進一步涵蓋所有包含至少一個對抗原具有結合特異性且與免疫球蛋白之可變域具有結構類似性之互補位的分子。
因此，抗體或免疫球蛋白或Ig分子可包含單株抗體、人類抗體、人源化抗體、嵌合抗體、抗體片段，特定言之Fv、Fab、Fab'或F(ab')2片段、單鏈抗體，特定言之單鏈可變片段(scFv)、小模組免疫藥物(SMIP)、域抗體、奈米抗體、雙功能抗體。抗體可具有效應功能，諸如ADCC或CDC，其通常藉由抗體之Fc部分(抗體恆定區)介導，或其可不具有效應功能，例如藉由缺乏Fc部分或具有阻斷、遮蔽之Fc部分，本質上免疫細胞或免疫系統組分(如補體系統)不識別或未充分識別之Fc部分。單株抗體(mAb)為胺基酸序列相同之單特異性抗體。其可藉由融合瘤技術自雜交細胞株(稱為融合瘤)製備，該雜交細胞株代表產生特異性抗體之B細胞與骨髓瘤(B細胞癌症)細胞融合的純系(Kohler G, Milstein C. Continuous cultures of fused cells secreting antibody of predefined specificity. Nature 1975;256:495-7)。替代地，單株抗體可藉由在宿主細胞中之重組表現製備(Norderhaug L, Olafsen T, Michaelsen TE, Sandlie I. (1997年5月). 「Versatile vectors for transient and stable expression of recombinant antibody molecules in mammalian cells.」 J Immunol Methods 204 (1): 77-87；亦參見下文)。「重組抗體」或「重組結合分子」為已藉由以重組方式工程改造之宿主細胞產生之抗體或結合分子。其視情況經分離或純化。
對於人類中之應用，常需要降低最初來源於如小鼠之其他物種之抗體的免疫原性。此可藉由構築嵌合抗體，或藉由稱為「人源化」之方法進行。在此背景下，「嵌合抗體」應理解為包含來源於一種物種(例如小鼠)之序列部分(例如可變域)與來源於不同物種(例如人類)之序列部分(例如恆定域)融合的抗體。「人源化抗體」為包含最初來源於非人類物種之可變域的抗體，其中已使某些胺基酸突變，使得可變域之總序列更近似於人類可變域之序列。抗體嵌合化及人源化之方法為此項技術中熟知的(Billetta R, Lobuglio AF. 「Chimeric antibodies」. Int Rev Immunol. 1993;10(2-3):165-76；Riechmann L, Clark M, Waldmann H, Winter G (1988). 「Reshaping human antibodies for therapy」. Nature: 332:323)。
「人源化」抗體係指包含來自非人類高變區(HVR)之胺基酸殘基及來自人類FR之胺基酸殘基的抗體。在某些實施例中，人源化抗體將包含至少一個及通常兩個可變域之實質上所有，其中所有或實質上所有之HVR (例如互補決定區(CDR))對應於非人類抗體之HVR，且所有或實質上全部構架區(FR)對應於人類抗體之構架區。人源化抗體視情況可包含來源於人類抗體之抗體恆定區的至少一部分。抗體(例如非人類抗體)之「人源化形式」係指已經受人源化之抗體。
此外，已研發出用於基於來源於人類基因體之序列產生抗體之技術，例如藉由噬菌體顯示或使用基因轉殖動物(WO 90/05144；D. Marks, H.R. Hoogenboom, T.P. Bonnert, J. McCafferty, A.D. Griffiths及G. Winter (1991) 「By-passing immunisation. Human antibodies from V-gene libraries displayed on phage.」 J.Mol.Biol., 222, 581-597；Knappik等人, J. Mol. Biol. 296: 57-86, 2000；S. Carmen及L. Jermutus, 「Concepts in antibody phage display」. Briefings in Functional Genomics and Proteomics 2002 1(2):189-203；Lonberg N, Huszar D. 「Human antibodies from transgenic mice」. Int Rev Immunol. 1995;13(1):65-93.；Brüggemann M, Taussig MJ. 「Production of human antibody repertoires in transgenic mice」. Curr Opin Biotechnol. 1997年8月;8(4):455-8.)。在本發明之上下文中，此類抗體為「人類抗體」。
抗體亦可包括保留抗原結合特性之免疫球蛋白片段，如Fab、Fab'或F(ab')2片段。此類片段可藉由免疫球蛋白之片段化，例如藉由蛋白分解消化，或藉由此類片段之重組表現來獲得。舉例而言，免疫球蛋白消化可藉助於常規技術，例如使用番木瓜蛋白酶或胃蛋白酶(WO 94/29348)實現。抗體之番木瓜蛋白酶消化通常產生兩個一致抗原結合片段，所謂Fab片段，各自具有單一抗原結合位點，及殘餘Fc片段。胃蛋白酶處理產生F(ab')2。在Fab分子中，可變域各自與較佳地人類來源之免疫球蛋白恆定域融合。因此，重鏈可變域可與CH1域(所謂Fd片段)融合，且輕鏈可變域可與CL域融合。Fab分子可藉由宿主細胞中各別核酸之重組表現來產生，參見下文。
已研發多種用於在不同分子環境下置放免疫球蛋白之可變域或來源於此類可變域之分子的技術。彼等亦應視為根據本發明之「抗體」。一般而言，此等抗體分子在大小上相較於免疫球蛋白更小，且可包含單一胺基酸鏈或若干胺基酸鏈。舉例而言，單鏈可變片段(scFv)為免疫球蛋白之重鏈及輕鏈之可變區的融合物，該等可變區用通常為絲胺酸(S)或甘胺酸(G)之短連接子連接在一起(WO 88/01649；WO 91/17271；Huston等人; International Reviews of Immunology, 第10卷, 1993, 195-217)。「單域抗體」或「奈米抗體」在單一Ig樣域中具有抗原結合位點(WO 94/04678；WO 03/050531，Ward等人, Nature. 1989年10月12日;341(6242):544-6；Revets等人, Expert Opin Biol Ther. 5(1):111-24, 2005)。對相同或不同抗原具有結合特異性之一或多種單域抗體可連接在一起。雙功能抗體為由兩個包含兩個可變域之胺基酸鏈組成之二價抗體分子(WO 94/13804，Holliger等人, Proc Natl Acad Sci U S A. 1993年7月15日;90(14):6444-8)。抗體樣分子之其他實例為免疫球蛋白超家族抗體(IgSF；Srinivasan及Roeske, Current Protein Pept. Sci. 2005, 6(2): 185-96)。不同概念產生所謂小模組免疫藥物(SMIP)，其包含Fv域與單鏈鉸鏈及效應子域連接，缺乏恆定域CH1 (WO 02/056910)。
如本文所用，術語「結合」或「特異性結合」係指在活體外分析中，抗體或抗原結合位點(例如在本文所描述之結合分子中)與抗原之抗原決定基的結合。親和力為抗體分子上之單一抗原結合位點與單一抗原決定基之間的相互作用。其由平衡締合常數Ka = kon/koff或平衡解離常數Kd = koff/kon表示。
抗體分子之結合親和力可藉由稱為親和力成熟之方法增強(Marks等人, 1992, Biotechnology 10:779-783；Barbas等人, 1994, Proc. Nat. Acad. Sci, USA 91:3809-3813；Shier等人, 1995, Gene 169:147-155)。因此，親和力成熟抗體亦涵蓋於本發明中。
抗原決定基為由抗體或抗原結合部分結合之抗原區域。術語「抗原決定基」包括能夠與抗體或抗原結合部分特異性結合之任何多肽決定子。在某些實施例中，抗原決定基決定子包括分子之化學活性表面基團(諸如胺基酸、聚糖側鏈、磷醯基或磺醯基)，且在某些實施例中，可具有特定三維結構特徵，及/或特定電荷特徵。構形抗原決定基與非構形抗原決定基之區別在於，在變性溶劑存在下，與前者的結合消失，但後者則不然。如本文所用，術語「結合」及「特異性結合」係指在活體外分析中，較佳在用經純化之野生型抗原的電漿子共振分析(BIAcore®, GE-Healthcare Uppsala, Sweden)中，抗體或抗原結合部分與抗原之抗原決定基的結合。
「單鏈Fv片段」(scFv)為一種包含抗體重鏈可變域(VH)、連接子及抗體輕鏈可變域(VL)之多肽，其中該抗體域及該連接子在N端至C端方向上具有以下次序之一：a) VH-連接子-VL，b) VL-連接子-VH；且其中該連接子為長度在15至25個胺基酸，較佳20個胺基酸之多肽。
如本文所用，術語「一致」或「百分比一致性」在兩個或更多個核酸或多肽序列之情況下係指在針對最大對應性比較及比對時，兩個或更多個序列或子序列相同或有指定百分比之核苷酸或胺基酸殘基相同。為了測定百分比一致性，出於最佳比較目的而比對序列(舉例而言，可在第一胺基酸或核酸序列的序列中引入間隙以與第二胺基酸或核酸序列最佳比對)。接著比較對應胺基酸位置或核苷酸位置處的胺基酸殘基或核苷酸。當第一序列中之位置被與第二序列中之對應位置相同的胺基酸殘基或核苷酸佔據時，則分子在該位置處一致。兩個序列之間的百分比一致性為該等序列共有的相同位置數之函數(亦即，一致性%=相同位置數/位置(亦即重疊位置)總數×100)。在一些實施例中，適當時，在序列內引入間隙之後，進行比較之兩個序列長度相同(例如不包括延伸超過比較序列之額外序列)。舉例而言，當比較可變區序列時，不考慮前導序列及/或恆定域序列。對於兩個序列之間的序列比較，「對應」CDR係指兩個序列中相同位置之CDR (例如各序列之CDR-H1)。
可使用數學演算法實現測定兩個序列之間的百分比一致性或百分比類似性。用於比較兩個序列之數學演算法之較佳非限制性實例為Karlin及Altschul, 1990, Proc. Natl. Acad. Sci. USA 87:2264-2268之算法，如Karlin及Altschul, 1993, Proc. Natl. Acad. Sci. USA 90:5873-5877中所修改。將此類演算法併入Altschul等人, 1990, J. Mol. Biol. 215:403-410之NBLAST及XBLAST程式中。可用分數=100、字長=12之NBLAST程式進行BLAST核苷酸檢索，以獲得與編碼所關注蛋白質之核酸同源之核苷酸序列。BLAST蛋白質檢索可用XBLAST程式(分數=50，字長=3)執行，以獲得與所關注蛋白質同源之胺基酸序列。為了使間隙式比對達成比較目的，可如Altschul等人, 1997, Nucleic Acids Res. 25:3389-3402中所描述使用間隙式BLAST。替代地，PSI-Blast可用於進行迭代檢索，其偵測分子間之遠緣關係(同上)。在使用BLAST、間隙式BLAST及PSI-Blast程式時，可使用各別程式(例如XBLAST及NBLAST)之預設參數。用於比較序列之數學演算法之另一較佳非限制性實例為Myers及Miller, CABIOS (1989)之演算法。將此類算法併入ALIGN程式(版本2.0)中，該程式為GCG序列比對套裝軟體之一部分。當利用ALIGN程式來比較胺基酸序列時，可使用PAM120權重殘基表、間隙長度罰分12及間隙罰分4。用於序列分析之額外演算法在此項技術中已知且包括如Torellis及Robotti, 1994, Comput. Appl. Biosci. 10:3-5中所描述之ADVANCE及ADAM；及Pearson及Lipman, 1988, Proc. Natl. Acad. Sci. USA 85:2444-8中描述之FASTA。在FASTA內，ktup為設定檢索之敏感性及速度的對照選項。若ktup = 2，則藉由觀察比對殘基對得到比較之兩個序列中之相似區域；若ktup = 1，則檢查單一比對胺基酸。對於蛋白質序列，ktup可設定為2或1，或對於DNA序列設定為1至6。若ktup未規定，則對於蛋白質預設值為2，且對於DNA為6。替代地，可使用CLUSTAL W演算法進行蛋白質序列比對，如Higgins等人, 1996, Methods Enzymol. 266:383-402所描述。
待投與分子之「治療有效量」為預防、改善或治療例如眼部或視網膜或神經退化性疾病之臨床症狀所必需的最少量，特定言之對於此等病症有效的最少量。
如本文所用，術語「單價」、「二價」、「四價」係指結合分子中之抗原結合元件之數目(分別為一個、兩個或四個)。
如本文所用，術語「單特異性」、「雙特異性」係指結合分子特異性結合不同抗原或抗原決定基之數目(一個、兩個)。
藉助於實例，典型單株抗體(MAb)為二價且單特異性的，具有兩個均識別相同抗原決定基之抗原結合臂。雙特異性抗體具有兩個能夠識別且結合兩種不同抗原或抗原決定基之抗原結合位點。
TrkB 結合
肌旋蛋白受體激酶B (TrkB)亦稱為酪胺酸受體激酶B或BDNF/NT-3生長因子受體或2型神經營養酪胺酸激酶受體，為一種人體內由NTRK2基因編碼之蛋白質(Genbank ID：4915)。TrkB為用於大腦衍生神經滋養因子(brain-derived neurotrophic factor；BDNF)之受體。
神經營養酪胺酸激酶受體B (TrkB；基因符號：NTRK2)由視網膜神經元及神經膠細胞表現。在正常視網膜中，TrkB傳訊抵消細胞應激且促進細胞存活。在病變眼睛中，諸如在糖尿病性視網膜病變或地圖狀萎縮中，出現產生視覺減損及視覺損失之視網膜神經元及神經膠細胞之損失及功能減損。活化TrkB傳訊高於基礎水準(其在糖尿病性視網膜病變中降低)可抵消神經元及神經膠細胞之損失及功能減損，因此改善視覺功能。此外，TrkB活化可使病變眼睛中之損失之突觸連接再生，從而促進視覺功能恢復。在配體結合後，TrkB經歷均二聚化，隨後經歷自體磷酸化。視磷酸化位點(Y516、Y702、Y706、Y707或Y817)而定，活化不同訊息傳導路徑，包括調節不同的重疊訊號級聯從而誘導軸索/神經突生長、增加突觸可塑性或增加細胞存活的PLCγ1或AKT及ERK之不同亞型之活性。
本發明之結合分子(例如scFv或scFv 2)之TrkB結合組分與天然或重組人類TrkB特異性結合。藉由與TrkB結合，本發明之結合分子從而活化TrkB傳訊，因此本發明之結合分子充當TrkB促效劑。
本發明之結合分子識別特定「TrkB抗原決定基(TrkB antigen epitope/TrkB epitope)」。特定言之，本發明之結合分子與人類TrkB之胞外域中之抗原決定基結合。較佳地，結合分子之TrkB結合組分為TrkB促效劑且更佳地完全促效劑。
人類TrkB之胞外域基本上包含以下序列(SEQ ID NO.226)：
Figure 02_image001
Figure 02_image003
如本文所用，術語「TrkB抗原決定基(TrkB antigen epitope/TrkB epitope)」係指能夠與特異性結合肌旋蛋白受體激酶B之根據本發明之結合分子或結合分子片段之抗原結合位點結合的分子(例如肽)或分子片段。此等術語進一步包括例如由本發明之結合分子或結合分子片段中之任一者識別的TrkB抗原決定子，其具有選自以下之輕鏈及重鏈CDR組合：
輕鏈CDR，其包含SEQ ID NO:201 (CDR1)、SEQ ID NO:202 (CDR2)及SEQ ID NO:203 (CDR3)之胺基酸序列，及 重鏈CDR，其包含SEQ ID NO:204 (CDR1)、SEQ ID NO:205 (CDR2)及SEQ ID NO:206 (CDR3)之胺基酸序列；或 重鏈CDR，其包含SEQ ID NO:207 (CDR1)、SEQ ID NO:208 (CDR2)及SEQ ID NO:209 (CDR3)之胺基酸序列；或 重鏈CDR，其包含SEQ ID NO:210 (CDR1)、SEQ ID NO:211 (CDR2)及SEQ ID NO:212 (CDR3)之胺基酸序列。
TrkB抗原決定基可包括於蛋白質、蛋白質片段、肽或其類似物中。抗原決定基最常為蛋白質、短寡肽、寡肽模擬物(亦即模擬TrkB抗原之抗體結合特性之有機化合物)或其組合。
VEGF 結合
血管內皮生長因子(VEGF)為最重要的促血管生成因子之一，亦稱為VEGF-A或血管滲透性因子(vascular permeability factor；VPF)。VEGF屬於包括胎盤生長因子(PlGF)、VEGF-B、VEGF-C、VEGF-D、VEGF-E及VEGF-F之基因家族。人類VEGF之單一基因之mRNA之選擇式剪接產生至少六種同功型(VEGF121、VEGF145、VEGF165、VEGF183、VEGF189及VEGF206)，VEGF165為最豐富的同功型。
已鑑別出與VEGF相互作用之兩種VEGF酪胺酸激酶受體(VEGFR)，亦即VEGFR-1 (亦稱為FIt-1)及VEGFR-2 (亦稱為KDR或FIK-1)。VEGFR-1針對VEGF具有最高親和力，而VEGFR-2針對VEGF具有略微降低的親和力。Ferrara (Endocrine Rev. 2004, 25: 581-611)提供VEGF之詳細描述，與其受體之相互作用及其在正常及病理過程中之功能可見於Hoeben等人Pharmacol. Rev. 2004, 56: 549-580中。
VEGF已報導為正常及異常血管生成之關鍵調節劑(Ferrara及Davis-Smyth, Endocrine Rev. 1997, 18: 4-25；Ferrara J. MoL Med. 1999, 77: 527-543)。相較於有助於血管形成過程之其他生長因子，VEGF之獨特之處在於其針對血管系統內之內皮細胞的高特異性。
VEGF尤其涉及眼部疾病。眼流體中VEGF之濃度與患有糖尿病及其他局部缺血相關視網膜病之患者之血管存在活躍增殖高度相關。此外，研究已表明VEGF在受老年性黃斑變性(AMD)影響之患者之脈絡膜新生血管膜中之定位。
本發明之結合分子(例如免疫球蛋白(Ig)分子)之VEGF結合組分對於VEGF具有特異性，原因在於其與VEGF分子內之一或多個抗原決定基特異性結合。藉由與VEGF結合，本發明之結合分子充當VEGF拮抗劑。較佳地，本發明之結合分子與VEGF-A特異性結合。
可以本身已知的任何適合方式，包括(例如)本文所描述之分析、史卡查分析(Scatchard analysis)及/或競爭性結合分析，諸如放射免疫分析(RIA)、酶免疫分析(EIA及ELISA)及夾心競爭分析，及此項技術中本身已知的其不同變體來測定抗原結合組分與其抗原VEGF之特異性結合。當與其抗原結合時，對於TrkB結合組分而言，此亦成立。
關於抗原VEGF，本發明之VEGF結合組分(例如免疫球蛋白(Ig)分子)關於物種不受限制。因此，若預期用於人類中之治療目的，則免疫球蛋白(Ig)分子較佳地與人類VEGF結合。然而，與來自另一哺乳動物物種之VEGF結合之免疫球蛋白(Ig)分子亦在本發明之範疇內。與一種VEGF物種形式結合之免疫球蛋白(Ig)分子可與VEGF交叉反應，該VEGF具有來自一或多種其他物種，與人類VEGF不同的序列。舉例而言，與人類VEGF結合之免疫球蛋白(Ig)分子可與以下展現交叉反應性：來自一或多種其他靈長類物種之VEGF；及/或與來自疾病動物模型中使用之一或多種動物物種之VEGF，該等動物例如猴、小鼠、大鼠、兔、豬、狗，且特定言之與VEGF介導之血管生成效果相關之疾病及病症動物模型中(諸如本文中提及的物種及動物模型)。顯示此類交叉反應性之免疫球蛋白(Ig)分子有利於研究及/或藥物研發，此係由於其允許本發明之免疫球蛋白單一可變域在已確認的疾病模型(諸如猴，特定言之石蟹獼猴或恆河猴；或小鼠及大鼠)中進行測試。
較佳地，鑒於與預期用於在研發治療性VEGF拮抗劑期間用作動物模型之一或多種來自除人類外之物種之VEGF分子之交叉反應性，VEGF結合組分識別與人類VEGF具有高度一致性的所關注VEGF區域中的抗原決定基。
因此，根據本發明之結合分子(例如免疫球蛋白(Ig)分子)之VEGF結合組分識別完全或部分位於與其受體結合相關之VEGF區域中之抗原決定基。根據較佳態樣，根據本發明之結合分子之VEGF結合組分阻斷VEGF受體活化，較佳地實質上且最佳完全阻斷。
如上文所描述，VEGF結合組分阻斷VEGF與其受體之間的相互作用之能力可藉由放大發光接近性均相分析(AlphaScreen®)、競爭ELISA或基於電漿子共振(SPR)之分析(Biacore®)測定，如實例中所描述。
TrkB 及 VEGF 結合分子
本發明係關於結合分子，其對至少兩種不同目標具有結合特異性。相對於本發明，結合分子來源於抗體。用於製備結合分子之技術包括但不限於：具有不同特異性之兩個免疫球蛋白重鏈-輕鏈對之重組共表現(參見Milstein及Cuello, Nature 305: 537 (1983))、WO 93/08829及Traunecker等人, EMBO J. 10: 3655 (1991))，及「杵-臼」工程改造(參見例如美國專利第5,731,168號)。本發明之結合分子亦可如下製備：用於製備抗體Fc-雜二聚分子之工程改造靜電導向效應(WO 2009/089004A1)；使兩種或更多種抗體或片段交聯(參見例如美國專利第4,676,980號及Brennan等人, Science, 229: 81 (1985))；使用白胺酸拉鏈產生雙特異性抗體(參見例如Kostelny等人, Immunol., 148(5):1547-1553 (1992))；使用用於製備雙特異性抗體片段之「雙功能抗體」技術(參見例如Hollinger等人, Proc. Natl. Acad. Sci. USA, 90:6444-6448 (1993))；及使用單鏈Fv (sFv)二聚體(參見例如Gruber等人, J. Immunol., 152:5368 (1994))；及如例如Tutt等人, J. Immunol. 147: 60 (1991)中所描述製備三特異性抗體。
在一個實施例中，結合分子包含以下或由以下組成：至少一個與血管內皮生長因子(VEGF)，較佳地VEGF-A特異性結合之抗原結合位點；及至少一個與肌旋蛋白受體激酶B (TrkB)特異性結合之抗原結合位點。在一相關實施例中，結合分子為雙特異性且四價的。
在另一實施例中，結合分子包含以下或由以下組成：至少一個與血管內皮生長因子(VEGF)特異性結合之抗原結合位點；及至少一個與肌旋蛋白受體激酶B (TrkB)特異性結合之抗原結合位點，其中該至少一個與VEGF特異性結合之抗原結合位點為免疫球蛋白(Ig)分子，較佳地IgG分子。在一相關實施例中，結合分子為雙特異性且四價的。
在另一實施例中，結合分子包含以下或由以下組成：至少一個與血管內皮生長因子(VEGF)特異性結合之抗原結合位點；及至少一個與肌旋蛋白受體激酶B (TrkB)特異性結合之抗原結合位點，其中該至少一個與TrkB特異性結合之抗原結合位點包含一或多個scFv，較佳地在N端至C端呈VL-VH定向。在一相關實施例中，結合分子為雙特異性且四價的。
在另一實施例中，結合分子包含以下或由以下組成：至少一個與血管內皮生長因子(VEGF)特異性結合之抗原結合位點；及至少一個與肌旋蛋白受體激酶B (TrkB)特異性結合之抗原結合位點，其中該至少一個與VEGF特異性結合之抗原結合位點為免疫球蛋白(Ig)分子，較佳地IgG分子，且其中該至少一個與TrkB特異性結合之抗原結合位點與Ig分子重鏈之C端融合。在一相關實施例中，結合分子為雙特異性且四價的。
在另一實施例中，結合分子包含以下或由以下組成：至少一個與血管內皮生長因子(VEGF)特異性結合之抗原結合位點；及至少一個與肌旋蛋白受體激酶B (TrkB)特異性結合之抗原結合位點，其中該至少一個與VEGF特異性結合之抗原結合位點為免疫球蛋白(Ig)分子，較佳地IgG分子，且其中該至少一個與TrkB特異性結合之抗原結合位點包含一或多個scFv，較佳地在N端至C端呈VL-VH定向。在一相關實施例中，結合分子為雙特異性且四價的。
在另一實施例中，結合分子包含以下或由以下組成：至少一個與血管內皮生長因子(VEGF)特異性結合之抗原結合位點；及至少一個與肌旋蛋白受體激酶B (TrkB)特異性結合之抗原結合位點，其中該至少一個與VEGF特異性結合之抗原結合位點為免疫球蛋白(Ig)分子，較佳地IgG分子，且其中該至少一個與TrkB特異性結合之抗原結合位點包含一或多個scFv，較佳地在N端至C端呈VL-VH定向，且與Ig分子重鏈之C端融合。在一相關實施例中，結合分子為雙特異性且四價的。
在一較佳實施例中，本發明之結合分子包含以下或由以下組成：(i)兩條重鏈，其各自包含以下或由以下組成：對VEGF具有特異性之重鏈可變區、恆定IgG域及對TrkB具有特異性之scFv；及(ii)兩條輕鏈，其各自包含以下或由以下組成：對VEGF具有特異性之輕鏈可變區。
另外，此等單鏈Fv片段可藉由經由併入半胱胺酸殘基將二硫鍵併入VH與VL域之間、VH域內或VL域內來進一步穩定。術語N端表示多肽鏈之第一個胺基酸，而術語C端表示多肽鏈之C端之最後一個胺基酸。因此，本發明之一實施例為其中一或多個scFv包含額外半胱胺酸殘基以形成二硫鍵。
在一個實施例中，本發明提供一種結合分子，其為多特異性結合蛋白，其包含(i)具有兩條重鏈及兩條輕鏈之與VEGF特異性結合的Ig分子，及(ii)兩個各自與TrkB特異性結合之scFv分子(scFv(s))。較佳地，Ig分子之各重鏈具有一個與其C端融合之scFv，從而形成雙特異性四價結合蛋白。
在一個實施例中，本發明提供一種結合分子(本文中亦稱為多特異性結合蛋白或經修飾之Ig分子)，其具有： (i)兩條重鏈，其自N端至C端各自包含： -  對VEGF具有特異性之重鏈可變域(例如鼠類、人源化或人類VH域) -  IgG (例如人類IgG1或IgG4)之恆定域 -  肽連接子(例如GS迷你連接子)及 -  對TrkB具有特異性之scFv (例如自N端至C端包含VH域(例如鼠類、人源化或人類VH域)、連接子及VL域(例如鼠類、人源化或人類VL域)或反過來VL域、連接子及VH域的scFv)；及 (ii)兩條輕鏈，其自N端至C端各自包含： 對VEGF具有特異性之輕鏈可變域(例如鼠類、人源化或人類VL域)， 輕鏈恆定域(例如人類κ鏈)。
本發明提供一種結合分子，其具有至少一個與血管內皮生長因子(VEGF)特異性結合之抗原結合位點及至少一個與肌旋蛋白受體激酶B (TrkB)特異性結合之抗原結合位點。
製備與特異性目標抗原結合之結合位點之方法為此項技術中所熟知。技術人員可容易地使用此等方法來設計具有對於VEGF或TrkB目標抗原之必需特異性的抗原結合位點。
產生抗體及抗體片段之方法為此項技術中所熟知。舉例而言，抗體可經由採用以下之若干方法中之任一者產生：誘導抗體分子之活體內產生、篩選免疫球蛋白庫(Orlandi等人, 1989. Proc. Natl. Acad. Sci. U.S.A. 86:3833-3837；Winter等人1991, Nature 349:293-299)或藉由培養中之細胞株產生單株抗體分子。此等包括但不限於融合瘤技術、人類B細胞融合瘤技術及埃-巴二氏病毒(EBV)融合瘤技術(Kohler等人1975. Nature 256:4950497；Kozbor等人1985. J. Immunol. Methods 81 :31 -42；Cote等人1983. Proc. Natl. Acad. Sci. USA 80:2026-2030；Cole等人1984. Mol. Cell. Biol. 62:109-120)。
使用此項技術中已知及本文所描述之方法，熟習此項技術者將常規製備具有結合位點之抗體，該結合位點對於VEGF及/或TrkB目標抗原具有必需的特異性；以及本文所描述之結合分子。自此類抗體分離結合域為常規實踐，且實際上關於可用於產生如本文所描述之抗體及結合分子方法的其他資訊提供於隨附實例中。
本發明人構想本發明之針對VEGF/TrkB之結合分子，如表1中所示；及製備一系列彼等分子且論述於隨附實例中。
表1：
結合分子 序列 SEQ ID NO:
TPP-11735 輕鏈 DIQMTQSPSSLSASVGDRVTITCRTSENVYSNLAWYQQKPGKAPKLLIYAASNLQSGVPSRFSGSGSGTDYTFTISSLQPEDIATYYCQHFWGSPFTFGQGTKLEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC 1
TPP-11735 重鏈 QVQLVQSGAEVKKPGASVKVSCKASGYTFTNYDIIWVRQAPGQGLEWMGYINPYNDGTKYNEKFKGRVTMTRDTSTSTVYMELSSLRSEDTAVYYCARLLKYRRFRYYAIDYWGQGTTVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGGGSEGKSSGSGSESKSTGGSEVQLVESGGGLVQPGGSLRLSCAASGFTINASWIHWVRQAPGKGLEWVGAIYPYSGYTNYADSVKGRFTISADTSKNTAYLQMNSLRAEDTAVYYCARWGHSTSPWAMDYWGQGTLVTVSSGGSEGKSSGSGSESKSTGGSDIQMTQSPSSLSASVGDRVTITCRASQVIRRSLAWYQQKPGKAPKLLIYAASNLASGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQSNTSPLTFGQGTKVEIK 2
TPP-11736 輕鏈 DIQMTQSPSSLSASVGDRVTITCRTSENVYSNLAWYQQKPGKAPKLLIYAASNLQSGVPSRFSGSGSGTDYTFTISSLQPEDIATYYCQHFWGSPFTFGQGTKLEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC 3
TPP-11736 重鏈 QVQLVQSGAEVKKPGASVKVSCKASGYTFTNYDIIWVRQAPGQGLEWMGYINPYNDGTKYNEKFKGRVTMTRDTSTSTVYMELSSLRSEDTAVYYCARLLKYRRFRYYAIDYWGQGTTVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGGGSEGKSSGSGSESKSTGGSDIQMTQSPSSLSASVGDRVTITCRASQVIRRSLAWYQQKPGKAPKLLIYAASNLASGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQSNTSPLTFGQGTKVEIKGGSEGKSSGSGSESKSTGGSEVQLVESGGGLVQPGGSLRLSCAASGFTINASWIHWVRQAPGKGLEWVGAIYPYSGYTNYADSVKGRFTISADTSKNTAYLQMNSLRAEDTAVYYCARWGHSTSPWAMDYWGQGTLVTVSS 4
TPP-11737 輕鏈 DIQMTQSPSSLSASVGDRVTITCRTSENVYSNLAWYQQKPGKAPKLLIYAASNLQSGVPSRFSGSGSGTDYTFTISSLQPEDIATYYCQHFWGSPFTFGQGTKLEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC 5
TPP-11737 重鏈 QVQLVQSGAEVKKPGASVKVSCKASGYTFTNYDIIWVRQAPGQGLEWMGYINPYNDGTKYNEKFKGRVTMTRDTSTSTVYMELSSLRSEDTAVYYCARLLKYRRFRYYAIDYWGQGTTVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGGGSEGKSSGSGSESKSTGGSEVQLVESGGGLVQPGGSLRLSCAASGFTISDYWIHWVRQAPGKGLEWVAGITPAGGYTYYADSVKGRFTISADTSKNTAYLQMNSLRAEDTAVYYCARFVFFLPYAMDYWGQGTLVTVSSGGSEGKSSGSGSESKSTGGSDIQMTQSPSSLSASVGDRVTITCRASQDVSTAVAWYQQKPGKAPKLLIYSASFLYSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQSYTTPPTFGQGTKVEIK 6
TPP-11738 輕鏈 DIQMTQSPSSLSASVGDRVTITCRTSENVYSNLAWYQQKPGKAPKLLIYAASNLQSGVPSRFSGSGSGTDYTFTISSLQPEDIATYYCQHFWGSPFTFGQGTKLEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC 7
TPP-11738 重鏈 QVQLVQSGAEVKKPGASVKVSCKASGYTFTNYDIIWVRQAPGQGLEWMGYINPYNDGTKYNEKFKGRVTMTRDTSTSTVYMELSSLRSEDTAVYYCARLLKYRRFRYYAIDYWGQGTTVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGGGSEGKSSGSGSESKSTGGSDIQMTQSPSSLSASVGDRVTITCRASQDVSTAVAWYQQKPGKAPKLLIYSASFLYSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQSYTTPPTFGQGTKVEIKGGSEGKSSGSGSESKSTGGSEVQLVESGGGLVQPGGSLRLSCAASGFTISDYWIHWVRQAPGKGLEWVAGITPAGGYTYYADSVKGRFTISADTSKNTAYLQMNSLRAEDTAVYYCARFVFFLPYAMDYWGQGTLVTVSS 8
TPP-14936 輕鏈 DIQMTQSPSSLSASVGDRVTITCRTSENVYSNLAWYQQKPGKAPKLLIYAASNLQSGVPSRFSGSGSGTDYTFTISSLQPEDIATYYCQHFWGSPFTFGQGTKLEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC 9
TPP-14936 重鏈 QVQLVQSGAEVKKPGASVKVSCKASGYTFTNYDIIWVRQAPGQGLEWMGYINPYNDGTKYNEKFKGRVTMTRDTSTSTVYMELSSLRSEDTAVYYCARLLKYRRFRYYAIDYWGQGTTVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGGGSEGKSSGSGSESKSTGGSEVQLVESGGGLVQPGGSLRLSCAASGYDFTHYGMNWVRQAPGKGLEWVGWINTYTGEPTYAADFKRRFTFSLDTSKSTAYLQMNSLRAEDTAVYYCAKYPYYYGTSHWYFDVWGQGTLVTVSSGGSEGKSSGSGSESKSTGGSDIQLTQSPSSLSASVGDRVTITCSASQDISNYLNWYQQKPGKAPKVLIYFTSSLHSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQYSTVPWTFGQGTKVEIK 10
TPP-14937 輕鏈 DIQMTQSPSSLSASVGDRVTITCRTSENVYSNLAWYQQKPGKAPKLLIYAASNLQSGVPSRFSGSGSGTDYTFTISSLQPEDIATYYCQHFWGSPFTFGQGTKLEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC 11
TPP-14937 重鏈 QVQLVQSGAEVKKPGASVKVSCKASGYTFTNYDIIWVRQAPGQGLEWMGYINPYNDGTKYNEKFKGRVTMTRDTSTSTVYMELSSLRSEDTAVYYCARLLKYRRFRYYAIDYWGQGTTVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGGGSEGKSSGSGSESKSTGGSDIQLTQSPSSLSASVGDRVTITCSASQDISNYLNWYQQKPGKAPKVLIYFTSSLHSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQYSTVPWTFGQGTKVEIKGGSEGKSSGSGSESKSTGGSEVQLVESGGGLVQPGGSLRLSCAASGYDFTHYGMNWVRQAPGKGLEWVGWINTYTGEPTYAADFKRRFTFSLDTSKSTAYLQMNSLRAEDTAVYYCAKYPYYYGTSHWYFDVWGQGTLVTVSS 12
TPP-16061 輕鏈 DIQMTQSPSSLSASVGDRVTITCRTSENVYSNLAWYQQKPGKAPKLLIYAASNLQSGVPSRFSGSGSGTDYTFTISSLQPEDIATYYCQHFWGSPFTFGQGTKLEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC 13
TPP-16061 重鏈 QVQLVQSGAEVKKPGASVKVSCKASGYTFTNYDIIWVRQAPGQGLEWMGYINPYNDGTKYNEKFKGRVTMTRDTSTSTVYMELSSLRSEDTAVYYCARLLKYRRFRYYAIDYWGQGTTVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGGGGGSGGGGSGGGGSGGGGSDIQMTQSPSSLSASVGDRVTITCRASQVIRRSLAWYQQKPGKAPKLLIYAASNLASGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQSNTSPLTFGQGTKVEIKGGSEGKSSGSGSESKSTGGSEVQLVESGGGLVQPGGSLRLSCAASGFTINASWIHWVRQAPGKGLEWVGAIYPYSGYTNYADSVKGRFTISADTSKNTAYLQMNSLRAEDTAVYYCARWGHSTSPWAMDYWGQGTLVTVSS 14
TPP-16062 輕鏈 DIQMTQSPSSLSASVGDRVTITCRTSENVYSNLAWYQQKPGKAPKLLIYAASNLQSGVPSRFSGSGSGTDYTFTISSLQPEDIATYYCQHFWGSPFTFGQGTKLEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC 15
TPP-16062 重鏈 QVQLVQSGAEVKKPGASVKVSCKASGYTFTNYDIIWVRQAPGQGLEWMGYINPYNDGTKYNEKFKGRVTMTRDTSTSTVYMELSSLRSEDTAVYYCARLLKYRRFRYYAIDYWGQGTTVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGGGGGSGGGGSGGGGSDIQMTQSPSSLSASVGDRVTITCRASQVIRRSLAWYQQKPGKAPKLLIYAASNLASGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQSNTSPLTFGQGTKVEIKGGSEGKSSGSGSESKSTGGSEVQLVESGGGLVQPGGSLRLSCAASGFTINASWIHWVRQAPGKGLEWVGAIYPYSGYTNYADSVKGRFTISADTSKNTAYLQMNSLRAEDTAVYYCARWGHSTSPWAMDYWGQGTLVTVSS 16
TPP-16063 輕鏈 DIQMTQSPSSLSASVGDRVTITCRTSENVYSNLAWYQQKPGKAPKLLIYAASNLQSGVPSRFSGSGSGTDYTFTISSLQPEDIATYYCQHFWGSPFTFGQGTKLEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC 17
TPP-16063 重鏈 QVQLVQSGAEVKKPGASVKVSCKASGYTFTNYDIIWVRQAPGQGLEWMGYINPYNDGTKYNEKFKGRVTMTRDTSTSTVYMELSSLRSEDTAVYYCARLLKYRRFRYYAIDYWGQGTTVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGGGGGSGGGGSDIQMTQSPSSLSASVGDRVTITCRASQVIRRSLAWYQQKPGKAPKLLIYAASNLASGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQSNTSPLTFGQGTKVEIKGGSEGKSSGSGSESKSTGGSEVQLVESGGGLVQPGGSLRLSCAASGFTINASWIHWVRQAPGKGLEWVGAIYPYSGYTNYADSVKGRFTISADTSKNTAYLQMNSLRAEDTAVYYCARWGHSTSPWAMDYWGQGTLVTVSS 18
TPP-16064 輕鏈 DIQMTQSPSSLSASVGDRVTITCRTSENVYSNLAWYQQKPGKAPKLLIYAASNLQSGVPSRFSGSGSGTDYTFTISSLQPEDIATYYCQHFWGSPFTFGQGTKLEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC 19
TPP-16064 重鏈 QVQLVQSGAEVKKPGASVKVSCKASGYTFTNYDIIWVRQAPGQGLEWMGYINPYNDGTKYNEKFKGRVTMTRDTSTSTVYMELSSLRSEDTAVYYCARLLKYRRFRYYAIDYWGQGTTVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGGGSGGSDIQMTQSPSSLSASVGDRVTITCRASQVIRRSLAWYQQKPGKAPKLLIYAASNLASGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQSNTSPLTFGQGTKVEIKGGSEGKSSGSGSESKSTGGSEVQLVESGGGLVQPGGSLRLSCAASGFTINASWIHWVRQAPGKGLEWVGAIYPYSGYTNYADSVKGRFTISADTSKNTAYLQMNSLRAEDTAVYYCARWGHSTSPWAMDYWGQGTLVTVSS 20
TPP-19984 輕鏈 DIQMTQSPSSLSASVGDRVTITCRTSENVYSNLAWYQQKPGKAPKLLIYAASNLQSGVPSRFSGSGSGTDYTFTISSLQPEDIATYYCQHFWGSPFTFGQGTKLEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC 21
TPP-19984 重鏈 QVQLVQSGAEVKKPGASVKVSCKASGYTFTNYDIIWVRQAPGQGLEWMGYINPYNDGTKYNEKFKGRVTMTRDTSTSTVYMELSSLRSEDTAVYYCARLLKYRRFRYYAIDYWGQGTTVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGGGGGSGGGGSEVQLVESGGGLVQPGGSLRLSCAASGYDFTHYGMNWVRQAPGKGLEWVGWINTYTGEPTYAADFKRRFTFSLDTSKSTAYLQMNSLRAEDTAVYYCAKYPYYYGTSHWYFDVWGQGTLVTVSSGGSEGKSSGSGSESKSTGGSDIQLTQSPSSLSASVGDRVTITCSASQDISNYLNWYQQKPGKAPKVLIYFTSSLHSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQYSTVPWTFGQGTKVEIK 22
TPP-19985 輕鏈 DIQMTQSPSSLSASVGDRVTITCRTSENVYSNLAWYQQKPGKAPKLLIYAASNLQSGVPSRFSGSGSGTDYTFTISSLQPEDIATYYCQHFWGSPFTFGQGTKLEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC 23
TPP-19985 重鏈 QVQLVQSGAEVKKPGASVKVSCKASGYTFTNYDIIWVRQAPGQGLEWMGYINPYNDGTKYNEKFKGRVTMTRDTSTSTVYMELSSLRSEDTAVYYCARLLKYRRFRYYAIDYWGQGTTVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGGGGGSGGGGSGGGGSGGGGSEVQLVESGGGLVQPGGSLRLSCAASGYDFTHYGMNWVRQAPGKGLEWVGWINTYTGEPTYAADFKRRFTFSLDTSKSTAYLQMNSLRAEDTAVYYCAKYPYYYGTSHWYFDVWGQGTLVTVSSGGSEGKSSGSGSESKSTGGSDIQLTQSPSSLSASVGDRVTITCSASQDISNYLNWYQQKPGKAPKVLIYFTSSLHSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQYSTVPWTFGQGTKVEIK 24
TPP-14938 輕鏈 DIQMTQSPSSLSASVGDRVTITCRASQVIRRSLAWYQQKPGKAPKLLIYAASNLASGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQSNTSPLTFGQGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC 25
TPP-14938 重鏈 EVQLVESGGGLVQPGGSLRLSCAASGFTINASWIHWVRQAPGKGLEWVGAIYPYSGYTNYADSVKGRFTISADTSKNTAYLQMNSLRAEDTAVYYCARWGHSTSPWAMDYWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGGGSEGKSSGSGSESKSTGGSQVQLVQSGAEVKKPGASVKVSCKASGYTFTNYDIIWVRQAPGQGLEWMGYINPYNDGTKYNEKFKGRVTMTRDTSTSTVYMELSSLRSEDTAVYYCARLLKYRRFRYYAIDYWGQGTTVTVSSGGSEGKSSGSGSESKSTGGSDIQMTQSPSSLSASVGDRVTITCRTSENVYSNLAWYQQKPGKAPKLLIYAASNLQSGVPSRFSGSGSGTDYTFTISSLQPEDIATYYCQHFWGSPFTFGQGTKLEIK 26
TPP-14939 輕鏈 DIQMTQSPSSLSASVGDRVTITCRASQVIRRSLAWYQQKPGKAPKLLIYAASNLASGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQSNTSPLTFGQGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC 27
TPP-14939 重鏈 EVQLVESGGGLVQPGGSLRLSCAASGFTINASWIHWVRQAPGKGLEWVGAIYPYSGYTNYADSVKGRFTISADTSKNTAYLQMNSLRAEDTAVYYCARWGHSTSPWAMDYWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGGGSEGKSSGSGSESKSTGGSDIQMTQSPSSLSASVGDRVTITCRTSENVYSNLAWYQQKPGKAPKLLIYAASNLQSGVPSRFSGSGSGTDYTFTISSLQPEDIATYYCQHFWGSPFTFGQGTKLEIKGGSEGKSSGSGSESKSTGGSQVQLVQSGAEVKKPGASVKVSCKASGYTFTNYDIIWVRQAPGQGLEWMGYINPYNDGTKYNEKFKGRVTMTRDTSTSTVYMELSSLRSEDTAVYYCARLLKYRRFRYYAIDYWGQGTTVTVSS 28
TPP-14940 輕鏈 DIQLTQSPSSLSASVGDRVTITCSASQDISNYLNWYQQKPGKAPKVLIYFTSSLHSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQYSTVPWTFGQGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC 29
TPP-14940 重鏈 EVQLVESGGGLVQPGGSLRLSCAASGYDFTHYGMNWVRQAPGKGLEWVGWINTYTGEPTYAADFKRRFTFSLDTSKSTAYLQMNSLRAEDTAVYYCAKYPYYYGTSHWYFDVWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGGGSEGKSSGSGSESKSTGGSQVQLVQSGAEVKKPGASVKVSCKASGYTFTNYDIIWVRQAPGQGLEWMGYINPYNDGTKYNEKFKGRVTMTRDTSTSTVYMELSSLRSEDTAVYYCARLLKYRRFRYYAIDYWGQGTTVTVSSGGSEGKSSGSGSESKSTGGSDIQMTQSPSSLSASVGDRVTITCRTSENVYSNLAWYQQKPGKAPKLLIYAASNLQSGVPSRFSGSGSGTDYTFTISSLQPEDIATYYCQHFWGSPFTFGQGTKLEIK 30
TPP-14941 輕鏈 DIQLTQSPSSLSASVGDRVTITCSASQDISNYLNWYQQKPGKAPKVLIYFTSSLHSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQYSTVPWTFGQGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC 31
TPP-14941 重鏈 EVQLVESGGGLVQPGGSLRLSCAASGYDFTHYGMNWVRQAPGKGLEWVGWINTYTGEPTYAADFKRRFTFSLDTSKSTAYLQMNSLRAEDTAVYYCAKYPYYYGTSHWYFDVWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGGGSEGKSSGSGSESKSTGGSDIQMTQSPSSLSASVGDRVTITCRTSENVYSNLAWYQQKPGKAPKLLIYAASNLQSGVPSRFSGSGSGTDYTFTISSLQPEDIATYYCQHFWGSPFTFGQGTKLEIKGGSEGKSSGSGSESKSTGGSQVQLVQSGAEVKKPGASVKVSCKASGYTFTNYDIIWVRQAPGQGLEWMGYINPYNDGTKYNEKFKGRVTMTRDTSTSTVYMELSSLRSEDTAVYYCARLLKYRRFRYYAIDYWGQGTTVTVSS 32
TPP-19986 輕鏈 DIQLTQSPSSLSASVGDRVTITCSASQDISNYLNWYQQKPGKAPKVLIYFTSSLHSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQYSTVPWTFGQGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC 33
TPP-19986 重鏈 EVQLVESGGGLVQPGGSLRLSCAASGYDFTHYGMNWVRQAPGKGLEWVGWINTYTGEPTYAADFKRRFTFSLDTSKSTAYLQMNSLRAEDTAVYYCAKYPYYYGTSHWYFDVWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGGGGGSGGGGSQVQLVQSGAEVKKPGASVKVSCKASGYTFTNYDIIWVRQAPGQGLEWMGYINPYNDGTKYNEKFKGRVTMTRDTSTSTVYMELSSLRSEDTAVYYCARLLKYRRFRYYAIDYWGQGTTVTVSSGGSEGKSSGSGSESKSTGGSDIQMTQSPSSLSASVGDRVTITCRTSENVYSNLAWYQQKPGKAPKLLIYAASNLQSGVPSRFSGSGSGTDYTFTISSLQPEDIATYYCQHFWGSPFTFGQGTKLEIK 34
TPP-19987 輕鏈 DIQLTQSPSSLSASVGDRVTITCSASQDISNYLNWYQQKPGKAPKVLIYFTSSLHSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQYSTVPWTFGQGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC 35
TPP-19987 重鏈 EVQLVESGGGLVQPGGSLRLSCAASGYDFTHYGMNWVRQAPGKGLEWVGWINTYTGEPTYAADFKRRFTFSLDTSKSTAYLQMNSLRAEDTAVYYCAKYPYYYGTSHWYFDVWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGGGGGSGGGGSGGGGSGGGGSQVQLVQSGAEVKKPGASVKVSCKASGYTFTNYDIIWVRQAPGQGLEWMGYINPYNDGTKYNEKFKGRVTMTRDTSTSTVYMELSSLRSEDTAVYYCARLLKYRRFRYYAIDYWGQGTTVTVSSGGSEGKSSGSGSESKSTGGSDIQMTQSPSSLSASVGDRVTITCRTSENVYSNLAWYQQKPGKAPKLLIYAASNLQSGVPSRFSGSGSGTDYTFTISSLQPEDIATYYCQHFWGSPFTFGQGTKLEIK 36
TPP-19988 輕鏈 DIQLTQSPSSLSASVGDRVTITCSASQDISNYLNWYQQKPGKAPKVLIYFTSSLHSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQYSTVPWTFGQGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC 37
TPP-19988 重鏈 EVQLVESGGGLVQPGGSLRLSCAASGYDFTHYGMNWVRQAPGKGLEWVGWINTYTGEPTYAADFKRRFTFSLDTSKSTAYLQMNSLRAEDTAVYYCAKYPYYYGTSHWYFDVWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGGGGGSGGGGSDIQMTQSPSSLSASVGDRVTITCRTSENVYSNLAWYQQKPGKAPKLLIYAASNLQSGVPSRFSGSGSGTDYTFTISSLQPEDIATYYCQHFWGSPFTFGQGTKLEIKGGSEGKSSGSGSESKSTGGSQVQLVQSGAEVKKPGASVKVSCKASGYTFTNYDIIWVRQAPGQGLEWMGYINPYNDGTKYNEKFKGRVTMTRDTSTSTVYMELSSLRSEDTAVYYCARLLKYRRFRYYAIDYWGQGTTVTVSS 38
TPP-19989 輕鏈 DIQLTQSPSSLSASVGDRVTITCSASQDISNYLNWYQQKPGKAPKVLIYFTSSLHSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQYSTVPWTFGQGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC 39
TPP-19989 重鏈 EVQLVESGGGLVQPGGSLRLSCAASGYDFTHYGMNWVRQAPGKGLEWVGWINTYTGEPTYAADFKRRFTFSLDTSKSTAYLQMNSLRAEDTAVYYCAKYPYYYGTSHWYFDVWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGGGGGSGGGGSGGGGSGGGGSDIQMTQSPSSLSASVGDRVTITCRTSENVYSNLAWYQQKPGKAPKLLIYAASNLQSGVPSRFSGSGSGTDYTFTISSLQPEDIATYYCQHFWGSPFTFGQGTKLEIKGGSEGKSSGSGSESKSTGGSQVQLVQSGAEVKKPGASVKVSCKASGYTFTNYDIIWVRQAPGQGLEWMGYINPYNDGTKYNEKFKGRVTMTRDTSTSTVYMELSSLRSEDTAVYYCARLLKYRRFRYYAIDYWGQGTTVTVSS 40
TPP-22171 輕鏈 DIQLTQSPSSLSASVGDRVTITCSASQDISNYLNWYQQKPGKAPKVLIYFTSSLHSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQYSTVPWTFGQGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC 41
TPP-22171 重鏈 EVQLVESGGGLVQPGGSLRLSCAASGYDFTHYGMNWVRQAPGKGLEWVGWINTYTGEPTYAADFKRRFTFSLDTSKSTAYLQMNSLRAEDTAVYYCAKYPYYYGTSHWYFDVWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGGGGGSGGGGSQVQLVQSGAEVKKPGASVKVSCKASGYTFTNYDIIWVRQAPGQCLEWMGYINPYNDGTKYNEKFKGRVTMTRDTSTSTVYMELSSLRSEDTAVYYCARLLKYRRFRYYAIDYWGQGTTVTVSSGGSEGKSSGSGSESKSTGGSDIQMTQSPSSLSASVGDRVTITCRTSENVYSNLAWYQQKPGKAPKLLIYAASNLQSGVPSRFSGSGSGTDYTFTISSLQPEDIATYYCQHFWGSPFTFGCGTKLEIK 42
TPP-22172 輕鏈 DIQLTQSPSSLSASVGDRVTITCSASQDISNYLNWYQQKPGKAPKVLIYFTSSLHSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQYSTVPWTFGQGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC 43
TPP-22172 重鏈 EVQLVESGGGLVQPGGSLRLSCAASGYDFTHYGMNWVRQAPGKGLEWVGWINTYTGEPTYAADFKRRFTFSLDTSKSTAYLQMNSLRAEDTAVYYCAKYPYYYGTSHWYFDVWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGGGGGSGGGGSGGGGSGGGGSQVQLVQSGAEVKKPGASVKVSCKASGYTFTNYDIIWVRQAPGQCLEWMGYINPYNDGTKYNEKFKGRVTMTRDTSTSTVYMELSSLRSEDTAVYYCARLLKYRRFRYYAIDYWGQGTTVTVSSGGSEGKSSGSGSESKSTGGSDIQMTQSPSSLSASVGDRVTITCRTSENVYSNLAWYQQKPGKAPKLLIYAASNLQSGVPSRFSGSGSGTDYTFTISSLQPEDIATYYCQHFWGSPFTFGCGTKLEIK 44
TPP-22173 輕鏈 DIQLTQSPSSLSASVGDRVTITCSASQDISNYLNWYQQKPGKAPKVLIYFTSSLHSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQYSTVPWTFGQGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC 45
TPP-22173 重鏈 EVQLVESGGGLVQPGGSLRLSCAASGYDFTHYGMNWVRQAPGKGLEWVGWINTYTGEPTYAADFKRRFTFSLDTSKSTAYLQMNSLRAEDTAVYYCAKYPYYYGTSHWYFDVWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGGGGGSGGGGSDIQMTQSPSSLSASVGDRVTITCRTSENVYSNLAWYQQKPGKAPKLLIYAASNLQSGVPSRFSGSGSGTDYTFTISSLQPEDIATYYCQHFWGSPFTFGCGTKLEIKGGSEGKSSGSGSESKSTGGSQVQLVQSGAEVKKPGASVKVSCKASGYTFTNYDIIWVRQAPGQCLEWMGYINPYNDGTKYNEKFKGRVTMTRDTSTSTVYMELSSLRSEDTAVYYCARLLKYRRFRYYAIDYWGQGTTVTVSS 46
TPP-22174 輕鏈 DIQLTQSPSSLSASVGDRVTITCSASQDISNYLNWYQQKPGKAPKVLIYFTSSLHSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQYSTVPWTFGQGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC 47
TPP-22174 重鏈 EVQLVESGGGLVQPGGSLRLSCAASGYDFTHYGMNWVRQAPGKGLEWVGWINTYTGEPTYAADFKRRFTFSLDTSKSTAYLQMNSLRAEDTAVYYCAKYPYYYGTSHWYFDVWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGGGGGSGGGGSGGGGSGGGGSDIQMTQSPSSLSASVGDRVTITCRTSENVYSNLAWYQQKPGKAPKLLIYAASNLQSGVPSRFSGSGSGTDYTFTISSLQPEDIATYYCQHFWGSPFTFGCGTKLEIKGGSEGKSSGSGSESKSTGGSQVQLVQSGAEVKKPGASVKVSCKASGYTFTNYDIIWVRQAPGQCLEWMGYINPYNDGTKYNEKFKGRVTMTRDTSTSTVYMELSSLRSEDTAVYYCARLLKYRRFRYYAIDYWGQGTTVTVSS 48
TPP-22175 輕鏈 DIQLTQSPSSLSASVGDRVTITCSASQDISNYLNWYQQKPGKAPKVLIYFTSSLHSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQYSTVPWTFGQGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC 49
TPP-22175 重鏈 QVQLVESGGGLVQPGGSLRLSCAASGYDFTHYGMNWVRQAPGKGLEWVGWINTYTGEPTYAADFKRRFTFSLDTSKSTAYLQMNSLRAEDTAVYYCAKYPYYYGTSHWYFDVWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGGGGGSGGGGSQVQLVQSGAEVKKPGASVKVSCKASGYTFTNYDIIWVRQAPGQGLEWMGYINPYNDGTKYNEKFKGRVTMTRDTSTSTVYMELSSLRSEDTAVYYCARLLKYRRFRYYAIDYWGQGTTVTVSSGGSEGKSSGSGSESKSTGGSDIQMTQSPSSLSASVGDRVTITCRTSENVYSNLAWYQQKPGKAPKLLIYAASNLQSGVPSRFSGSGSGTDYTFTISSLQPEDIATYYCQHFWGSPFTFGQGTKLEIK 50
TPP-22176 輕鏈 DIQLTQSPSSLSASVGDRVTITCSASQDISNYLNWYQQKPGKAPKVLIYFTSSLHSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQYSTVPWTFGQGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC 51
TPP-22176 重鏈 EVQLVQSGGGLVQPGGSLRLSCAASGYDFTHYGMNWVRQAPGKGLEWVGWINTYTGEPTYAADFKRRFTFSLDTSKSTAYLQMNSLRAEDTAVYYCAKYPYYYGTSHWYFDVWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGGGGGSGGGGSQVQLVQSGAEVKKPGASVKVSCKASGYTFTNYDIIWVRQAPGQGLEWMGYINPYNDGTKYNEKFKGRVTMTRDTSTSTVYMELSSLRSEDTAVYYCARLLKYRRFRYYAIDYWGQGTTVTVSSGGSEGKSSGSGSESKSTGGSDIQMTQSPSSLSASVGDRVTITCRTSENVYSNLAWYQQKPGKAPKLLIYAASNLQSGVPSRFSGSGSGTDYTFTISSLQPEDIATYYCQHFWGSPFTFGQGTKLEIK 52
TPP-22177 輕鏈 DIQLTQSPSSLSASVGDRVTITCSASQDISNYLNWYQQKPGKAPKVLIYFTSSLHSGVPSRFSGSGSGTGFTLTISSLQPEDFATYYCQQYSTVPWTFGQGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC 53
TPP-22177 重鏈 EVQLVESGGGLVQPGGSLRLSCAASGYDFTHYGMNWVRQAPGKGLEWVGWINTYTGEPTYAADFKRRFTFSLDTSKSTAYLQMNSLRAEDTAVYYCAKYPYYYGTSHWYFDVWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGGGGGSGGGGSQVQLVQSGAEVKKPGASVKVSCKASGYTFTNYDIIWVRQAPGQGLEWMGYINPYNDGTKYNEKFKGRVTMTRDTSTSTVYMELSSLRSEDTAVYYCARLLKYRRFRYYAIDYWGQGTTVTVSSGGSEGKSSGSGSESKSTGGSDIQMTQSPSSLSASVGDRVTITCRTSENVYSNLAWYQQKPGKAPKLLIYAASNLQSGVPSRFSGSGSGTDYTFTISSLQPEDIATYYCQHFWGSPFTFGQGTKLEIK 54
TPP-22178 輕鏈 DIQLTQSPSSLSASVGDRVTITCSASQDISNYLNWYQQKPGKAPKVLIYFTSSLHSGVPSRFSGSGSGTGFTLTISSLQPEDFATYYCQQYSTVPWTFGQGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC 55
TPP-22178 重鏈 QVQLVESGGGLVQPGGSLRLSCAASGYDFTHYGMNWVRQAPGKGLEWVGWINTYTGEPTYAADFKRRFTFSLDTSKSTAYLQMNSLRAEDTAVYYCAKYPYYYGTSHWYFDVWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGGGGGSGGGGSQVQLVQSGAEVKKPGASVKVSCKASGYTFTNYDIIWVRQAPGQGLEWMGYINPYNDGTKYNEKFKGRVTMTRDTSTSTVYMELSSLRSEDTAVYYCARLLKYRRFRYYAIDYWGQGTTVTVSSGGSEGKSSGSGSESKSTGGSDIQMTQSPSSLSASVGDRVTITCRTSENVYSNLAWYQQKPGKAPKLLIYAASNLQSGVPSRFSGSGSGTDYTFTISSLQPEDIATYYCQHFWGSPFTFGQGTKLEIK 56
TPP-22179 輕鏈 DIQLTQSPSSLSASVGDRVTITCSASQDISNYLNWYQQKPGKAPKVLIYFTSSLHSGVPSRFSGSGSGTGFTLTISSLQPEDFATYYCQQYSTVPWTFGQGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC 57
TPP-22179 重鏈 EVQLVQSGGGLVQPGGSLRLSCAASGYDFTHYGMNWVRQAPGKGLEWVGWINTYTGEPTYAADFKRRFTFSLDTSKSTAYLQMNSLRAEDTAVYYCAKYPYYYGTSHWYFDVWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGGGGGSGGGGSQVQLVQSGAEVKKPGASVKVSCKASGYTFTNYDIIWVRQAPGQGLEWMGYINPYNDGTKYNEKFKGRVTMTRDTSTSTVYMELSSLRSEDTAVYYCARLLKYRRFRYYAIDYWGQGTTVTVSSGGSEGKSSGSGSESKSTGGSDIQMTQSPSSLSASVGDRVTITCRTSENVYSNLAWYQQKPGKAPKLLIYAASNLQSGVPSRFSGSGSGTDYTFTISSLQPEDIATYYCQHFWGSPFTFGQGTKLEIK 58
TPP-22180 輕鏈 DIQLTQSPSSLSASVGDRVTITCSASQDISNYLNWYQQKPGKAPKVLIYFTSSLHSGVPSRFSGSGSGTGFTLTISSLQPEDFATYYCQQYSTVPWTFGQGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC 59
TPP-22180 重鏈 QVQLVQSGGGLVQPGGSLRLSCAASGYDFTHYGMNWVRQAPGKGLEWVGWINTYTGEPTYAADFKRRFTFSLDTSKSTAYLQMNSLRAEDTAVYYCAKYPYYYGTSHWYFDVWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGGGGGSGGGGSQVQLVQSGAEVKKPGASVKVSCKASGYTFTNYDIIWVRQAPGQGLEWMGYINPYNDGTKYNEKFKGRVTMTRDTSTSTVYMELSSLRSEDTAVYYCARLLKYRRFRYYAIDYWGQGTTVTVSSGGSEGKSSGSGSESKSTGGSDIQMTQSPSSLSASVGDRVTITCRTSENVYSNLAWYQQKPGKAPKLLIYAASNLQSGVPSRFSGSGSGTDYTFTISSLQPEDIATYYCQHFWGSPFTFGQGTKLEIK 60
TPP-22181 輕鏈 DIQLTQSPSSLSASVGDRVTITCSASQDISNYLNWYQQKPGKAPKVLIYFTSSLHSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQYSTVPWTFGQGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC 61
TPP-22181 重鏈 QVQLVESGGGLVQPGGSLRLSCAASGYDFTHYGMNWVRQAPGKGLEWVGWINTYTGEPTYAADFKRRFTFSLDTSKSTAYLQMNSLRAEDTAVYYCAKYPYYYGTSHWYFDVWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGGGGGSGGGGSGGGGSGGGGSQVQLVQSGAEVKKPGASVKVSCKASGYTFTNYDIIWVRQAPGQGLEWMGYINPYNDGTKYNEKFKGRVTMTRDTSTSTVYMELSSLRSEDTAVYYCARLLKYRRFRYYAIDYWGQGTTVTVSSGGSEGKSSGSGSESKSTGGSDIQMTQSPSSLSASVGDRVTITCRTSENVYSNLAWYQQKPGKAPKLLIYAASNLQSGVPSRFSGSGSGTDYTFTISSLQPEDIATYYCQHFWGSPFTFGQGTKLEIK 62
TPP-22182 輕鏈 DIQLTQSPSSLSASVGDRVTITCSASQDISNYLNWYQQKPGKAPKVLIYFTSSLHSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQYSTVPWTFGQGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC 63
TPP-22182 重鏈 EVQLVQSGGGLVQPGGSLRLSCAASGYDFTHYGMNWVRQAPGKGLEWVGWINTYTGEPTYAADFKRRFTFSLDTSKSTAYLQMNSLRAEDTAVYYCAKYPYYYGTSHWYFDVWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGGGGGSGGGGSGGGGSGGGGSQVQLVQSGAEVKKPGASVKVSCKASGYTFTNYDIIWVRQAPGQGLEWMGYINPYNDGTKYNEKFKGRVTMTRDTSTSTVYMELSSLRSEDTAVYYCARLLKYRRFRYYAIDYWGQGTTVTVSSGGSEGKSSGSGSESKSTGGSDIQMTQSPSSLSASVGDRVTITCRTSENVYSNLAWYQQKPGKAPKLLIYAASNLQSGVPSRFSGSGSGTDYTFTISSLQPEDIATYYCQHFWGSPFTFGQGTKLEIK 64
TPP-22183 輕鏈 DIQLTQSPSSLSASVGDRVTITCSASQDISNYLNWYQQKPGKAPKVLIYFTSSLHSGVPSRFSGSGSGTGFTLTISSLQPEDFATYYCQQYSTVPWTFGQGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC 65
TPP-22183 重鏈 EVQLVESGGGLVQPGGSLRLSCAASGYDFTHYGMNWVRQAPGKGLEWVGWINTYTGEPTYAADFKRRFTFSLDTSKSTAYLQMNSLRAEDTAVYYCAKYPYYYGTSHWYFDVWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGGGGGSGGGGSGGGGSGGGGSQVQLVQSGAEVKKPGASVKVSCKASGYTFTNYDIIWVRQAPGQGLEWMGYINPYNDGTKYNEKFKGRVTMTRDTSTSTVYMELSSLRSEDTAVYYCARLLKYRRFRYYAIDYWGQGTTVTVSSGGSEGKSSGSGSESKSTGGSDIQMTQSPSSLSASVGDRVTITCRTSENVYSNLAWYQQKPGKAPKLLIYAASNLQSGVPSRFSGSGSGTDYTFTISSLQPEDIATYYCQHFWGSPFTFGQGTKLEIK 66
TPP-22184 輕鏈 DIQLTQSPSSLSASVGDRVTITCSASQDISNYLNWYQQKPGKAPKVLIYFTSSLHSGVPSRFSGSGSGTGFTLTISSLQPEDFATYYCQQYSTVPWTFGQGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC 67
TPP-22184 重鏈 QVQLVESGGGLVQPGGSLRLSCAASGYDFTHYGMNWVRQAPGKGLEWVGWINTYTGEPTYAADFKRRFTFSLDTSKSTAYLQMNSLRAEDTAVYYCAKYPYYYGTSHWYFDVWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGGGGGSGGGGSGGGGSGGGGSQVQLVQSGAEVKKPGASVKVSCKASGYTFTNYDIIWVRQAPGQGLEWMGYINPYNDGTKYNEKFKGRVTMTRDTSTSTVYMELSSLRSEDTAVYYCARLLKYRRFRYYAIDYWGQGTTVTVSSGGSEGKSSGSGSESKSTGGSDIQMTQSPSSLSASVGDRVTITCRTSENVYSNLAWYQQKPGKAPKLLIYAASNLQSGVPSRFSGSGSGTDYTFTISSLQPEDIATYYCQHFWGSPFTFGQGTKLEIK 68
TPP-22185 輕鏈 DIQLTQSPSSLSASVGDRVTITCSASQDISNYLNWYQQKPGKAPKVLIYFTSSLHSGVPSRFSGSGSGTGFTLTISSLQPEDFATYYCQQYSTVPWTFGQGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC 69
TPP-22185 重鏈 EVQLVQSGGGLVQPGGSLRLSCAASGYDFTHYGMNWVRQAPGKGLEWVGWINTYTGEPTYAADFKRRFTFSLDTSKSTAYLQMNSLRAEDTAVYYCAKYPYYYGTSHWYFDVWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGGGGGSGGGGSGGGGSGGGGSQVQLVQSGAEVKKPGASVKVSCKASGYTFTNYDIIWVRQAPGQGLEWMGYINPYNDGTKYNEKFKGRVTMTRDTSTSTVYMELSSLRSEDTAVYYCARLLKYRRFRYYAIDYWGQGTTVTVSSGGSEGKSSGSGSESKSTGGSDIQMTQSPSSLSASVGDRVTITCRTSENVYSNLAWYQQKPGKAPKLLIYAASNLQSGVPSRFSGSGSGTDYTFTISSLQPEDIATYYCQHFWGSPFTFGQGTKLEIK 70
TPP-22186 輕鏈 DIQLTQSPSSLSASVGDRVTITCSASQDISNYLNWYQQKPGKAPKVLIYFTSSLHSGVPSRFSGSGSGTGFTLTISSLQPEDFATYYCQQYSTVPWTFGQGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC 71
TPP-22186 重鏈 QVQLVQSGGGLVQPGGSLRLSCAASGYDFTHYGMNWVRQAPGKGLEWVGWINTYTGEPTYAADFKRRFTFSLDTSKSTAYLQMNSLRAEDTAVYYCAKYPYYYGTSHWYFDVWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGGGGGSGGGGSGGGGSGGGGSQVQLVQSGAEVKKPGASVKVSCKASGYTFTNYDIIWVRQAPGQGLEWMGYINPYNDGTKYNEKFKGRVTMTRDTSTSTVYMELSSLRSEDTAVYYCARLLKYRRFRYYAIDYWGQGTTVTVSSGGSEGKSSGSGSESKSTGGSDIQMTQSPSSLSASVGDRVTITCRTSENVYSNLAWYQQKPGKAPKLLIYAASNLQSGVPSRFSGSGSGTDYTFTISSLQPEDIATYYCQHFWGSPFTFGQGTKLEIK 72
TPP-22187 輕鏈 DIQLTQSPSSLSASVGDRVTITCSASQDISNYLNWYQQKPGKAPKVLIYFTSSLHSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQYSTVPWTFGQGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC 73
TPP-22187 重鏈 QVQLVESGGGLVQPGGSLRLSCAASGYDFTHYGMNWVRQAPGKGLEWVGWINTYTGEPTYAADFKRRFTFSLDTSKSTAYLQMNSLRAEDTAVYYCAKYPYYYGTSHWYFDVWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGGGGGSGGGGSDIQMTQSPSSLSASVGDRVTITCRTSENVYSNLAWYQQKPGKAPKLLIYAASNLQSGVPSRFSGSGSGTDYTFTISSLQPEDIATYYCQHFWGSPFTFGQGTKLEIKGGSEGKSSGSGSESKSTGGSQVQLVQSGAEVKKPGASVKVSCKASGYTFTNYDIIWVRQAPGQGLEWMGYINPYNDGTKYNEKFKGRVTMTRDTSTSTVYMELSSLRSEDTAVYYCARLLKYRRFRYYAIDYWGQGTTVTVSS 74
TPP-22188 輕鏈 DIQLTQSPSSLSASVGDRVTITCSASQDISNYLNWYQQKPGKAPKVLIYFTSSLHSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQYSTVPWTFGQGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC 75
TPP-22188 重鏈 EVQLVQSGGGLVQPGGSLRLSCAASGYDFTHYGMNWVRQAPGKGLEWVGWINTYTGEPTYAADFKRRFTFSLDTSKSTAYLQMNSLRAEDTAVYYCAKYPYYYGTSHWYFDVWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGGGGGSGGGGSDIQMTQSPSSLSASVGDRVTITCRTSENVYSNLAWYQQKPGKAPKLLIYAASNLQSGVPSRFSGSGSGTDYTFTISSLQPEDIATYYCQHFWGSPFTFGQGTKLEIKGGSEGKSSGSGSESKSTGGSQVQLVQSGAEVKKPGASVKVSCKASGYTFTNYDIIWVRQAPGQGLEWMGYINPYNDGTKYNEKFKGRVTMTRDTSTSTVYMELSSLRSEDTAVYYCARLLKYRRFRYYAIDYWGQGTTVTVSS 76
TPP-22189 輕鏈 DIQLTQSPSSLSASVGDRVTITCSASQDISNYLNWYQQKPGKAPKVLIYFTSSLHSGVPSRFSGSGSGTGFTLTISSLQPEDFATYYCQQYSTVPWTFGQGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC 77
TPP-22189 重鏈 EVQLVESGGGLVQPGGSLRLSCAASGYDFTHYGMNWVRQAPGKGLEWVGWINTYTGEPTYAADFKRRFTFSLDTSKSTAYLQMNSLRAEDTAVYYCAKYPYYYGTSHWYFDVWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGGGGGSGGGGSDIQMTQSPSSLSASVGDRVTITCRTSENVYSNLAWYQQKPGKAPKLLIYAASNLQSGVPSRFSGSGSGTDYTFTISSLQPEDIATYYCQHFWGSPFTFGQGTKLEIKGGSEGKSSGSGSESKSTGGSQVQLVQSGAEVKKPGASVKVSCKASGYTFTNYDIIWVRQAPGQGLEWMGYINPYNDGTKYNEKFKGRVTMTRDTSTSTVYMELSSLRSEDTAVYYCARLLKYRRFRYYAIDYWGQGTTVTVSS 78
TPP-22190 輕鏈 DIQLTQSPSSLSASVGDRVTITCSASQDISNYLNWYQQKPGKAPKVLIYFTSSLHSGVPSRFSGSGSGTGFTLTISSLQPEDFATYYCQQYSTVPWTFGQGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC 79
TPP-22190 重鏈 QVQLVESGGGLVQPGGSLRLSCAASGYDFTHYGMNWVRQAPGKGLEWVGWINTYTGEPTYAADFKRRFTFSLDTSKSTAYLQMNSLRAEDTAVYYCAKYPYYYGTSHWYFDVWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGGGGGSGGGGSDIQMTQSPSSLSASVGDRVTITCRTSENVYSNLAWYQQKPGKAPKLLIYAASNLQSGVPSRFSGSGSGTDYTFTISSLQPEDIATYYCQHFWGSPFTFGQGTKLEIKGGSEGKSSGSGSESKSTGGSQVQLVQSGAEVKKPGASVKVSCKASGYTFTNYDIIWVRQAPGQGLEWMGYINPYNDGTKYNEKFKGRVTMTRDTSTSTVYMELSSLRSEDTAVYYCARLLKYRRFRYYAIDYWGQGTTVTVSS 80
TPP-22191 輕鏈 DIQLTQSPSSLSASVGDRVTITCSASQDISNYLNWYQQKPGKAPKVLIYFTSSLHSGVPSRFSGSGSGTGFTLTISSLQPEDFATYYCQQYSTVPWTFGQGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC 81
TPP-22191 重鏈 EVQLVQSGGGLVQPGGSLRLSCAASGYDFTHYGMNWVRQAPGKGLEWVGWINTYTGEPTYAADFKRRFTFSLDTSKSTAYLQMNSLRAEDTAVYYCAKYPYYYGTSHWYFDVWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGGGGGSGGGGSDIQMTQSPSSLSASVGDRVTITCRTSENVYSNLAWYQQKPGKAPKLLIYAASNLQSGVPSRFSGSGSGTDYTFTISSLQPEDIATYYCQHFWGSPFTFGQGTKLEIKGGSEGKSSGSGSESKSTGGSQVQLVQSGAEVKKPGASVKVSCKASGYTFTNYDIIWVRQAPGQGLEWMGYINPYNDGTKYNEKFKGRVTMTRDTSTSTVYMELSSLRSEDTAVYYCARLLKYRRFRYYAIDYWGQGTTVTVSS 82
TPP-22192 輕鏈 DIQLTQSPSSLSASVGDRVTITCSASQDISNYLNWYQQKPGKAPKVLIYFTSSLHSGVPSRFSGSGSGTGFTLTISSLQPEDFATYYCQQYSTVPWTFGQGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC 83
TPP-22192 重鏈 QVQLVQSGGGLVQPGGSLRLSCAASGYDFTHYGMNWVRQAPGKGLEWVGWINTYTGEPTYAADFKRRFTFSLDTSKSTAYLQMNSLRAEDTAVYYCAKYPYYYGTSHWYFDVWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGGGGGSGGGGSDIQMTQSPSSLSASVGDRVTITCRTSENVYSNLAWYQQKPGKAPKLLIYAASNLQSGVPSRFSGSGSGTDYTFTISSLQPEDIATYYCQHFWGSPFTFGQGTKLEIKGGSEGKSSGSGSESKSTGGSQVQLVQSGAEVKKPGASVKVSCKASGYTFTNYDIIWVRQAPGQGLEWMGYINPYNDGTKYNEKFKGRVTMTRDTSTSTVYMELSSLRSEDTAVYYCARLLKYRRFRYYAIDYWGQGTTVTVSS 84
TPP-22193 輕鏈 DIQLTQSPSSLSASVGDRVTITCSASQDISNYLNWYQQKPGKAPKVLIYFTSSLHSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQYSTVPWTFGQGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC 85
TPP-22193 重鏈 QVQLVESGGGLVQPGGSLRLSCAASGYDFTHYGMNWVRQAPGKGLEWVGWINTYTGEPTYAADFKRRFTFSLDTSKSTAYLQMNSLRAEDTAVYYCAKYPYYYGTSHWYFDVWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGGGGGSGGGGSGGGGSGGGGSDIQMTQSPSSLSASVGDRVTITCRTSENVYSNLAWYQQKPGKAPKLLIYAASNLQSGVPSRFSGSGSGTDYTFTISSLQPEDIATYYCQHFWGSPFTFGQGTKLEIKGGSEGKSSGSGSESKSTGGSQVQLVQSGAEVKKPGASVKVSCKASGYTFTNYDIIWVRQAPGQGLEWMGYINPYNDGTKYNEKFKGRVTMTRDTSTSTVYMELSSLRSEDTAVYYCARLLKYRRFRYYAIDYWGQGTTVTVSS 86
TPP-22194 輕鏈 DIQLTQSPSSLSASVGDRVTITCSASQDISNYLNWYQQKPGKAPKVLIYFTSSLHSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQYSTVPWTFGQGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC 87
TPP-22194 重鏈 EVQLVQSGGGLVQPGGSLRLSCAASGYDFTHYGMNWVRQAPGKGLEWVGWINTYTGEPTYAADFKRRFTFSLDTSKSTAYLQMNSLRAEDTAVYYCAKYPYYYGTSHWYFDVWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGGGGGSGGGGSGGGGSGGGGSDIQMTQSPSSLSASVGDRVTITCRTSENVYSNLAWYQQKPGKAPKLLIYAASNLQSGVPSRFSGSGSGTDYTFTISSLQPEDIATYYCQHFWGSPFTFGQGTKLEIKGGSEGKSSGSGSESKSTGGSQVQLVQSGAEVKKPGASVKVSCKASGYTFTNYDIIWVRQAPGQGLEWMGYINPYNDGTKYNEKFKGRVTMTRDTSTSTVYMELSSLRSEDTAVYYCARLLKYRRFRYYAIDYWGQGTTVTVSS 88
TPP-22195 輕鏈 DIQLTQSPSSLSASVGDRVTITCSASQDISNYLNWYQQKPGKAPKVLIYFTSSLHSGVPSRFSGSGSGTGFTLTISSLQPEDFATYYCQQYSTVPWTFGQGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC 89
TPP-22195 重鏈 EVQLVESGGGLVQPGGSLRLSCAASGYDFTHYGMNWVRQAPGKGLEWVGWINTYTGEPTYAADFKRRFTFSLDTSKSTAYLQMNSLRAEDTAVYYCAKYPYYYGTSHWYFDVWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGGGGGSGGGGSGGGGSGGGGSDIQMTQSPSSLSASVGDRVTITCRTSENVYSNLAWYQQKPGKAPKLLIYAASNLQSGVPSRFSGSGSGTDYTFTISSLQPEDIATYYCQHFWGSPFTFGQGTKLEIKGGSEGKSSGSGSESKSTGGSQVQLVQSGAEVKKPGASVKVSCKASGYTFTNYDIIWVRQAPGQGLEWMGYINPYNDGTKYNEKFKGRVTMTRDTSTSTVYMELSSLRSEDTAVYYCARLLKYRRFRYYAIDYWGQGTTVTVSS 90
TPP-22196 輕鏈 DIQLTQSPSSLSASVGDRVTITCSASQDISNYLNWYQQKPGKAPKVLIYFTSSLHSGVPSRFSGSGSGTGFTLTISSLQPEDFATYYCQQYSTVPWTFGQGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC 91
TPP-22196 重鏈 QVQLVESGGGLVQPGGSLRLSCAASGYDFTHYGMNWVRQAPGKGLEWVGWINTYTGEPTYAADFKRRFTFSLDTSKSTAYLQMNSLRAEDTAVYYCAKYPYYYGTSHWYFDVWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGGGGGSGGGGSGGGGSGGGGSDIQMTQSPSSLSASVGDRVTITCRTSENVYSNLAWYQQKPGKAPKLLIYAASNLQSGVPSRFSGSGSGTDYTFTISSLQPEDIATYYCQHFWGSPFTFGQGTKLEIKGGSEGKSSGSGSESKSTGGSQVQLVQSGAEVKKPGASVKVSCKASGYTFTNYDIIWVRQAPGQGLEWMGYINPYNDGTKYNEKFKGRVTMTRDTSTSTVYMELSSLRSEDTAVYYCARLLKYRRFRYYAIDYWGQGTTVTVSS 92
TPP-22197 輕鏈 DIQLTQSPSSLSASVGDRVTITCSASQDISNYLNWYQQKPGKAPKVLIYFTSSLHSGVPSRFSGSGSGTGFTLTISSLQPEDFATYYCQQYSTVPWTFGQGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC 93
TPP-22197 重鏈 EVQLVQSGGGLVQPGGSLRLSCAASGYDFTHYGMNWVRQAPGKGLEWVGWINTYTGEPTYAADFKRRFTFSLDTSKSTAYLQMNSLRAEDTAVYYCAKYPYYYGTSHWYFDVWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGGGGGSGGGGSGGGGSGGGGSDIQMTQSPSSLSASVGDRVTITCRTSENVYSNLAWYQQKPGKAPKLLIYAASNLQSGVPSRFSGSGSGTDYTFTISSLQPEDIATYYCQHFWGSPFTFGQGTKLEIKGGSEGKSSGSGSESKSTGGSQVQLVQSGAEVKKPGASVKVSCKASGYTFTNYDIIWVRQAPGQGLEWMGYINPYNDGTKYNEKFKGRVTMTRDTSTSTVYMELSSLRSEDTAVYYCARLLKYRRFRYYAIDYWGQGTTVTVSS 94
TPP-22198 輕鏈 DIQLTQSPSSLSASVGDRVTITCSASQDISNYLNWYQQKPGKAPKVLIYFTSSLHSGVPSRFSGSGSGTGFTLTISSLQPEDFATYYCQQYSTVPWTFGQGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC 95
TPP-22198 重鏈 QVQLVQSGGGLVQPGGSLRLSCAASGYDFTHYGMNWVRQAPGKGLEWVGWINTYTGEPTYAADFKRRFTFSLDTSKSTAYLQMNSLRAEDTAVYYCAKYPYYYGTSHWYFDVWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGGGGGSGGGGSGGGGSGGGGSDIQMTQSPSSLSASVGDRVTITCRTSENVYSNLAWYQQKPGKAPKLLIYAASNLQSGVPSRFSGSGSGTDYTFTISSLQPEDIATYYCQHFWGSPFTFGQGTKLEIKGGSEGKSSGSGSESKSTGGSQVQLVQSGAEVKKPGASVKVSCKASGYTFTNYDIIWVRQAPGQGLEWMGYINPYNDGTKYNEKFKGRVTMTRDTSTSTVYMELSSLRSEDTAVYYCARLLKYRRFRYYAIDYWGQGTTVTVSS 96
TPP-22199 輕鏈 DIQLTQSPSSLSASVGDRVTITCSASQDISNYLNWYQQKPGKAPKVLIYFTSSLHSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQYSTVPWTFGQGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC 97
TPP-22199 重鏈 QVQLVESGGGLVQPGGSLRLSCAASGYDFTHYGMNWVRQAPGKGLEWVGWINTYTGEPTYAADFKRRFTFSLDTSKSTAYLQMNSLRAEDTAVYYCAKYPYYYGTSHWYFDVWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGGGGGSGGGGSQVQLVQSGAEVKKPGASVKVSCKASGYTFTNYDIIWVRQAPGQCLEWMGYINPYNDGTKYNEKFKGRVTMTRDTSTSTVYMELSSLRSEDTAVYYCARLLKYRRFRYYAIDYWGQGTTVTVSSGGSEGKSSGSGSESKSTGGSDIQMTQSPSSLSASVGDRVTITCRTSENVYSNLAWYQQKPGKAPKLLIYAASNLQSGVPSRFSGSGSGTDYTFTISSLQPEDIATYYCQHFWGSPFTFGCGTKLEIK 98
TPP-22200 輕鏈 DIQLTQSPSSLSASVGDRVTITCSASQDISNYLNWYQQKPGKAPKVLIYFTSSLHSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQYSTVPWTFGQGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC 99
TPP-22200 重鏈 EVQLVQSGGGLVQPGGSLRLSCAASGYDFTHYGMNWVRQAPGKGLEWVGWINTYTGEPTYAADFKRRFTFSLDTSKSTAYLQMNSLRAEDTAVYYCAKYPYYYGTSHWYFDVWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGGGGGSGGGGSQVQLVQSGAEVKKPGASVKVSCKASGYTFTNYDIIWVRQAPGQCLEWMGYINPYNDGTKYNEKFKGRVTMTRDTSTSTVYMELSSLRSEDTAVYYCARLLKYRRFRYYAIDYWGQGTTVTVSSGGSEGKSSGSGSESKSTGGSDIQMTQSPSSLSASVGDRVTITCRTSENVYSNLAWYQQKPGKAPKLLIYAASNLQSGVPSRFSGSGSGTDYTFTISSLQPEDIATYYCQHFWGSPFTFGCGTKLEIK 100
TPP-22201 輕鏈 DIQLTQSPSSLSASVGDRVTITCSASQDISNYLNWYQQKPGKAPKVLIYFTSSLHSGVPSRFSGSGSGTGFTLTISSLQPEDFATYYCQQYSTVPWTFGQGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC 101
TPP-22201 重鏈 EVQLVESGGGLVQPGGSLRLSCAASGYDFTHYGMNWVRQAPGKGLEWVGWINTYTGEPTYAADFKRRFTFSLDTSKSTAYLQMNSLRAEDTAVYYCAKYPYYYGTSHWYFDVWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGGGGGSGGGGSQVQLVQSGAEVKKPGASVKVSCKASGYTFTNYDIIWVRQAPGQCLEWMGYINPYNDGTKYNEKFKGRVTMTRDTSTSTVYMELSSLRSEDTAVYYCARLLKYRRFRYYAIDYWGQGTTVTVSSGGSEGKSSGSGSESKSTGGSDIQMTQSPSSLSASVGDRVTITCRTSENVYSNLAWYQQKPGKAPKLLIYAASNLQSGVPSRFSGSGSGTDYTFTISSLQPEDIATYYCQHFWGSPFTFGCGTKLEIK 102
TPP-22202 輕鏈 DIQLTQSPSSLSASVGDRVTITCSASQDISNYLNWYQQKPGKAPKVLIYFTSSLHSGVPSRFSGSGSGTGFTLTISSLQPEDFATYYCQQYSTVPWTFGQGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC 103
TPP-22202 重鏈 QVQLVESGGGLVQPGGSLRLSCAASGYDFTHYGMNWVRQAPGKGLEWVGWINTYTGEPTYAADFKRRFTFSLDTSKSTAYLQMNSLRAEDTAVYYCAKYPYYYGTSHWYFDVWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGGGGGSGGGGSQVQLVQSGAEVKKPGASVKVSCKASGYTFTNYDIIWVRQAPGQCLEWMGYINPYNDGTKYNEKFKGRVTMTRDTSTSTVYMELSSLRSEDTAVYYCARLLKYRRFRYYAIDYWGQGTTVTVSSGGSEGKSSGSGSESKSTGGSDIQMTQSPSSLSASVGDRVTITCRTSENVYSNLAWYQQKPGKAPKLLIYAASNLQSGVPSRFSGSGSGTDYTFTISSLQPEDIATYYCQHFWGSPFTFGCGTKLEIK 104
TPP-22203 輕鏈 DIQLTQSPSSLSASVGDRVTITCSASQDISNYLNWYQQKPGKAPKVLIYFTSSLHSGVPSRFSGSGSGTGFTLTISSLQPEDFATYYCQQYSTVPWTFGQGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC 105
TPP-22203 重鏈 EVQLVQSGGGLVQPGGSLRLSCAASGYDFTHYGMNWVRQAPGKGLEWVGWINTYTGEPTYAADFKRRFTFSLDTSKSTAYLQMNSLRAEDTAVYYCAKYPYYYGTSHWYFDVWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGGGGGSGGGGSQVQLVQSGAEVKKPGASVKVSCKASGYTFTNYDIIWVRQAPGQCLEWMGYINPYNDGTKYNEKFKGRVTMTRDTSTSTVYMELSSLRSEDTAVYYCARLLKYRRFRYYAIDYWGQGTTVTVSSGGSEGKSSGSGSESKSTGGSDIQMTQSPSSLSASVGDRVTITCRTSENVYSNLAWYQQKPGKAPKLLIYAASNLQSGVPSRFSGSGSGTDYTFTISSLQPEDIATYYCQHFWGSPFTFGCGTKLEIK 106
TPP-22204 輕鏈 DIQLTQSPSSLSASVGDRVTITCSASQDISNYLNWYQQKPGKAPKVLIYFTSSLHSGVPSRFSGSGSGTGFTLTISSLQPEDFATYYCQQYSTVPWTFGQGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC 107
TPP-22204 重鏈 QVQLVQSGGGLVQPGGSLRLSCAASGYDFTHYGMNWVRQAPGKGLEWVGWINTYTGEPTYAADFKRRFTFSLDTSKSTAYLQMNSLRAEDTAVYYCAKYPYYYGTSHWYFDVWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGGGGGSGGGGSQVQLVQSGAEVKKPGASVKVSCKASGYTFTNYDIIWVRQAPGQCLEWMGYINPYNDGTKYNEKFKGRVTMTRDTSTSTVYMELSSLRSEDTAVYYCARLLKYRRFRYYAIDYWGQGTTVTVSSGGSEGKSSGSGSESKSTGGSDIQMTQSPSSLSASVGDRVTITCRTSENVYSNLAWYQQKPGKAPKLLIYAASNLQSGVPSRFSGSGSGTDYTFTISSLQPEDIATYYCQHFWGSPFTFGCGTKLEIK 108
TPP-22205 輕鏈 DIQLTQSPSSLSASVGDRVTITCSASQDISNYLNWYQQKPGKAPKVLIYFTSSLHSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQYSTVPWTFGQGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC 109
TPP-22205 重鏈 QVQLVESGGGLVQPGGSLRLSCAASGYDFTHYGMNWVRQAPGKGLEWVGWINTYTGEPTYAADFKRRFTFSLDTSKSTAYLQMNSLRAEDTAVYYCAKYPYYYGTSHWYFDVWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGGGGGSGGGGSGGGGSGGGGSQVQLVQSGAEVKKPGASVKVSCKASGYTFTNYDIIWVRQAPGQCLEWMGYINPYNDGTKYNEKFKGRVTMTRDTSTSTVYMELSSLRSEDTAVYYCARLLKYRRFRYYAIDYWGQGTTVTVSSGGSEGKSSGSGSESKSTGGSDIQMTQSPSSLSASVGDRVTITCRTSENVYSNLAWYQQKPGKAPKLLIYAASNLQSGVPSRFSGSGSGTDYTFTISSLQPEDIATYYCQHFWGSPFTFGCGTKLEIK 110
TPP-22206 輕鏈 DIQLTQSPSSLSASVGDRVTITCSASQDISNYLNWYQQKPGKAPKVLIYFTSSLHSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQYSTVPWTFGQGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC 111
TPP-22206 重鏈 EVQLVQSGGGLVQPGGSLRLSCAASGYDFTHYGMNWVRQAPGKGLEWVGWINTYTGEPTYAADFKRRFTFSLDTSKSTAYLQMNSLRAEDTAVYYCAKYPYYYGTSHWYFDVWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGGGGGSGGGGSGGGGSGGGGSQVQLVQSGAEVKKPGASVKVSCKASGYTFTNYDIIWVRQAPGQCLEWMGYINPYNDGTKYNEKFKGRVTMTRDTSTSTVYMELSSLRSEDTAVYYCARLLKYRRFRYYAIDYWGQGTTVTVSSGGSEGKSSGSGSESKSTGGSDIQMTQSPSSLSASVGDRVTITCRTSENVYSNLAWYQQKPGKAPKLLIYAASNLQSGVPSRFSGSGSGTDYTFTISSLQPEDIATYYCQHFWGSPFTFGCGTKLEIK 112
TPP-22207 輕鏈 DIQLTQSPSSLSASVGDRVTITCSASQDISNYLNWYQQKPGKAPKVLIYFTSSLHSGVPSRFSGSGSGTGFTLTISSLQPEDFATYYCQQYSTVPWTFGQGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC 113
TPP-22207 重鏈 EVQLVESGGGLVQPGGSLRLSCAASGYDFTHYGMNWVRQAPGKGLEWVGWINTYTGEPTYAADFKRRFTFSLDTSKSTAYLQMNSLRAEDTAVYYCAKYPYYYGTSHWYFDVWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGGGGGSGGGGSGGGGSGGGGSQVQLVQSGAEVKKPGASVKVSCKASGYTFTNYDIIWVRQAPGQCLEWMGYINPYNDGTKYNEKFKGRVTMTRDTSTSTVYMELSSLRSEDTAVYYCARLLKYRRFRYYAIDYWGQGTTVTVSSGGSEGKSSGSGSESKSTGGSDIQMTQSPSSLSASVGDRVTITCRTSENVYSNLAWYQQKPGKAPKLLIYAASNLQSGVPSRFSGSGSGTDYTFTISSLQPEDIATYYCQHFWGSPFTFGCGTKLEIK 114
TPP-22208 輕鏈 DIQLTQSPSSLSASVGDRVTITCSASQDISNYLNWYQQKPGKAPKVLIYFTSSLHSGVPSRFSGSGSGTGFTLTISSLQPEDFATYYCQQYSTVPWTFGQGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC 115
TPP-22208 重鏈 QVQLVESGGGLVQPGGSLRLSCAASGYDFTHYGMNWVRQAPGKGLEWVGWINTYTGEPTYAADFKRRFTFSLDTSKSTAYLQMNSLRAEDTAVYYCAKYPYYYGTSHWYFDVWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGGGGGSGGGGSGGGGSGGGGSQVQLVQSGAEVKKPGASVKVSCKASGYTFTNYDIIWVRQAPGQCLEWMGYINPYNDGTKYNEKFKGRVTMTRDTSTSTVYMELSSLRSEDTAVYYCARLLKYRRFRYYAIDYWGQGTTVTVSSGGSEGKSSGSGSESKSTGGSDIQMTQSPSSLSASVGDRVTITCRTSENVYSNLAWYQQKPGKAPKLLIYAASNLQSGVPSRFSGSGSGTDYTFTISSLQPEDIATYYCQHFWGSPFTFGCGTKLEIK 116
TPP-22209 輕鏈 DIQLTQSPSSLSASVGDRVTITCSASQDISNYLNWYQQKPGKAPKVLIYFTSSLHSGVPSRFSGSGSGTGFTLTISSLQPEDFATYYCQQYSTVPWTFGQGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC 117
TPP-22209 重鏈 EVQLVQSGGGLVQPGGSLRLSCAASGYDFTHYGMNWVRQAPGKGLEWVGWINTYTGEPTYAADFKRRFTFSLDTSKSTAYLQMNSLRAEDTAVYYCAKYPYYYGTSHWYFDVWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGGGGGSGGGGSGGGGSGGGGSQVQLVQSGAEVKKPGASVKVSCKASGYTFTNYDIIWVRQAPGQCLEWMGYINPYNDGTKYNEKFKGRVTMTRDTSTSTVYMELSSLRSEDTAVYYCARLLKYRRFRYYAIDYWGQGTTVTVSSGGSEGKSSGSGSESKSTGGSDIQMTQSPSSLSASVGDRVTITCRTSENVYSNLAWYQQKPGKAPKLLIYAASNLQSGVPSRFSGSGSGTDYTFTISSLQPEDIATYYCQHFWGSPFTFGCGTKLEIK 118
TPP-22210 輕鏈 DIQLTQSPSSLSASVGDRVTITCSASQDISNYLNWYQQKPGKAPKVLIYFTSSLHSGVPSRFSGSGSGTGFTLTISSLQPEDFATYYCQQYSTVPWTFGQGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC 119
TPP-22210 重鏈 QVQLVQSGGGLVQPGGSLRLSCAASGYDFTHYGMNWVRQAPGKGLEWVGWINTYTGEPTYAADFKRRFTFSLDTSKSTAYLQMNSLRAEDTAVYYCAKYPYYYGTSHWYFDVWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGGGGGSGGGGSGGGGSGGGGSQVQLVQSGAEVKKPGASVKVSCKASGYTFTNYDIIWVRQAPGQCLEWMGYINPYNDGTKYNEKFKGRVTMTRDTSTSTVYMELSSLRSEDTAVYYCARLLKYRRFRYYAIDYWGQGTTVTVSSGGSEGKSSGSGSESKSTGGSDIQMTQSPSSLSASVGDRVTITCRTSENVYSNLAWYQQKPGKAPKLLIYAASNLQSGVPSRFSGSGSGTDYTFTISSLQPEDIATYYCQHFWGSPFTFGCGTKLEIK 120
TPP-22211 輕鏈 DIQLTQSPSSLSASVGDRVTITCSASQDISNYLNWYQQKPGKAPKVLIYFTSSLHSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQYSTVPWTFGQGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC 121
TPP-22211 重鏈 QVQLVESGGGLVQPGGSLRLSCAASGYDFTHYGMNWVRQAPGKGLEWVGWINTYTGEPTYAADFKRRFTFSLDTSKSTAYLQMNSLRAEDTAVYYCAKYPYYYGTSHWYFDVWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGGGGGSGGGGSDIQMTQSPSSLSASVGDRVTITCRTSENVYSNLAWYQQKPGKAPKLLIYAASNLQSGVPSRFSGSGSGTDYTFTISSLQPEDIATYYCQHFWGSPFTFGCGTKLEIKGGSEGKSSGSGSESKSTGGSQVQLVQSGAEVKKPGASVKVSCKASGYTFTNYDIIWVRQAPGQCLEWMGYINPYNDGTKYNEKFKGRVTMTRDTSTSTVYMELSSLRSEDTAVYYCARLLKYRRFRYYAIDYWGQGTTVTVSS 122
TPP-22212 輕鏈 DIQLTQSPSSLSASVGDRVTITCSASQDISNYLNWYQQKPGKAPKVLIYFTSSLHSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQYSTVPWTFGQGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC 123
TPP-22212 重鏈 EVQLVQSGGGLVQPGGSLRLSCAASGYDFTHYGMNWVRQAPGKGLEWVGWINTYTGEPTYAADFKRRFTFSLDTSKSTAYLQMNSLRAEDTAVYYCAKYPYYYGTSHWYFDVWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGGGGGSGGGGSDIQMTQSPSSLSASVGDRVTITCRTSENVYSNLAWYQQKPGKAPKLLIYAASNLQSGVPSRFSGSGSGTDYTFTISSLQPEDIATYYCQHFWGSPFTFGCGTKLEIKGGSEGKSSGSGSESKSTGGSQVQLVQSGAEVKKPGASVKVSCKASGYTFTNYDIIWVRQAPGQCLEWMGYINPYNDGTKYNEKFKGRVTMTRDTSTSTVYMELSSLRSEDTAVYYCARLLKYRRFRYYAIDYWGQGTTVTVSS 124
TPP-22213 輕鏈 DIQLTQSPSSLSASVGDRVTITCSASQDISNYLNWYQQKPGKAPKVLIYFTSSLHSGVPSRFSGSGSGTGFTLTISSLQPEDFATYYCQQYSTVPWTFGQGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC 125
TPP-22213 重鏈 EVQLVESGGGLVQPGGSLRLSCAASGYDFTHYGMNWVRQAPGKGLEWVGWINTYTGEPTYAADFKRRFTFSLDTSKSTAYLQMNSLRAEDTAVYYCAKYPYYYGTSHWYFDVWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGGGGGSGGGGSDIQMTQSPSSLSASVGDRVTITCRTSENVYSNLAWYQQKPGKAPKLLIYAASNLQSGVPSRFSGSGSGTDYTFTISSLQPEDIATYYCQHFWGSPFTFGCGTKLEIKGGSEGKSSGSGSESKSTGGSQVQLVQSGAEVKKPGASVKVSCKASGYTFTNYDIIWVRQAPGQCLEWMGYINPYNDGTKYNEKFKGRVTMTRDTSTSTVYMELSSLRSEDTAVYYCARLLKYRRFRYYAIDYWGQGTTVTVSS 126
TPP-22214 輕鏈 DIQLTQSPSSLSASVGDRVTITCSASQDISNYLNWYQQKPGKAPKVLIYFTSSLHSGVPSRFSGSGSGTGFTLTISSLQPEDFATYYCQQYSTVPWTFGQGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC 127
TPP-22214 重鏈 QVQLVESGGGLVQPGGSLRLSCAASGYDFTHYGMNWVRQAPGKGLEWVGWINTYTGEPTYAADFKRRFTFSLDTSKSTAYLQMNSLRAEDTAVYYCAKYPYYYGTSHWYFDVWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGGGGGSGGGGSDIQMTQSPSSLSASVGDRVTITCRTSENVYSNLAWYQQKPGKAPKLLIYAASNLQSGVPSRFSGSGSGTDYTFTISSLQPEDIATYYCQHFWGSPFTFGCGTKLEIKGGSEGKSSGSGSESKSTGGSQVQLVQSGAEVKKPGASVKVSCKASGYTFTNYDIIWVRQAPGQCLEWMGYINPYNDGTKYNEKFKGRVTMTRDTSTSTVYMELSSLRSEDTAVYYCARLLKYRRFRYYAIDYWGQGTTVTVSS 128
TPP-22215 輕鏈 DIQLTQSPSSLSASVGDRVTITCSASQDISNYLNWYQQKPGKAPKVLIYFTSSLHSGVPSRFSGSGSGTGFTLTISSLQPEDFATYYCQQYSTVPWTFGQGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC 129
TPP-22215 重鏈 EVQLVQSGGGLVQPGGSLRLSCAASGYDFTHYGMNWVRQAPGKGLEWVGWINTYTGEPTYAADFKRRFTFSLDTSKSTAYLQMNSLRAEDTAVYYCAKYPYYYGTSHWYFDVWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGGGGGSGGGGSDIQMTQSPSSLSASVGDRVTITCRTSENVYSNLAWYQQKPGKAPKLLIYAASNLQSGVPSRFSGSGSGTDYTFTISSLQPEDIATYYCQHFWGSPFTFGCGTKLEIKGGSEGKSSGSGSESKSTGGSQVQLVQSGAEVKKPGASVKVSCKASGYTFTNYDIIWVRQAPGQCLEWMGYINPYNDGTKYNEKFKGRVTMTRDTSTSTVYMELSSLRSEDTAVYYCARLLKYRRFRYYAIDYWGQGTTVTVSS 130
TPP-22216 輕鏈 DIQLTQSPSSLSASVGDRVTITCSASQDISNYLNWYQQKPGKAPKVLIYFTSSLHSGVPSRFSGSGSGTGFTLTISSLQPEDFATYYCQQYSTVPWTFGQGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC 131
TPP-22216 重鏈 QVQLVQSGGGLVQPGGSLRLSCAASGYDFTHYGMNWVRQAPGKGLEWVGWINTYTGEPTYAADFKRRFTFSLDTSKSTAYLQMNSLRAEDTAVYYCAKYPYYYGTSHWYFDVWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGGGGGSGGGGSDIQMTQSPSSLSASVGDRVTITCRTSENVYSNLAWYQQKPGKAPKLLIYAASNLQSGVPSRFSGSGSGTDYTFTISSLQPEDIATYYCQHFWGSPFTFGCGTKLEIKGGSEGKSSGSGSESKSTGGSQVQLVQSGAEVKKPGASVKVSCKASGYTFTNYDIIWVRQAPGQCLEWMGYINPYNDGTKYNEKFKGRVTMTRDTSTSTVYMELSSLRSEDTAVYYCARLLKYRRFRYYAIDYWGQGTTVTVSS 132
TPP-22217 輕鏈 DIQLTQSPSSLSASVGDRVTITCSASQDISNYLNWYQQKPGKAPKVLIYFTSSLHSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQYSTVPWTFGQGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC 133
TPP-22217 重鏈 QVQLVESGGGLVQPGGSLRLSCAASGYDFTHYGMNWVRQAPGKGLEWVGWINTYTGEPTYAADFKRRFTFSLDTSKSTAYLQMNSLRAEDTAVYYCAKYPYYYGTSHWYFDVWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGGGGGSGGGGSGGGGSGGGGSDIQMTQSPSSLSASVGDRVTITCRTSENVYSNLAWYQQKPGKAPKLLIYAASNLQSGVPSRFSGSGSGTDYTFTISSLQPEDIATYYCQHFWGSPFTFGCGTKLEIKGGSEGKSSGSGSESKSTGGSQVQLVQSGAEVKKPGASVKVSCKASGYTFTNYDIIWVRQAPGQCLEWMGYINPYNDGTKYNEKFKGRVTMTRDTSTSTVYMELSSLRSEDTAVYYCARLLKYRRFRYYAIDYWGQGTTVTVSS 134
TPP-22218 輕鏈 DIQLTQSPSSLSASVGDRVTITCSASQDISNYLNWYQQKPGKAPKVLIYFTSSLHSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQYSTVPWTFGQGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC 135
TPP-22218 重鏈 EVQLVQSGGGLVQPGGSLRLSCAASGYDFTHYGMNWVRQAPGKGLEWVGWINTYTGEPTYAADFKRRFTFSLDTSKSTAYLQMNSLRAEDTAVYYCAKYPYYYGTSHWYFDVWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGGGGGSGGGGSGGGGSGGGGSDIQMTQSPSSLSASVGDRVTITCRTSENVYSNLAWYQQKPGKAPKLLIYAASNLQSGVPSRFSGSGSGTDYTFTISSLQPEDIATYYCQHFWGSPFTFGCGTKLEIKGGSEGKSSGSGSESKSTGGSQVQLVQSGAEVKKPGASVKVSCKASGYTFTNYDIIWVRQAPGQCLEWMGYINPYNDGTKYNEKFKGRVTMTRDTSTSTVYMELSSLRSEDTAVYYCARLLKYRRFRYYAIDYWGQGTTVTVSS 136
TPP-22219 輕鏈 DIQLTQSPSSLSASVGDRVTITCSASQDISNYLNWYQQKPGKAPKVLIYFTSSLHSGVPSRFSGSGSGTGFTLTISSLQPEDFATYYCQQYSTVPWTFGQGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC 137
TPP-22219 重鏈 EVQLVESGGGLVQPGGSLRLSCAASGYDFTHYGMNWVRQAPGKGLEWVGWINTYTGEPTYAADFKRRFTFSLDTSKSTAYLQMNSLRAEDTAVYYCAKYPYYYGTSHWYFDVWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGGGGGSGGGGSGGGGSGGGGSDIQMTQSPSSLSASVGDRVTITCRTSENVYSNLAWYQQKPGKAPKLLIYAASNLQSGVPSRFSGSGSGTDYTFTISSLQPEDIATYYCQHFWGSPFTFGCGTKLEIKGGSEGKSSGSGSESKSTGGSQVQLVQSGAEVKKPGASVKVSCKASGYTFTNYDIIWVRQAPGQCLEWMGYINPYNDGTKYNEKFKGRVTMTRDTSTSTVYMELSSLRSEDTAVYYCARLLKYRRFRYYAIDYWGQGTTVTVSS 138
TPP-22220 輕鏈 DIQLTQSPSSLSASVGDRVTITCSASQDISNYLNWYQQKPGKAPKVLIYFTSSLHSGVPSRFSGSGSGTGFTLTISSLQPEDFATYYCQQYSTVPWTFGQGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC 139
TPP-22220 重鏈 QVQLVESGGGLVQPGGSLRLSCAASGYDFTHYGMNWVRQAPGKGLEWVGWINTYTGEPTYAADFKRRFTFSLDTSKSTAYLQMNSLRAEDTAVYYCAKYPYYYGTSHWYFDVWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGGGGGSGGGGSGGGGSGGGGSDIQMTQSPSSLSASVGDRVTITCRTSENVYSNLAWYQQKPGKAPKLLIYAASNLQSGVPSRFSGSGSGTDYTFTISSLQPEDIATYYCQHFWGSPFTFGCGTKLEIKGGSEGKSSGSGSESKSTGGSQVQLVQSGAEVKKPGASVKVSCKASGYTFTNYDIIWVRQAPGQCLEWMGYINPYNDGTKYNEKFKGRVTMTRDTSTSTVYMELSSLRSEDTAVYYCARLLKYRRFRYYAIDYWGQGTTVTVSS 140
TPP-22221 輕鏈 DIQLTQSPSSLSASVGDRVTITCSASQDISNYLNWYQQKPGKAPKVLIYFTSSLHSGVPSRFSGSGSGTGFTLTISSLQPEDFATYYCQQYSTVPWTFGQGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC 141
TPP-22221 重鏈 EVQLVQSGGGLVQPGGSLRLSCAASGYDFTHYGMNWVRQAPGKGLEWVGWINTYTGEPTYAADFKRRFTFSLDTSKSTAYLQMNSLRAEDTAVYYCAKYPYYYGTSHWYFDVWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGGGGGSGGGGSGGGGSGGGGSDIQMTQSPSSLSASVGDRVTITCRTSENVYSNLAWYQQKPGKAPKLLIYAASNLQSGVPSRFSGSGSGTDYTFTISSLQPEDIATYYCQHFWGSPFTFGCGTKLEIKGGSEGKSSGSGSESKSTGGSQVQLVQSGAEVKKPGASVKVSCKASGYTFTNYDIIWVRQAPGQCLEWMGYINPYNDGTKYNEKFKGRVTMTRDTSTSTVYMELSSLRSEDTAVYYCARLLKYRRFRYYAIDYWGQGTTVTVSS 142
TPP-22222 輕鏈 DIQLTQSPSSLSASVGDRVTITCSASQDISNYLNWYQQKPGKAPKVLIYFTSSLHSGVPSRFSGSGSGTGFTLTISSLQPEDFATYYCQQYSTVPWTFGQGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC 143
TPP-22222 重鏈    QVQLVQSGGGLVQPGGSLRLSCAASGYDFTHYGMNWVRQAPGKGLEWVGWINTYTGEPTYAADFKRRFTFSLDTSKSTAYLQMNSLRAEDTAVYYCAKYPYYYGTSHWYFDVWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGGGGGSGGGGSGGGGSGGGGSDIQMTQSPSSLSASVGDRVTITCRTSENVYSNLAWYQQKPGKAPKLLIYAASNLQSGVPSRFSGSGSGTDYTFTISSLQPEDIATYYCQHFWGSPFTFGCGTKLEIKGGSEGKSSGSGSESKSTGGSQVQLVQSGAEVKKPGASVKVSCKASGYTFTNYDIIWVRQAPGQCLEWMGYINPYNDGTKYNEKFKGRVTMTRDTSTSTVYMELSSLRSEDTAVYYCARLLKYRRFRYYAIDYWGQGTTVTVSS 144
VEGF結合劑蘭尼單抗(Ranibizumab) L-CDR1 S A S Q D I S N Y L N 145
VEGF結合劑蘭尼單抗 L-CDR2 F T S S L H S 146
VEGF結合劑蘭尼單抗 L-CDR3 Q Q Y S T V P W T 147
VEGF結合劑蘭尼單抗 H-CDR1 (CCG) G Y D F T H Y G M N 148
VEGF結合劑蘭尼單抗 H-CDR2 (CCG) W I N T Y T G E P T Y A A D F K R 149
VEGF結合劑蘭尼單抗 H-CDR3 (CCG) Y P Y Y Y G T S H W Y F D V 150
VEGF結合劑蘭尼單抗 H-CDR1 (Kabat) H Y G M N 151
VEGF結合劑蘭尼單抗 H-CDR2 (Kabat) W I N T Y T G E P T Y A A D F K R 152
VEGF結合劑蘭尼單抗 H-CDR3 (Kabat) Y P Y Y Y G T S H W Y F D V 153
VEGF結合劑蘭尼單抗 H-CDR1 (Chothia) G Y D F T H Y 154
VEGF結合劑蘭尼單抗 H-CDR2 (Chothia) N T Y T G E 155
VEGF結合劑蘭尼單抗 H-CDR3 (Chothia) Y P Y Y Y G T S H W Y F D V 156
VEGF結合劑B20 L-CDR1 R A S Q V I R R S L A 157
VEGF結合劑B20 L-CDR2 A A S N L A S 158
VEGF結合劑B20 L-CDR3 Q Q S N T S P L T 159
VEGF結合劑B20 H-CDR1 (CCG) G F T I N A S W I H 160
VEGF結合劑B20 H-CDR2 (CCG) A I Y P Y S G Y T N Y A D S V K G 161
VEGF結合劑B20 H-CDR3 (CCG) W G H S T S P W A M D Y 162
VEGF結合劑B20 H-CDR1 (Kabat) A S W I H 163
VEGF結合劑B20 H-CDR2 (Kabat) A I Y P Y S G Y T N Y A D S V K G 164
VEGF結合劑B20 H-CDR3 (Kabat) W G H S T S P W A M D Y 165
VEGF結合劑B20 H-CDR1 (Chothia) G F T I N A S 166
VEGF結合劑B20 H-CDR2 (Chothia) Y P Y S G Y 167
VEGF結合劑B20 H-CDR3 (Chothia) W G H S T S P W A M D Y 168
VEGF結合劑G6 L-CDR1 R A S Q D V S T A V A 169
VEGF結合劑G6 L-CDR2 S A S F L Y S 170
VEGF結合劑G6 L-CDR3 Q Q S Y T T P P T 171
VEGF結合劑G6 H-CDR1 (CCG) G F T I S D Y W I H 172
VEGF結合劑G6 H-CDR2 (CCG) G I T P A G G Y T Y Y A D S V K G 173
VEGF結合劑G6 H-CDR3 (CCG) F V F F L P Y A M D Y 174
VEGF結合劑G6 H-CDR1 (Kabat) D Y W I H 175
VEGF結合劑G6 H-CDR2 (Kabat) G I T P A G G Y T Y Y A D S V K G 176
VEGF結合劑G6 H-CDR3 (Kabat) F V F F L P Y A M D Y 177
VEGF結合劑G6 H-CDR1 (Chothia) G F T I S D Y 178
VEGF結合劑G6 H-CDR2 (Chothia) T P A G G Y 179
VEGF結合劑G6 H-CDR3 (Chothia) F V F F L P Y A M D Y 180
VEGF結合劑B20 可變輕鏈(VL) DIQMTQSPSSLSASVGDRVTITCRASQVIRRSLAWYQQKPGKAPKLLIYAASNLASGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQSNTSPLTFGQGTKVEIK 181
VEGF結合劑B20 可變重鏈(VH) EVQLVESGGGLVQPGGSLRLSCAASGFTINASWIHWVRQAPGKGLEWVGAIYPYSGYTNYADSVKGRFTISADTSKNTAYLQMNSLRAEDTAVYYCARWGHSTSPWAMDYWGQGTLVTVSS 182
VEGF結合劑G6 可變輕鏈(VL) DIQMTQSPSSLSASVGDRVTITCRASQDVSTAVAWYQQKPGKAPKLLIYSASFLYSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQSYTTPPTFGQGTKVEIK 183
VEGF結合劑G6 可變重鏈(VH) EVQLVESGGGLVQPGGSLRLSCAASGFTISDYWIHWVRQAPGKGLEWVAGITPAGGYTYYADSVKGRFTISADTSKNTAYLQMNSLRAEDTAVYYCARFVFFLPYAMDYWGQGTLVTVSS 184
VEGF結合劑B20 輕鏈 DIQMTQSPSSLSASVGDRVTITCRASQVIRRSLAWYQQKPGKAPKLLIYAASNLASGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQSNTSPLTFGQGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC 185
VEGF結合劑B20 重鏈 EVQLVESGGGLVQPGGSLRLSCAASGFTINASWIHWVRQAPGKGLEWVGAIYPYSGYTNYADSVKGRFTISADTSKNTAYLQMNSLRAEDTAVYYCARWGHSTSPWAMDYWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPG 186
VEGF結合劑G6 輕鏈 DIQMTQSPSSLSASVGDRVTITCRASQDVSTAVAWYQQKPGKAPKLLIYSASFLYSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQSYTTPPTFGQGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC 187
VEGF結合劑G6 重鏈 EVQLVESGGGLVQPGGSLRLSCAASGFTISDYWIHWVRQAPGKGLEWVAGITPAGGYTYYADSVKGRFTISADTSKNTAYLQMNSLRAEDTAVYYCARFVFFLPYAMDYWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPG 188
VEGF結合劑蘭尼單抗 可變輕鏈(VL) DIQLTQSPSSLSASVGDRVTITCSASQDISNYLNWYQQKPGKAPKVLIYFTSSLHSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQYSTVPWTFGQGTKVEIK 189
VEGF結合劑蘭尼單抗 可變重鏈(VH) EVQLVESGGGLVQPGGSLRLSCAASGYDFTHYGMNWVRQAPGKGLEWVGWINTYTGEPTYAADFKRRFTFSLDTSKSTAYLQMNSLRAEDTAVYYCAKYPYYYGTSHWYFDVWGQGTLVTVSS 190
VEGF結合劑蘭尼單抗(1Q) 可變重鏈(VH) QVQLVESGGGLVQPGGSLRLSCAASGYDFTHYGMNWVRQAPGKGLEWVGWINTYTGEPTYAADFKRRFTFSLDTSKSTAYLQMNSLRAEDTAVYYCAKYPYYYGTSHWYFDVWGQGTLVTVSS 191
VEGF結合劑蘭尼單抗(6Q) 可變重鏈(VH) EVQLVQSGGGLVQPGGSLRLSCAASGYDFTHYGMNWVRQAPGKGLEWVGWINTYTGEPTYAADFKRRFTFSLDTSKSTAYLQMNSLRAEDTAVYYCAKYPYYYGTSHWYFDVWGQGTLVTVSS 192
VEGF結合劑蘭尼單抗(70G) 可變輕鏈(VL) DIQLTQSPSSLSASVGDRVTITCSASQDISNYLNWYQQKPGKAPKVLIYFTSSLHSGVPSRFSGSGSGTGFTLTISSLQPEDFATYYCQQYSTVPWTFGQGTKVEIK 193
VEGF結合劑蘭尼單抗(1Q/6Q) 可變重鏈(VH) QVQLVQSGGGLVQPGGSLRLSCAASGYDFTHYGMNWVRQAPGKGLEWVGWINTYTGEPTYAADFKRRFTFSLDTSKSTAYLQMNSLRAEDTAVYYCAKYPYYYGTSHWYFDVWGQGTLVTVSS 194
VEGF結合劑蘭尼單抗 輕鏈 DIQLTQSPSSLSASVGDRVTITCSASQDISNYLNWYQQKPGKAPKVLIYFTSSLHSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQYSTVPWTFGQGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC 195
VEGF結合劑蘭尼單抗 重鏈 EVQLVESGGGLVQPGGSLRLSCAASGYDFTHYGMNWVRQAPGKGLEWVGWINTYTGEPTYAADFKRRFTFSLDTSKSTAYLQMNSLRAEDTAVYYCAKYPYYYGTSHWYFDVWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPG 196
VEGF結合劑蘭尼單抗(1Q) 重鏈 QVQLVESGGGLVQPGGSLRLSCAASGYDFTHYGMNWVRQAPGKGLEWVGWINTYTGEPTYAADFKRRFTFSLDTSKSTAYLQMNSLRAEDTAVYYCAKYPYYYGTSHWYFDVWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPG 197
VEGF結合劑蘭尼單抗(6Q) 重鏈 EVQLVQSGGGLVQPGGSLRLSCAASGYDFTHYGMNWVRQAPGKGLEWVGWINTYTGEPTYAADFKRRFTFSLDTSKSTAYLQMNSLRAEDTAVYYCAKYPYYYGTSHWYFDVWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPG 198
VEGF結合劑蘭尼單抗(70G) 輕鏈 DIQLTQSPSSLSASVGDRVTITCSASQDISNYLNWYQQKPGKAPKVLIYFTSSLHSGVPSRFSGSGSGTGFTLTISSLQPEDFATYYCQQYSTVPWTFGQGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC 199
VEGF結合劑蘭尼單抗(1Q/6Q) 重鏈 QVQLVQSGGGLVQPGGSLRLSCAASGYDFTHYGMNWVRQAPGKGLEWVGWINTYTGEPTYAADFKRRFTFSLDTSKSTAYLQMNSLRAEDTAVYYCAKYPYYYGTSHWYFDVWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPG 200
TrkB結合劑C2 L-CDR1 R T S E N V Y S N L A 201
TrkB結合劑C2 L-CDR2 A A S N L Q S 202
TrkB結合劑C2 L-CDR3 Q H F W G S P F T 203
TrkB結合劑C2 H-CDR1 (CCG) G Y T F T N Y D I I 204
TrkB結合劑C2 H-CDR2 (CCG) Y I N P Y N D G T K Y N E K F K G 205
TrkB結合劑C2 H-CDR3 (CCG) L L K Y R R F R Y Y A I D Y 206
TrkB結合劑C2 H-CDR1 (Kabat) N Y D I I 207
TrkB結合劑C2 H-CDR2 (Kabat) Y I N P Y N D G T K Y N E K F K G 208
TrkB結合劑C2 H-CDR3 (Kabat) L L K Y R R F R Y Y A I D Y 209
TrkB結合劑C2 H-CDR1 (Chothia) G Y T F T N Y 210
TrkB結合劑C2 H-CDR2 (Chothia) N P Y N D G 211
TrkB結合劑C2 H-CDR3 (Chothia) L L K Y R R F R Y Y A I D Y 212
TrkB結合劑C2 (100C) 可變輕鏈(VL) DIQMTQSPSSLSASVGDRVTITCRTSENVYSNLAWYQQKPGKAPKLLIYAASNLQSGVPSRFSGSGSGTDYTFTISSLQPEDIATYYCQHFWGSPFTFGCGTKLEIK 213
TrkB結合劑C2 (44C) 可變重鏈(VH) QVQLVQSGAEVKKPGASVKVSCKASGYTFTNYDIIWVRQAPGQCLEWMGYINPYNDGTKYNEKFKGRVTMTRDTSTSTVYMELSSLRSEDTAVYYCARLLKYRRFRYYAIDYWGQGTTVTVSS 214
TrkB結合劑C2 可變輕鏈(VL) DIQMTQSPSSLSASVGDRVTITCRTSENVYSNLAWYQQKPGKAPKLLIYAASNLQSGVPSRFSGSGSGTDYTFTISSLQPEDIATYYCQHFWGSPFTFGQGTKLEIK 215
TrkB結合劑C2 可變重鏈(VH) QVQLVQSGAEVKKPGASVKVSCKASGYTFTNYDIIWVRQAPGQGLEWMGYINPYNDGTKYNEKFKGRVTMTRDTSTSTVYMELSSLRSEDTAVYYCARLLKYRRFRYYAIDYWGQGTTVTVSS 216
6GS GGSGGS 217
10L1 GGGGSGGGGS 218
15L1 GGGGSGGGGSGGGGS 219
20L1 GGGGSGGGGSGGGGSGGGGS 220
20L3 GGSEGKSSGSGSESKSTGGS 221
TrkB結合劑 VL-VH (44C/100C) DIQMTQSPSSLSASVGDRVTITCRTSENVYSNLAWYQQKPGKAPKLLIYAASNLQSGVPSRFSGSGSGTDYTFTISSLQPEDIATYYCQHFWGSPFTFGCGTKLEIKGGSEGKSSGSGSESKSTGGSQVQLVQSGAEVKKPGASVKVSCKASGYTFTNYDIIWVRQAPGQCLEWMGYINPYNDGTKYNEKFKGRVTMTRDTSTSTVYMELSSLRSEDTAVYYCARLLKYRRFRYYAIDYWGQGTTVTVSS 222
TrkB結合劑 VH-VL (44C/100C) QVQLVQSGAEVKKPGASVKVSCKASGYTFTNYDIIWVRQAPGQCLEWMGYINPYNDGTKYNEKFKGRVTMTRDTSTSTVYMELSSLRSEDTAVYYCARLLKYRRFRYYAIDYWGQGTTVTVSSGGSEGKSSGSGSESKSTGGSDIQMTQSPSSLSASVGDRVTITCRTSENVYSNLAWYQQKPGKAPKLLIYAASNLQSGVPSRFSGSGSGTDYTFTISSLQPEDIATYYCQHFWGSPFTFGCGTKLEIK 223
TrkB結合劑 VL-VH DIQMTQSPSSLSASVGDRVTITCRTSENVYSNLAWYQQKPGKAPKLLIYAASNLQSGVPSRFSGSGSGTDYTFTISSLQPEDIATYYCQHFWGSPFTFGQGTKLEIKGGSEGKSSGSGSESKSTGGSQVQLVQSGAEVKKPGASVKVSCKASGYTFTNYDIIWVRQAPGQGLEWMGYINPYNDGTKYNEKFKGRVTMTRDTSTSTVYMELSSLRSEDTAVYYCARLLKYRRFRYYAIDYWGQGTTVTVSS 224
TrkB結合劑 VH-VL QVQLVQSGAEVKKPGASVKVSCKASGYTFTNYDIIWVRQAPGQGLEWMGYINPYNDGTKYNEKFKGRVTMTRDTSTSTVYMELSSLRSEDTAVYYCARLLKYRRFRYYAIDYWGQGTTVTVSSGGSEGKSSGSGSESKSTGGSDIQMTQSPSSLSASVGDRVTITCRTSENVYSNLAWYQQKPGKAPKLLIYAASNLQSGVPSRFSGSGSGTDYTFTISSLQPEDIATYYCQHFWGSPFTFGQGTKLEIK 225
4GS GGGS 227
在另一實施例中，本發明之結合分子或TrkB結合分子可基於下文揭示之TrkB結合劑(其亦揭示於WO2018/224630中)中之任一者。
表2：
TrkB結合劑 277 L-CDR1 k s s q s l l y s s n q k n y l a 228
TrkB結合劑 277 L-CDR2 W A S T R E S 229
TrkB結合劑 277 L-CDR3 Q Q Y Y S Y P Y T 230
TrkB結合劑 277 H-CDR1 (CCG) G Y T F T G Y W M H 231
TrkB結合劑 277 H-CDR2 (CCG) Y I N P S T D Y T E Y N Q K F K D 232
TrkB結合劑 277 H-CDR3 (CCG) S R T G N Y 233
TrkB結合劑 277 H-CDR1 (Kabat) G Y W M H 234
TrkB結合劑 277 H-CDR2 (Kabat) Y I N P S T D Y T E Y N Q K F K D 235
TrkB結合劑 277 H-CDR3 (Kabat) S R T G N Y 236
TrkB結合劑 277 H-CDR1 (Chothia) G Y T F T G Y 237
TrkB結合劑 277 H-CDR2 (Chothia) N P S T D Y 238
TrkB結合劑 277 H-CDR3 (Chothia) S R T G N Y 239
TrkB結合劑 277-gr_VL，(人源化)可變輕鏈 DIVMTQSPDSLAVSLGERATINCKSSQSLLYSSNQKNYLAWYQQKPGQPPKLLIYWASTRESGVPDRFSGSGSGTDFTLTISSLQAEDVAVYYCQQYYSYPYTFGQGTKLEIK 240
TrkB結合劑 277-gr_VH，(人源化)可變重鏈 QVQLVQSGAEVKKPGASVKVSCKASGYTFTGYWMHWVRQAPGQGLEWMGYINPSTDYTEYNQKFKDRVTMTRDTSTSTVYMELSSLRSEDTAVYYCARSRTGNYWGQGTLVTVSS 241
TrkB結合劑 277-33_VL：(人源化)可變輕鏈 DIVMTQSPDSLAVSLGERATISCKSSQSLLYSSNQKNYLAWYQQKPGQPPKLLIYWASTRESGVPDRFSGSGSGTDFTLTISSLQAEDVAVYYCQQYYSYPYTFGGGTKLEIK 242
TrkB結合劑 277-33_VH，(人源化)可變重鏈 QVQLVQSGAEVKKPGASVKVSCKASGYTFTGYWMHWVRQRPGQGLEWIGYINPSTDYTEYNQKFKDRVTLTRDTSTSTVYMELSSLTSEDTAVYYCARSRTGNYWGQGTTVTVSS 243
TrkB結合劑 277-35_VL：(人源化)可變輕鏈 DIVMTQSPDSLAVSLGERATISCKSSQSLLYSSNQKNYLAWYQQKPGQPPKLLIYWASTRESGVPDRFSGSGSGTDFTLTISSLQAEDVAVYYCQQYYSYPYTFGGGTKLEIK 244
TrkB結合劑 277-35_VH，(人源化)可變重鏈 QVQLVQSGAEVKKPGASVKVSCKASGYTFTGYWMHWVRQRPGQGLEWIGYINPSTDYTEYNQKFKDRVTLTRDTSTSTVYMELSSLRSEDTAVYYCARSRTGNYWGQGTTVTVSS 245
TrkB binder 277-42_VL，(人源化)可變輕鏈 DIVMTQSPDSLAVSLGERATINCKSSQSLLYSSNQKNYLAWYQQKPGQPPKLLIYWASTRESGVPDRFSGSGSGTDFTLTISSLQAEDVAVYYCQQYYSYPYTFGGGTKLEIK 246
TrkB結合劑 277-42_VH，(人源化)可變重鏈 QVQLVQSGAEVKKPGASVKVSCKASGYTFTGYWMHWVRQRPGQGLEWIGYINPSTDYTEYNQKFKDRVTLTRDTSTSTVYMELSSLRSEDTAVYYCARSRTGNYWGQGTTVTVSS 247
TrkB結合劑 277-44_VL，(人源化)可變輕鏈 DIVMTQSPDSLAVSLGERATINCKSSQSLLYSSNQKNYLAWYQQKPGQSPKLLIYWASTRESGVPDRFSGSGSGTDFTLTISSLQAEDVAVYYCQQYYSYPYTFGQGTKLEIK 248
TrkB結合劑 277-44_VH，(人源化)可變重鏈 QVQLVQSGAEVKKPGASVKVSCKASGYTFTGYWMHWVRQAPGQGLEWIGYINPSTDYTEYNQKFKDRVTMTRDTSTSTVYMELSSLTSEDTAVYYCARSRTGNYWGQGTTVTVSS 249
TrkB結合劑 277-48_VL，(人源化)可變輕鏈 DIVMTQSPDSLAVSLGERATINCKSSQSLLYSSNQKNYLAWYQQKPGQPPKLLIYWASTRESGVPDRFSGSGSGTDFTLTISSLQAEDVAVYYCQQYYSYPYTFGQGTKLEIK 250
TrkB結合劑 277-48_VH，(人源化)可變重鏈 QVQLVQSGAEVKKPGASVKVSCKASGYTFTGYWMHWVRQRPGQGLEWIGYINPSTDYTEYNQKFKDRVTMTRDTSTSTVYMELSSLRSEDTAVYYCARSRTGNYWGQGTTVTVS 251
TrkB結合劑 277-51_VL，(人源化)可變輕鏈 DIVMTQSPDSLAVSLGERATISCKSSQSLLYSSNQKNYLAWYQQKPGQPPKLLIYWASTRESGVPDRFSGSGSGTDFTLTISSLQAEDVAVYYCQQYYSYPYTFGGGTKLEIK 252
TrkB結合劑 277-51_VH，(人源化)可變重鏈 QVQLVQSGAEVKKPGASVKVSCKASGYTFTGYWMHWVRQRPGQGLEWIGYINPSTDYTEYNQKFKDRATLTRDTSTSTVYMELSSLRSEDTAVYYCARSRTGNYWGQGTTVTVSS 253
TrkB結合劑 277-64_VL，(人源化)可變輕鏈 DIVMTQSPDSLAVSLGERATISCKSSQSLLYSSNQKNYLAWYQQKPGQPPKLLIYWASTRESGVPDRFSGSGSGTDFTLTISSLQAEDVAVYYCQQYYSYPYTFGQGTKLEIK 254
TrkB結合劑 277-64_VH，(人源化)可變重鏈 QVQLVQSGAEVKKPGASVKVSCKASGYTFTGYWMHWVRQAPGQGLEWIGYINPSTDYTEYNQKFKDRVTMTRDTSTSTVYMELSSLRSEDTAVYYCARSRTGNYWGQGTTVTVSS 255
TrkB結合劑 277-67_VL，(人源化)可變輕鏈 DIVMTQSPDSLAVSLGERATINCKSSQSLLYSSNQKNYLAWYQQKPGQSPKLLIYWASTRESGVPDRFSGSGSGTDFTLTISSLQAEDVAVYYCQQYYSYPYTFGQGTKLEIK 256
TrkB結合劑 277-67_VH，(人源化)可變重鏈 QVQLVQSGAEVKKPGASVKVSCKASGYTFTGYWMHWVRQAPGQGLEWIGYINPSTDYTEYNQKFKDRVTMTRDTSTSTVYMELSSLRSEDTAVYYCARSRTGNYWGQGTTVTVSS 257
在一較佳實施例中，結合分子包含至少一個與血管內皮生長因子(VEGF)特異性結合之抗原結合位點及至少一個與肌旋蛋白受體激酶B (TrkB)特異性結合之抗原結合位點，其中與TrkB特異性結合之抗原結合位點包含：輕鏈CDR，其包含SEQ ID NO:201 (CDR1)、SEQ ID NO:202 (CDR2)及SEQ ID NO:203 (CDR3)的胺基酸序列或由其組成；及重鏈CDR，其包含SEQ ID NO:204 (CDR1)、SEQ ID NO:205 (CDR2)及SEQ ID NO:206 (CDR3)的胺基酸序列或由其組成；或重鏈CDR，其包含SEQ ID NO:207 (CDR1)、SEQ ID NO:208 (CDR2)及SEQ ID NO:209 (CDR3)的胺基酸序列或由其組成；或重鏈CDR，其包含SEQ ID NO:210 (CDR1)、SEQ ID NO:211 (CDR2)及SEQ ID NO:212 (CDR3)的胺基酸序列或由其組成；且其中與VEGF特異性結合之抗原結合位點包含：輕鏈CDR，其包含SEQ ID NO:145 (CDR1)、SEQ ID NO:146 (CDR2)及SEQ ID NO:147 (CDR3)的胺基酸序列或由其組成；及重鏈CDR，其包含SEQ ID NO:148 (CDR1)、SEQ ID NO:149 (CDR2)及SEQ ID NO:150 (CDR3)的胺基酸序列或由其組成；或重鏈CDR，其包含SEQ ID NO:151 (CDR1)、SEQ ID NO:152 (CDR2)及SEQ ID NO:153 (CDR3)的胺基酸序列或由其組成；或重鏈CDR，其包含SEQ ID NO:154 (CDR1)、SEQ ID NO:155 (CDR2)及SEQ ID NO:156 (CDR3)的胺基酸序列或由其組成。
在一另外較佳實施例中，結合分子包含至少一個與血管內皮生長因子(VEGF)特異性結合之抗原結合位點及至少一個與肌旋蛋白受體激酶B (TrkB)特異性結合之抗原結合位點，其中與TrkB特異性結合之抗原結合位點包含：輕鏈可變域，其包含與SEQ ID NO:213或215之胺基酸序列至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或至少99%一致的胺基酸序列或由其組成；及重鏈可變域，其包含與SEQ ID NO:214或216之胺基酸序列至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或至少99%一致的胺基酸序列或由其組成；且其中與VEGF特異性結合之抗原結合位點包含：輕鏈可變域，其包含與SEQ ID NO:189或193之胺基酸序列至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或至少99%一致的胺基酸序列或由其組成；及重鏈可變域，其包含與SEQ ID NO:190、191、192或194之胺基酸序列至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或至少99%一致的胺基酸序列或由其組成。
在一另外較佳實施例中，結合分子包含至少一個與血管內皮生長因子(VEGF)特異性結合之抗原結合位點及至少一個與肌旋蛋白受體激酶B (TrkB)特異性結合之抗原結合位點，其中與TrkB特異性結合之抗原結合位點包含：輕鏈可變域，其包含SEQ ID NO:213或215的胺基酸序列或由其組成；及重鏈可變域，其包含SEQ ID NO:214或216的胺基酸序列或由其組成；且其中與VEGF特異性結合之抗原結合位點包含：輕鏈可變域，其包含SEQ ID NO:189或193的胺基酸序列或由其組成；及重鏈可變域，其包含SEQ ID NO:190、191、192或194的胺基酸序列或由其組成。
在一另外較佳實施例中，結合分子包含至少一個與血管內皮生長因子(VEGF)特異性結合之抗原結合位點及至少一個與肌旋蛋白受體激酶B (TrkB)特異性結合之抗原結合位點，其中與TrkB特異性結合之抗原結合位點包含：輕鏈可變域，其包含SEQ ID NO:213的胺基酸序列或由其組成；及重鏈可變域，其包含SEQ ID NO:214的胺基酸序列或由其組成；且其中與VEGF特異性結合之抗原結合位點包含：輕鏈可變域，其包含SEQ ID NO:193的胺基酸序列或由其組成；及重鏈可變域，其包含SEQ ID NO:191的胺基酸序列或由其組成。
在一另外較佳實施例中，結合分子包含至少一個與血管內皮生長因子(VEGF)特異性結合之抗原結合位點及至少一個與肌旋蛋白受體激酶B (TrkB)特異性結合之抗原結合位點，其中與TrkB特異性結合之抗原結合位點包含：輕鏈可變域，其包含與SEQ ID NO:213或215之胺基酸序列至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或至少99%一致的胺基酸序列或由其組成；及重鏈可變域，其包含與SEQ ID NO:214或216之胺基酸序列至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或至少99%一致的胺基酸序列或由其組成，其中輕鏈可變域中的輕鏈CDR由SEQ ID NO:201 (CDR1)、SEQ ID NO:202 (CDR2)及SEQ ID NO:203 (CDR3)的胺基酸序列組成，且重鏈可變域中的重鏈CDR由SEQ ID NO:204 (CDR1)、SEQ ID NO:205 (CDR2)及SEQ ID NO:206 (CDR3)的胺基酸序列組成；或重鏈可變域中的重鏈CDR由SEQ ID NO:207 (CDR1)、SEQ ID NO:208 (CDR2)及SEQ ID NO:209 (CDR3)的胺基酸序列組成；或重鏈可變域中的重鏈CDR由SEQ ID NO:210 (CDR1)、SEQ ID NO:211 (CDR2)及SEQ ID NO:212 (CDR3)的胺基酸序列組成；且其中與VEGF特異性結合之抗原結合位點包含：輕鏈可變域，其包含與SEQ ID NO:189或193之胺基酸序列至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或至少99%一致的胺基酸序列或由其組成；及重鏈可變域，其包含與SEQ ID NO:190、191、192或194之胺基酸序列至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或至少99%一致的胺基酸序列或由其組成，其中輕鏈可變域中的輕鏈CDR由SEQ ID NO:145 (CDR1)、SEQ ID NO:146 (CDR2)及SEQ ID NO:147 (CDR3)的胺基酸序列組成，且重鏈可變域中的重鏈CDR由SEQ ID NO:148 (CDR1)、SEQ ID NO:149 (CDR2)及SEQ ID NO:150 (CDR3)的胺基酸序列組成；或重鏈可變域中的重鏈CDR由SEQ ID NO:151 (CDR1)、SEQ ID NO:152 (CDR2)及SEQ ID NO:153 (CDR3)的胺基酸序列組成；或重鏈可變域中的重鏈CDR由SEQ ID NO:154 (CDR1)、SEQ ID NO:155 (CDR2)及SEQ ID NO:156 (CDR3)的胺基酸序列組成。
在一另外較佳實施例中，結合分子包含至少一個與血管內皮生長因子(VEGF)特異性結合之抗原結合位點及至少一個與肌旋蛋白受體激酶B (TrkB)特異性結合之抗原結合位點，其中與TrkB特異性結合之抗原結合位點包含：輕鏈可變域，其包含SEQ ID NO:213的胺基酸序列或由其組成；及重鏈可變域，其包含SEQ ID NO:214的胺基酸序列或由其組成，其中輕鏈可變域中的輕鏈CDR由SEQ ID NO:201 (CDR1)、SEQ ID NO:202 (CDR2)及SEQ ID NO:203 (CDR3)的胺基酸序列組成；且重鏈可變域中的重鏈CDR由SEQ ID NO:204 (CDR1)、SEQ ID NO:205 (CDR2)及SEQ ID NO:206 (CDR3)的胺基酸序列組成；或重鏈可變域中的重鏈CDR由SEQ ID NO:207 (CDR1)、SEQ ID NO:208 (CDR2)及SEQ ID NO:209 (CDR3)的胺基酸序列組成；或重鏈可變域中的重鏈CDR由SEQ ID NO:210 (CDR1)、SEQ ID NO:211 (CDR2)及SEQ ID NO:212 (CDR3)的胺基酸序列組成；且其中與VEGF特異性結合之抗原結合位點包含：輕鏈可變域，其包含SEQ ID NO:193的胺基酸序列或由其組成；及重鏈可變域，其包含SEQ ID NO:191的胺基酸序列或由其組成，其中輕鏈可變域中的輕鏈CDR由SEQ ID NO:145 (CDR1)、SEQ ID NO:146 (CDR2)及SEQ ID NO:147 (CDR3)的胺基酸序列組成；且重鏈可變域中的重鏈CDR由SEQ ID NO:148 (CDR1)、SEQ ID NO:149 (CDR2)及SEQ ID NO:150 (CDR3)的胺基酸序列組成；或重鏈可變域中的重鏈CDR由SEQ ID NO:151 (CDR1)、SEQ ID NO:152 (CDR2)及SEQ ID NO:153 (CDR3)的胺基酸序列組成；或重鏈可變域中的重鏈CDR由SEQ ID NO:154 (CDR1)、SEQ ID NO:155 (CDR2)及SEQ ID NO:156 (CDR3)的胺基酸序列組成。
在一個實施例中，結合分子包含至少一個與血管內皮生長因子(VEGF)特異性結合之抗原結合位點及至少一個與肌旋蛋白受體激酶B (TrkB)特異性結合之抗原結合位點，其中與TrkB特異性結合之抗原結合位點包含：輕鏈CDR，其包含SEQ ID NO:228 (CDR1)、SEQ ID NO:229 (CDR2)及SEQ ID NO:230 (CDR3)的胺基酸序列或由其組成；及重鏈CDR，其包含SEQ ID NO:231 (CDR1)、SEQ ID NO:232 (CDR2)及SEQ ID NO:23 (CDR3)的胺基酸序列或由其組成；或重鏈CDR，其包含SEQ ID NO:234 (CDR1)、SEQ ID NO:235 (CDR2)及SEQ ID NO:236 (CDR3)的胺基酸序列或由其組成；或重鏈CDR，其包含SEQ ID NO:237 (CDR1)、SEQ ID NO:238 (CDR2)及SEQ ID NO:239 (CDR3)的胺基酸序列或由其組成；且其中與VEGF特異性結合之抗原結合位點包含：輕鏈CDR，其包含SEQ ID NO:145 (CDR1)、SEQ ID NO:146 (CDR2)及SEQ ID NO:147 (CDR3)的胺基酸序列或由其組成；及重鏈CDR，其包含SEQ ID NO:148 (CDR1)、SEQ ID NO:149 (CDR2)及SEQ ID NO:150 (CDR3)的胺基酸序列或由其組成；或重鏈CDR，其包含SEQ ID NO:151 (CDR1)、SEQ ID NO:152 (CDR2)及SEQ ID NO:153 (CDR3)的胺基酸序列或由其組成；或重鏈CDR，其包含SEQ ID NO:154 (CDR1)、SEQ ID NO:155 (CDR2)及SEQ ID NO:156 (CDR3)的胺基酸序列或由其組成。
在另一實施例中，結合分子包含至少一個與血管內皮生長因子(VEGF)特異性結合之抗原結合位點及至少一個與肌旋蛋白受體激酶B (TrkB)特異性結合之抗原結合位點，其中與TrkB特異性結合之抗原結合位點包含輕鏈可變域及重鏈可變域，其各自包含與SEQ ID NO:240及241、242及243、244及245、246及247、248及249、250及251、252及253、254及255或256及257之胺基酸序列至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或至少99%一致的胺基酸序列或由其組成；且其中與VEGF特異性結合之抗原結合位點包含：輕鏈可變域，其包含與SEQ ID NO:189或193之胺基酸序列至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或至少99%一致的胺基酸序列或由其組成；及重鏈可變域，其包含與SEQ ID NO:190、191、192或194之胺基酸序列至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或至少99%一致的胺基酸序列或由其組成。
在關於前述實施例中任一者之一另外較佳實施例中，結合分子為雙特異性且四價的。為避免疑問，藉由本發明之結合分子與其各別目標VEGF及TrkB之結合，本發明之結合分子分別充當VEGF拮抗劑或TrkB促效劑。
在關於前述實施例中任一者之一另外較佳實施例中，與VEGF特異性結合之抗原結合位點為免疫球蛋白(Ig)分子，且至少一個與TrkB特異性結合之抗原結合位點包含一或多個scFv。
在關於前述實施例中任一者之一另外較佳實施例中，一或多個scFv與Ig分子重鏈之C端融合。
在關於前述實施例中任一者之一另外較佳實施例中，至少一個與VEGF特異性結合之抗原結合位點為免疫球蛋白(Ig)分子，更佳IgG，且至少一個與TrkB特異性結合之抗原結合位點包含一或多個scFv，更佳兩個scFv。
本文所描述之抗體分子或結合分子可與對抗體分子之特性具有所需影響之其他分子實體融合(呈融合蛋白)或者連接(藉由共價或非共價鍵)。舉例而言，可能需要改善本文所描述之抗體或結合分子之藥物動力學特性，例如在諸如血液之體液中之穩定性，尤其在單鏈抗體或域抗體之情況下。關於此，特別是為了延長此類抗體分子之循環半衰期，已研發出大量技術，諸如聚乙二醇化(WO 98/25971；WO 98/48837；WO 2004081026)，抗體分子與對如白蛋白之血清蛋白具有親和力之另一抗體分子融合或共價連接(WO 2004041865；WO 2004003019)，或抗體分子表現為與如白蛋白或運鐵蛋白之血清蛋白之全部或部分的融合蛋白(WO 01/79258)。
由於抗體之Fc區與多種Fc受體相互作用，此產生多種重要功能能力(其稱為「效應功能」)，所以在某些實施例中，抗體為全長抗體或含有Fc區之一部分的抗體，後者只要抗體呈現與抗原之相關部分及Fc受體與補體兩者特異性結合即可。恆定區之類型及長度之選擇視效應功能(如補體結合或抗體依賴性細胞介導之細胞毒性)是否為所需特徵以及視抗體蛋白之所需藥理學特性而定。
在本發明之實施例中，scFv部分之穩定性可藉由併入緊密3維接近的兩個半胱胺酸殘基以在scFv內形成二硫鍵而增加。為了經由經工程改造之二硫鍵而實現穩定，此等位置處之殘基較佳經半胱胺酸殘基取代。
如隨附實例中所顯示，本發明人已顯示，自N端至C端具有VL-VH定向之TrkB scFv可在本發明之結合分子中起作用以活化TrkB傳訊。雖然自N端至C端具有VH-VL定向之TrkB scFv亦可起作用，但在此定向中活性可能降低。因此，本發明之一較佳實施例為其中自N端至C端之次序為VL-VH。
本發明之另一較佳實施例為，其中一或多個與TrkB特異性結合之scFv藉由肽連接子，較佳地長度為約4至20個胺基酸(例如6、9、10、12或15個中之任一者)之肽連接子，與特異性結合VEGF之Ig分子(例如人類IgG1、IgG1(KO)、IgG1FcRnmut、IgG4Pro)融合。較佳地，scFv與Ig分子重鏈之C端融合。較佳地，Ig分子為IgG。
連接scFv分子與IgG分子重鏈之C端或連接scFv分子內之可變域之方法為此項技術中熟知。通常，使用甘胺酸及絲胺酸(稱為GS迷你連接子)胺基酸之小連接子序列。連接子中胺基酸之數目可在4 (GGGS) (SEQ ID NO:227)、6 (GGSGGS) (SEQ ID NO:217)、10 (GGGGSGGGGS) (SEQ ID NO:218)、15 (GGGGSGGGGSGGGGS) (SEQ ID NO:219)、20 (GGGGSGGGGSGGGGSGGGGS) (SEQ ID NO:220)或更多變化。實際上，連接子通常係藉由將以下組合而形成：編碼所關注IgG之核酸分子(在本發明之情況下，其將包括編碼重鏈可變域(對於VEGF結合位點)及IgG類型之恆定域的核酸)；與編碼所需scFv之核酸(在本發明之情況下，其將包括編碼重鏈及輕鏈之可變域的核酸，對於TrkB結合位點，其呈VL-VH或VH-VL定向)，該等核酸由編碼連接子序列(例如具有5、10、15或20個胺基酸中之任一者之GS迷你連接子，較佳地SEQ ID NO:218之連接子)的核酸分子隔開。接著如下文進一步解釋，將此完整HC-scFv編碼核酸分子置放於表現載體內且引入適當宿主細胞中，使得形成完整IgG重鏈-scFv單一多肽。
較佳地，scFV分子與IgG分子重鏈之C端之間的GS迷你連接子為10L1 (SEQ ID NO:218)。
在本發明之一實施例中，藉由本發明中之結合分子與補體產物C1q或Fcγ受體之結合係藉由使用IgG4恆定區或在位置234及235處具有L至A定向誘變之IgG1恆定區來去除。
在本發明之一實施例中，本發明之結合分子可具有已經工程改造以避免可溶性Fcγ受體或補體C1q之不希望的交聯的Fc區或其相關區段。在一個實施例中，此類結合分子或抗體變體對Fcγ受體及補體C1q之親和力比親本抗體低得多。(在下文中，若不另外陳述，則在抗體分子上下文中或在IgG或Fc區上下文中，術語「親本」分別係指未經工程改造之衍生突變(經工程改造)分子的抗體分子、Fc區或IgG。)。因此，本發明之一實施例為其中Ig分子包含對Fcγ受體或補體受體或兩者之親和力相較於野生型Fc區降低的Fc變體。此類Ig分子在本文中稱為IgG1(KO)。
亦考慮包含Fc區或其相關區段之結合分子，該Fc區或其相關區段已經工程改造以藉由最佳化其與新生Fc受體(FcRn)之相互作用，例如藉由CH2域中位置H310A處之點突變或位置H435A處之點突變，而調節血清含量(半衰期)。此類Ig分子在本文中稱為IgG1FcRnmut。
進一步考慮包含Ig分子之結合分子，該Ig分子包含去除重鏈與其他IgG4分子之交換的IgG4之鉸鏈區變體。此類Ig分子在本文中稱為IgG4Pro。
本發明之另一態樣提供編碼本發明之結合分子或本發明之抗體分子的經分離之核酸分子；或包含此類核酸分子的表現載體。
在一些實施例中，本發明之結合分子或本發明之抗體分子包含抗體重鏈及/或輕鏈多肽。如技術人員可瞭解，可容易地製備編碼重鏈多肽、輕鏈多肽或重鏈多肽及輕鏈多肽之核酸分子。
編碼輕鏈及重鏈之核酸分子可藉由聚合酶鏈反應(PCR)使用標準方法以化學及酶方式合成。首先，可利用此項技術中已知之方法(例如Gait,1984)合成合適寡核苷酸，其可用於產生合成基因。自寡核苷酸產生合成基因之方法為此項技術中已知(例如Stemmer等人, 1995；Ye等人, 1992；Hayden et Mandecki, 1988；Frank等人, 1987)。
本發明之核酸分子包括但不限於編碼序列表中顯示之多肽序列的DNA分子。此外，本發明亦係關於核酸分子，該等核酸分子在高嚴格度結合及洗滌條件下，與編碼序列表中顯示之多肽序列之DNA分子雜交，如WO 2007/042309中所定義。較佳的分子(自mRNA觀點)為與本文所描述之DNA分子中之一者具有至少75%或80% (較佳地至少85%，更佳地至少90%且最佳地至少95%)同源性或序列一致性的彼等分子。藉助於實例，鑒於在真核細胞中表現抗體，序列表顯示中之DNA序列已設計成匹配真核細胞中之密碼子使用。若需要在大腸桿菌( E. coli)中表現抗體，則可改變此等序列以匹配大腸桿菌密碼子使用。可以若干種不同方式構築本發明之DNA分子之變體，如例如WO 2007/042309中所描述。
本發明之另一態樣提供一種製備本文所描述之結合分子或抗體分子之方法，其包含： (a)    在允許該分子表現之條件下培養本發明之宿主細胞；及 (b)    回收該分子；及視情況
本發明之此態樣之一實施例為其中該製備方法進一步包含步驟(c)進一步純化及/或修飾及/或調配本發明之結合分子。
為了製備本發明之結合分子或抗體，將編碼全長輕鏈及/或重鏈或其片段之DNA分子插入表現載體中，使得序列與轉錄及轉譯控制序列可操作地連接。
為了製造本發明之結合分子或抗體，熟習此項技術者可自此項技術中熟知之大量表現系統選擇，例如由Kipriyanov及Le Gall, Curr Opin Drug Discov Devel. 2004年3月;7(2):233-42綜述之彼等表現系統。
表現載體包括質體、反轉錄病毒、黏質體、EBV源性游離基因體及其類似物。選擇表現載體及表現控制序列以與宿主細胞相容。可將抗體輕鏈基因及抗體重鏈基因或本文所描述之結合分子之重鏈基因(例如包含C端與scFv序列連接之免疫球蛋白重鏈序列之基因)插入單獨載體中。在某些實施例中，將DNA序列、輕鏈及重鏈序列兩者插入同一表現載體中。適宜載體為編碼功能完整之人類CH或CL免疫球蛋白序列且具有經工程改造以使得可容易地插入及表現任何VH或VL序列之適當限制位點的載體，如上文所描述。對於抗體輕鏈，恆定鏈通常為κ或λ，對於抗體重鏈，其可為但不限於任何IgG同型(IgG1、IgG2、IgG3、IgG4)或其他免疫球蛋白，包括等位基因變體。
重組表現載體亦可編碼有助於自宿主細胞分泌抗體鏈(例如本文所描述之結合分子或抗體之重鏈及輕鏈)的訊號肽。可將編碼抗體鏈之DNA選殖至載體中，使得訊號肽框內連接於成熟抗體鏈DNA之胺基端。訊號肽可為免疫球蛋白訊號肽或來自非免疫球蛋白蛋白質之異源肽。替代地，編碼抗體鏈(例如本文所描述之結合分子或抗體之重鏈及輕鏈)之DNA序列可能已經含有信號肽序列。
除編碼抗體鏈(例如本文所描述之結合分子或抗體之重鏈及輕鏈)之DNA序列以外，重組表現載體攜帶調控序列，包括啟動子、增強子、終止及聚腺苷酸化訊號以及其他控制抗體鏈在宿主細胞中表現之表現控制元件。啟動子序列之實例(針對在哺乳動物細胞中表現所例示)為來源於CMV (諸如CMV猿猴病毒40 (SV40) (諸如SV40啟動子/增強子))、腺病毒(例如腺病毒主要晚期啟動子(AdMLP))、多瘤病毒之啟動子及/或增強子，及強哺乳動物啟動子，諸如天然免疫球蛋白及肌蛋白啟動子。聚腺苷酸化訊號之實例為BGH polyA、SV40晚期或早期polyA；替代地，可使用免疫球蛋白基因之3´UTR等。
重組表現載體亦可攜帶調控宿主細胞中載體複製之序列(例如複製起點)及可選標記基因。可根據此項技術中熟知之轉染方法，包括脂質體介導之轉染、聚陽離子介導之轉染、原生質體融合、顯微注射、磷酸鈣沈澱、電穿孔或藉由病毒載體轉移，將編碼本文所描述之結合分子或抗體之重鏈或其抗原結合部分及/或輕鏈或其抗原結合部分的核酸分子及包含此等DNA分子之載體引入宿主細胞，例如細菌細胞或高級真核細胞(例如哺乳動物細胞)中。
較佳地，編碼本文所描述之結合分子或抗體之重鏈及輕鏈之核酸分子存在於兩個載體上，該兩個載體共轉染至宿主細胞，較佳地哺乳動物細胞中。
因此，另一態樣提供一種包含含有編碼重鏈之核酸分子之表現載體的宿主細胞以及一種包含編碼本文所描述之結合分子或抗體之輕鏈之核酸分子的表現載體。
可用作宿主進行表現之哺乳動物細胞株為此項技術中熟知且尤其包括中國倉鼠卵巢(CHO、CHO-DG44)細胞、NSO、SP2/0細胞、HeLa細胞、幼倉鼠腎(baby hamster kidney；BHK)細胞、猴腎細胞(COS)、人類癌瘤細胞(例如Hep G2)、A549細胞、3T3細胞或任何此類細胞株之衍生物/後代。可使用其他哺乳動物細胞，包括但不限於人類、小鼠、大鼠、猴及嚙齒動物細胞株；或其他真核細胞，包括但不限於酵母、昆蟲及植物細胞；或原核細胞，諸如細菌。本發明之結合分子藉由將宿主細胞培養一段足以允許在宿主細胞中表現結合分子的時間來製備。
如本文所描述之結合分子及抗體分子較佳地自培養基作為分泌多肽回收，或若例如在無分泌訊號之情況下表現，則其可自宿主細胞溶解物回收。有必要以獲得實質上均勻的如本文所描述之結合分子或抗體製劑之方式，使用重組蛋白及宿主細胞蛋白所使用之標準蛋白質純化方法來純化本文所描述之結合分子或抗體分子。藉助於實例，適用於獲得本發明之結合分子及抗體之最佳技術純化方法包括自培養基或溶解物移除細胞及/或顆粒細胞碎片作為第一步驟。接著例如藉由在免疫親和力或離子交換管柱上分級分離、乙醇沈澱、逆相HPLC、葡聚糖凝膠層析、二氧化矽層析或在陽離子交換樹脂上自雜質可溶性蛋白質、多肽及核酸純化出結合分子或抗體。作為用於獲得如本文所描述之VEGF及TrkB單一結合分子之方法中之最終步驟，純化的結合分子可經乾燥，例如凍乾，如下文關於治療性應用所描述。
本發明之另一態樣提供本發明之結合分子，其用於醫藥中。應理解，此醫藥中之用途及用於治療如以下中所描述之疾病之用途亦包括根據本發明之TrkB結合分子、scFv及抗體。
本發明之結合分子經指示例如用於眼部或視網膜或神經退化性疾病之療法/治療中，較佳地用於治療神經/神經元眼部或視網膜疾病。在另一態樣中，本發明係關於用於治療及/或預防眼部或視網膜或神經退化性疾病之方法，該方法包含向人類(例如罹患wAMD或處於發展地圖狀萎縮風險下之個體)投與有效量之本發明之結合分子，從而改善眼部或視網膜或神經退化性疾病之一或多個症狀。
如本文所用，術語「治療」及「療法」及其類似術語意謂包括疾病或病症之治療以及防治性，或遏制措施，從而產生任何臨床上所需或有益的效果，包括但不限於緩解或減輕一或多個症狀、消退、減緩或停止疾病或病症之進展。因此，舉例而言，術語治療包括在疾病或病症之症狀發作之前或之後投與結合分子，從而預防或移除疾病或病症之一或多個徵象。作為另一實例，該術語包括在疾病之臨床表現之後投與結合分子，以對抗疾病之症狀。此外，在投與影響疾病或病症之臨床參數，諸如組織損傷程度或癌轉移之量或程度的情況下，無論治療是否引起疾病得到改善，在發作之後及已發展臨床症狀之後投與結合分子包含如本文所使用之「治療」或「療法」。此外，只要相較於在不存在使用結合分子之情況下的症狀相比，單獨本發明之組合物或與另一治療劑組合緩解或改善所治療之病症之至少一個症狀，則結果應視為對潛在病症之有效治療，而與病症之所有症狀是否得到緩解無關。
可向患有眼部或視網膜疾病或處於罹患眼部或視網膜疾病風險下之個體投與本發明之結合分子。本發明進一步提供一種結合分子之用途，其用於製造用於預防及/或治療眼部或視網膜疾病之藥物。如本文所用，術語「個體」意謂可向其投與結合分子之任何哺乳動物患者，包括例如人類及非人類哺乳動物，諸如靈長類動物、嚙齒動物及狗。特定預期使用本文所描述之方法治療之個體包括人類。結合分子可單獨或與其他組合物組合投與。
在一個實施例中，使用本發明之結合分子來治療黃斑變性、老年性黃斑變性、糖尿病性視網膜病變、糖尿病性黃斑水腫、色素性視網膜炎、遺傳性視網膜營養性萎縮、遺傳性黃斑營養不良、近視變性、地圖狀萎縮、繼發於老年性黃斑變性之地圖狀萎縮、視網膜動脈阻塞、眼內炎、葡萄膜炎、囊樣黃斑水腫、繼發於任何視網膜疾病之脈絡膜新生血管性膜、視神經病、青光眼、視網膜脫落、毒性視網膜病、輻射性視網膜病、及創傷性視網膜病、前驅性及輕度至中度阿茲海默氏症，延遲患有阿茲海默氏病、杭丁頓氏症、帕金森氏症、嚴重抑鬱症、精神分裂症、與精神分裂症相關之認知障礙之患者的疾病進展，預防患有減弱精神病症候群之個體的第一次精神病發作，預防患有精神分裂症、難治性抑鬱、暴食、肥胖症或代謝症候群之患者復發。
在一較佳實施例中，本發明之結合分子在治療wAMD中具有效用。更佳的，本發明之結合分子在治療wAMD及治療地圖狀萎縮中具有效用。在又另一較佳實施例中，本發明之結合分子在治療繼發於老年性黃斑變性之地圖狀萎縮中具有效用。在一另外較佳實施例中，本發明之結合分子在治療地圖狀萎縮或治療處於發展地圖狀萎縮風險下之患者中具有效用。在一另外較佳實施例中，本發明之結合分子在預防地圖狀萎縮中具有效用。在一最佳實施例中，本發明之結合分子在治療處於發展地圖狀萎縮風險下之患者之wAMD中具有效用。
在另一實施例中，本發明之結合分子可適用於治療聽力損失，尤其順鉑誘發之聽力損失以及噪音及年齡相關之聽力損失。
本發明之結合分子係藉由任何合適的手段，包括玻璃體內、經口、非經腸、皮下、腹膜內、肺內及鼻內投與。非經腸輸注包括肌肉內、靜脈內、動脈內、腹膜內或皮下投與。另外，本發明之結合分子適合藉由脈衝輸注，尤其在降低劑量之情況下投與。在一個態樣中，部分視投與之短期或長期性而定，可藉由注射，最佳地靜脈內或皮下注射給藥。較佳地，本發明之結合分子係經由玻璃體內注射至眼睛中給與。
在另一態樣中，本發明之結合分子與適用於投與結合分子之裝置，諸如注射器、注射筆或其他裝置組合使用。在另一態樣中，本發明之結合分子包含於分裝部分之套組(kit of parts)中，其例如亦包括具有使用結合分子之指示之藥品說明書。
視涉及之特定疾病而定，可使用任何適合的活體外分析、基於細胞之分析、活體內分析及/或本身已知的動物模型或其任何組合測試本發明之結合分子及包含其之組合物的功效。適合的分析及動物模型對技術人員將為清楚的，且例如包括下文實例中所用之分析及動物模型。
當然實際醫藥學上有效量或治療劑量將視而熟習此項技術者已知之因素而定，諸如患者之年齡及體重、投與途徑及疾病之嚴重程度。在任何情況下，本發明之結合分子將基於患者之獨特病狀以允許遞送醫藥學上有效量之劑量及方式投與。
本發明之結合分子可獨自使用或與其他藥理學上活性成分(諸如最佳技術或標準照護化合物)組合使用。
因此，本發明之另一態樣提供一種醫藥組合物，其包含本發明之結合分子以及醫藥學上可接受之載劑及視情況一或多種其他活性成分。
對於結合分子之玻璃體內注射而言，較佳的是治療之間的間隔一般較長。在一個實施例中，每6週，較佳每7週，亦較佳每8週，更佳每9週，更佳每10週，更佳每11週及更佳每12週投與本發明之結合分子。在一另外較佳實施例中，每3個月一次投與TrkB抗體。視本發明之特異性結合分子及其特定藥物動力學及其他特性而定，投與頻率甚至可更長，諸如每13週、14週、15週、16週、17週、18週、19週或20週。
替代地，可應用其他給藥方案，包括例如負載劑量，其中本發明之結合分子可每月一次注射持續3個負載劑量及接著每12週一次。同樣，投與頻率亦可在此類情況下延長，且甚至可更長，諸如每13週、14週、15週、16週、17週、18週、19週或20週。
大致2.5 mg/眼之預測的人類估計劑量對應於50 mg/mL調配物，其中50 µL將注射至眼睛中。
為了用於療法中，將本發明之結合分子調配成適合於便於向動物或人類投與之醫藥組合物。本文所描述之結合分子或抗體分子之典型調配物可藉由將結合分子與生理學上可接受之載劑、賦形劑或穩定劑混合而製備，呈凍乾或乾燥調配物或水溶液或水性或非水性懸浮液形式。載劑、賦形劑、調節劑或穩定劑在所採用之劑量及濃度下無毒性。其包括緩衝劑系統，諸如磷酸鹽、檸檬酸鹽、乙酸鹽及其他無機酸或有機酸及其鹽；抗氧化劑，包括抗壞血酸及甲硫胺酸；防腐劑，諸如氯化十八烷基二甲基苯甲基銨；氯化六羥季銨、氯化苄烷銨、氯化苯索寧；苯酚、丁醇或苯甲醇；對羥苯甲酸烷酯，諸如對羥基苯甲酸甲酯或對羥基苯甲酸丙酯；兒茶酚；間苯二酚；環己醇；3-戊醇；及間甲酚；蛋白質，諸如血清白蛋白、明膠或免疫球蛋白；親水性聚合物，諸如聚乙烯吡咯啶酮或聚乙二醇(PEG)；胺基酸，諸如甘胺酸、麩醯胺酸、天冬醯胺、組胺酸、精胺酸或離胺酸；單醣、雙醣、寡醣或多醣及其他碳水化合物，包括葡萄糖、甘露糖、蔗糖、海藻糖、糊精或聚葡萄糖；螯合劑，諸如EDTA；糖醇，諸如甘露醇或山梨醇；成鹽相對離子，諸如鈉；金屬錯合物(例如Zn-蛋白質錯合物)；及/或離子或非離子界面活性劑，諸如TWEEN™ (聚山梨醇酯)、PLURONICS™或脂肪酸酯、脂肪酸醚或糖酯。有機溶劑亦可含於調配物中，諸如乙醇或異丙醇。賦形劑亦可具有修飾釋放或修飾吸收之功能。
通常，水溶液或懸浮液將為較佳的。一般而言，治療蛋白，諸如本發明之結合分子之適合的調配物為緩衝蛋白質溶液，諸如包括適合濃度(諸如0.001至400 mg/ml，較佳地0.005至200 mg/mL，更佳地0.01至200 mg/mL，更佳地1.0-100 mg/ml)之蛋白質的溶液。
然而，熟習此項技術者將清楚，如上文所給出的成分及其量僅表示一種較佳選擇。其替代方案及變體對熟習此項技術者將直接顯而易知，或可易於自以上揭示內容開始進行構想。
TrkB 結合分子
基於出人意料的發現，本發明之結合分子中之TrkB結合位點(兩個scFv)之設計明顯支持TrkB結合及活化之最佳空間形成—其可與其他抗原結合位點(諸如VEGF結合位點)或VEGF誘導之聚類機制無關—本發明進一步係針對一種TrkB結合分子，其包含兩個scFv或由其組成，其中各scFv與TrkB特異性結合且兩者共同充當TrkB促效劑。
不希望受理論所束縛，本發明人咸信，藉由將兩個scFv組合至TrkB結合分子中，達成其最佳空間形成，此導致所觀測到之完全TrkB促效活性。因此，在一個態樣中，TrkB結合分子為完全TrkB促效劑，亦即TrkB結合分子在活化TrkB方面與天然配體BDNF一樣有效。
應理解，TrkB結合分子中之兩個scFv彼此連接以形成TrkB結合分子。Trkb結合分子中之兩個scFv可彼此融合或彼此共價連接。替代地，兩個scFv可經由肽連接子，較佳地例如長度為約4至20個胺基酸之肽連接子且更佳地可撓性肽連接子而連接。
TrkB結合分子中之各scFv可與TrkB蛋白內之相同或不同抗原決定基結合。較佳地，兩個scFv與相同TrkB抗原決定基結合。
TrkB結合分子中之scFv自N端至C端可包含VH域(例如鼠類、人源化或人類VH域)、連接子及VL域(例如鼠類、人源化或人類VL域)，或反過來VL域、連接子及VH域)。較佳地，TrkB結合分子中之scFv自N端至C端具有VL-VH定向。
另外，單鏈Fv片段可藉由經由併入半胱胺酸殘基將二硫鍵併入VH與VL域之間、VH域內或VL域內來進一步穩定。術語N端表示多肽鏈之第一個胺基酸，而術語C端表示多肽鏈之C端之最後一個胺基酸。因此，在一個實施例中，一個或兩個scFv包含額外半胱胺酸殘基以形成二硫鍵。
在另一相關態樣中，TrkB結合分子可進一步包含Ig分子。就此而言，Ig分子可為單株抗體；人類單株抗體；人源化單株抗體；嵌合抗體；抗體之片段，諸如Fv、Fab、Fab'或F(ab')2片段；單鏈抗體，諸如單鏈可變片段(scFv)；小模組免疫藥物(SMIP)；域抗體；奈米抗體；或雙功能抗體。
藉由添加另一Ig分子，支持TrkB結合分子內之兩個scFv之最佳空間形成以達成完全TrkB促效劑效果。認為此效果與Ig分子之特異性無關，因為該效果係基於TrkB結合分子之空間形成而非Ig分子之特異性。因此，Ig分子可設計成與任何目標結合。由於咸信所觀測到之完全促效劑效果主要係基於TrkB結合分子內之scFv之空間形成，因此Ig分子亦可不特異性地與任何目標結合。
在一另外較佳實施例中，Ig分子包含Fc區或由其組成。較佳地，在此實施例中，各scFv與Fc區重鏈之C端融合。在關於此實施例之另一實施例中，各scFv藉由肽連接子，較佳地長度為約4至20個胺基酸之肽連接子與Fc區融合。
另外，此處，應理解TrkB結合分子中之兩個scFv及Ig分子彼此連接以形成TrkB結合分子。scFv可與Ig分子融合或直接與Ig分子共價連接，或其可經由連接子，較佳地例如長度為約4至20個胺基酸之肽連接子且更佳地可撓性肽連接子而與Ig分子連接。
較佳地，scFv與Ig分子重鏈之C端融合。較佳地，Ig分子為IgG、F(ab)或F(ab')2。因此，在一較佳實施例中，TrkB結合分子包含以下或由以下組成：兩個scFv及IgG、F(ab)或F(ab') 2，其中各scFv與TrkB特異性結合。在一相關較佳實施例中，TrkB結合分子為雙特異性且四價的且包含以下或由以下組成：兩個scFv及IgG或F(ab') 2，其中各scFv與TrkB特異性結合。在一較佳實施例中，Ig分子且更佳地IgG、F(ab)或F(ab') 2與VEGF特異性結合。
連接scFv分子與Ig分子(例如IgG分子)重鏈之C端或連接scFv分子內之可變域之方法為此項技術中熟知。通常，使用甘胺酸及絲胺酸(稱為GS迷你連接子)胺基酸之小連接子序列。連接子中胺基酸之數目可在4 (GGGS) (SEQ ID NO:227)、6 (GGSGGS) (SEQ ID NO:217)、10 (GGGGSGGGGS) (SEQ ID NO:218)、15 (GGGGSGGGGSGGGGS) (SEQ ID NO:219)、20 (GGGGSGGGGSGGGGSGGGGS) (SEQ ID NO:220)或更多變化。實際上，連接子通常係藉由將以下組合而形成：編碼所關注Ig之核酸分子與編碼所需scFv之核酸(在本發明之情況下，其將包括編碼重鏈及輕鏈之可變域之核酸，對於TrkB結合位點，呈VL-VH或VH-VL定向)，該等核酸分子由編碼連接子序列(例如具有5、10、15或20個胺基酸中之任一者之GS迷你連接子，較佳地SEQ ID NO:218之連接子)之核酸分子隔開。接著如先前所解釋，將此完整HC-scFv編碼核酸分子置放於表現載體內且引入適當宿主細胞中，使得形成完整Ig重鏈-scFv單一多肽。
較佳地，scFv分子與Ig分子重鏈之C端之間的GS迷你連接子為10L1 (SEQ ID NO:218)。
在一個態樣中，與天然TrkB配體BDNF相比，TrkB結合分子更強效地誘導TrkB下游傳訊路徑之活化。在另一態樣中，TrkB結合分子經由TrkB介導之傳訊路徑以與BDNF相當的模式調控基因表現。
在另一態樣中，TrkB結合分子對TrkB磷酸化及/或活化具有特異性，且不會非特異性地磷酸化/活化TrkA或TrkC。
在一個實施例中，TrkB結合分子包含以下或由以下組成： (i)兩條重鏈，其自N端至C端各自包含： -  (視情況)重鏈可變域(例如鼠類、人源化或人類VH域) -  恆定域，較佳地IgG (例如人類IgG1或IgG4)之恆定域 -  (視情況)肽連接子(例如GS迷你連接子)及 -  對TrkB具有特異性之scFv (例如自N端至C端包含VH域(例如鼠類、人源化或人類VH域)、連接子及VL域(例如鼠類、人源化或人類VL域)或反過來VL域、連接子及VH域的scFv)；及 (ii)兩條輕鏈，其自N端至C端各自包含： (視情況)輕鏈可變域(例如鼠類、人源化或人類VL域)， 輕鏈恆定域，較佳地IgG之輕鏈恆定域(例如人類κ鏈)。
本發明現藉助於以下非限制性實例描述。 實例
方法：
表現 Trk 受體之 CHO 細胞 之培養
在補充有10%胎牛血清、格魯塔瑪(glutamax)、非必需胺基酸、20 mM HEPES、5 µg/mL殺稻瘟菌素及200 µg/mL吉歐黴素(zeocin)之DMEM (Lonza, #BE12-604F)中，培養表現人類TrkB受體之CHO細胞(ThermoFisher Scientific, #K1491)及表現人類TrkA或TrkC受體之客製化CHO細胞。在具有5%胎牛血清、8 mM麩醯胺酸、0.5 mg/mL G418之Hams F12 (Lonza #BE12-615F)及DMEM (Lonza #BE12-604F)之1:1混合物中，培養表現石蟹獼猴、兔或大鼠TrkB受體之客製化CHO細胞。在補充有10%胎牛血清、格魯塔瑪、10 mM HEPES及0.8 mg/mL G418之DMEM (Lonza #BE12-604F)中培養表現小鼠TrkB受體之客製化CHO細胞。
表現人類、石蟹獼猴、兔、大鼠或小鼠 Trk 受體之 CHO 細胞中之 TrkA/B/C 及 ERK1/2 磷酸化之分析
將五千個表現各別Trk受體之CHO細胞接種於384孔透明組織培養盤(BD Falcon, #353963)之各空腔中，且在潮濕培育箱中在37℃及5% CO 2下培育。在接種後二十四小時，細胞上清液用室溫饑餓培養基(具有0.1% BSA (Sigma, #A-3059)但無其他補充劑之DMEM)置換。在15分鐘之後，在室溫添加饑餓培養基與增加濃度之人類BDNF (R&D #248-BD或Bachem #H-5594)、人類NGF (Biovision #4303R-20)、人類NT-3 (Sigma #N1905)、促效抗體或同型對照，重複三次，持續45分鐘，以刺激TrkB及ERK1/2磷酸化。單獨饑餓培養基充當對照。
在一些實驗中，在刺激細胞之前，將BDNF或促效抗體不與或與2、10、50或200 ng/mL人類VEGF (R&D Systems #293-VE-050)一起預培育一小時。在此等實驗中，與單獨人類VEGF一起培育充當對照。
為了分析促效TrkB抗體是否極限BDNF誘導之TrkB之磷酸化及/或下游ERK1/2磷酸化，在具有或不具有0.3 nM、1 nM或3 nM恆定濃度之BDNF之情況下，將表現人類TrkB受體之CHO細胞與增加濃度之抗體一起培育。
在刺激之後，移除細胞上清液，且在潤濕冰上在溶解緩衝液(1x Triton溶解緩衝液(Cell Signaling Technology #9803-S)，補充有完全迷你蛋白酶抑制劑錠劑(Roche #04693124001)及磷酸酶抑制劑混合物2 (Sigma #P5726)及3 (Sigma #P0044)，以及1 mM PMSF (Sigma #93482))中溶解細胞20分鐘。使用所得溶解物以根據製造商說明書，使用可商購分析(Perkin Elmer #ALSU-PTRKAB-A10K)，對Y680/681處之TrkA磷酸化、Y706/707處之TrkB磷酸化或Y709/710處之TrkC磷酸化進行定量。根據製造商說明書，使用另一可商購分析(Perkin Elmer #TGRES10K或ALSU-PERK-A10K)，類似地進行T202/Y204 (ERK1)及T185/Y187 (ERK2)處之ERK1/2磷酸化的定量。在Perking Elmer EnVision微量盤讀取器上記錄在570 nm下受體珠粒之光發射，其反映磷酸化事件。準備資料以用GraphPad Prism (版本8)呈現，包括原始資料(平均值± SEM)及非線性回歸(log(促效劑)相對於反應(三個參數))。
TkrB 胞外域 (TrkB-ECD) 之功能特徵
將穩定表現人類TrkB之CHO細胞與增加濃度之天然配體BDNF或10 nM BDNF與增加濃度之TrkB-ECD (R&D Systems #1494-TB)一起培育。如上文所概述，藉由量測Y706/707上之TrkB磷酸化評定TrkB活化。資料表示平均值+/- SEM。
TrkB 受體內化分析
在刺激之前二十四小時，將25000個表現人類TrkB受體之CHO細胞接種於96孔黑色透明底組織培養盤( PerkinElmer, #6055300)之各空腔中，且在潮濕培育箱中在37℃及5% CO 2下培育。CHO/hTrkB細胞之上清液用饑餓培養基(具有0.1% BSA (Sigma, #A-3059)及20 mM Hepes (Lonza, #BE17-737F)之DMEM)置換，且在37℃培育細胞30分鐘。接著，在饑餓培養基中，在37℃，用增加濃度之BDNF (R&D #248-BD或Bachem #H-5594)或單獨促效TrkB抗體、或1 nM BDNF與增加濃度之促效抗體之組合刺激細胞50分鐘。將細胞在4%多聚甲醛中固定20分鐘，洗滌，在含5%正常驢血清之PBS中阻斷一小時，且在室溫與1 µg/mL山羊抗TrkB抗體(R&D Systems, #AF-397)一起培育隔夜，隨後充分洗滌及在室溫在2 µg/mL AlexaFluor 647驢抗山羊抗體(ThermoFisher Scientific, #A21447)及1 µg/mL Hoechst #H3570中培育2小時。在充分洗滌之後，在PBS/0.05% Tween-20中，細胞用2 µg/mL HCS-Cellmask綠(ThermoFisher Scientific, #H32714)染色一小時。在配備有20x water物鏡之PerkinElmer Opera Phenix高通量篩選系統上使細胞表面受體成像，且用PerkinElmer Harmony高通量成像及分析軟體分析。資料呈現為熱圖，其中熱圖之深色及淺色場分別表示高於螢光臨限值之高及低百分比的細胞；或呈現為表示表面TrkB染色強度高於臨限值之細胞百分比的圖。在後者情況下，準備資料以用GraphPad Prism (版本8)呈現，包括原始資料(平均值± SEM)及非線性回歸(log(促效劑)相對於反應(三個參數))。
VEGF 誘導之 VEGF 受體 2 磷酸化及下游傳訊之抑制
在明膠(Millipore #ES-006B)塗佈之培養盤上在具有補充劑(Promocell #C-39210)及各10 U/mL青黴素/鏈黴素之內皮細胞基礎培養基(Promocell #C-22210)中培養人類視網膜微血管內皮細胞(HRMEC；Cell Systems #ACBRI181)。對於VEGF清除之分析而言，將12000個細胞接種於使用正常生長培養基之96孔透明組織培養盤之各空腔中，且在潮濕培育箱中在37℃及5% CO 2下培育。二十四小時後，培養基用饑餓培養基(Promocell #C-22210，補充有0.1% BSA (Sigma, #A-3059)及10 U/mL青黴素/鏈黴素)置換，且使細胞在潮濕培育箱中在37℃及5% CO 2下饑餓20小時。在刺激VEGFR2傳訊之前，將50 ng/mL人類VEGF (R&D Systems #293-VE-050)不與或與拮抗抗體或艾力雅一起在室溫在饑餓培養基中預培育30-60分鐘，且接著預溫熱至37℃持續15分鐘。藉由向細胞中添加預先形成之VEGF-抗體/艾力雅複合物或單獨VEGF，在37℃保溫板上進行細胞刺激5分鐘。單獨饑餓培養基充當對照。在室溫在溶解緩衝液(Perkin Elmer #ALSU-PVGFR-A500)中溶解細胞10分鐘，且接著在冰上培育額外10分鐘。根據製造商說明書，使用可商購分析來定量以下：Y1175處之VEGFR2磷酸化(Perkin Elmer #ALSU-PVGFR-A500或#ALSU-PVGFR-A10K)、Y1214處之VEGFR2磷酸化(Perkin Elmer #ALSU-PVGFR-C500)、Y951處之VEGFR2磷酸化(Perkin Elmer #ALSU-PVGFR-B500)、T202/Y204處之(ERK1)及T185/Y187 (ERK2)處之ERK1/2磷酸化(Perkin Elmer #TGRES10K或ALSU-PERK-A10K)、Y419處之Src磷酸化(Perkin Elmer #ALSU-PSRC-A10K)、Thr180/Tyr182處之p38-MAPK磷酸化(Perkin Elmer #ALSU-PP38-B500)。在Perking Elmer EnVision微量盤讀取器上在570 nm下記錄反映上文所提及之磷酸化事件之受體珠粒之光發射，且準備以用GraphPad Prism (版本8)呈現，包括原始資料(平均值± SEM)及非線性回歸(log(促效劑)相對於反應(三個參數))。
為了研究TrkB結合對於藉由雙特異性且四價多普單抗進行之VEGF清除之影響，在不存在或存在TrkB-ECD下，在饑餓HRMEC中評定VEGF誘導之VEGFR2磷酸化的抑制。在刺激之前，將增加濃度之各別多普單抗與100 nM TrkB-ECD (R&D Systems #1494-TB)一起在饑餓培養基中在室溫培育一小時，隨後與50 ng/mL人類VEGF一起另外培育小時。作為對照，將HRMEC與以下一起培育：(i)單獨饑餓培養基，(ii) 50 ng/mL人類VEGF，(iii) 50 ng/mL人類VEGF與增加濃度之TrkB-ECD預先形成之複合物(在室溫一小時)，(iv)50 ng/mL人類VEGF與增加濃度之各別多普單抗預先形成之複合物(在室溫一小時)，及(v)增加濃度之單獨TrkB-ECD。如上文所概述，藉由量測Y1175處之VEGF受體2 (VEGFR2)磷酸化評定VEGF-A清除。
VEGF 誘導之 HRMEC 增殖之抑制
將三千個HRMEC接種於使用具有補充劑(Promocell #C-39210)及各10 U/mL青黴素/鏈黴素之內皮細胞基礎培養基(Promocell #C-22210)之透明平底96孔盤之各空腔中，且在潮濕培育箱中在37℃及5% CO 2下培育。十六小時後，生長培養基經饑餓培養基(補充有2%胎牛血清之內皮細胞基礎培養基(Promocell #C-22210))置換，且使細胞在潮濕培育箱中在37℃及5% CO 2下饑餓八小時。在刺激之前，將人類VEGF (R&D Systems #293-VE-050)不與或與拮抗抗體或艾力雅一起在室溫在饑餓培養基中預培育60分鐘。藉由向細胞中添加預先形成之VEGF-抗體/艾力雅複合物或單獨VEGF進行細胞刺激。單獨饑餓培養基充當對照(基礎增殖)。藉由總HRMEC核區域之自動化基於相差影像之定量(Essen Bioscience, IncuCyte S3)評定細胞增殖，該定量視為與HRMEC數目成比例。用10x物鏡，每四個小時記錄每孔四個影像，持續總共96小時時段。資料表示作為時間函數之相對細胞數目(時間點t處之細胞數目/t = 0時之細胞數目)；將在t = 0時之細胞數目設定為一。對於一些實驗而言，繪製針對各別化合物濃度之十進位對數之各生長曲線與基礎生長曲線(饑餓培養基中之增殖)之間的面積。準備資料以用GraphPad Prism (版本8)呈現，包括原始資料(平均值± SEM)及非線性回歸(log(促效劑)相對於反應(三個參數)) (若適用)。
VEGF 誘導之 HRMEC 出芽之抑制
在基於HRMEC之球體分析中評定VEGF誘導之出芽之抑制。將HRMEC再懸浮於含有20%美多秀(Methocoel)之正常生長培養基(1.2%甲基纖維素及10%胎牛血清於內皮基礎培養基中)中，且將含有500個HRMEC之25 µl液滴塗覆在方形培養皿上。將培養盤顛倒以在懸掛液滴中培養細胞，此允許自發形成球體。在24小時之後，收集球體且包埋於48孔盤中之美多秀-膠原蛋白混合物(80%美多秀及20% FCS 1:1與3 mg/mL大鼠尾膠原蛋白I (Corning #354236)混合於M199培養基中)中，且在潮濕培育箱中在37℃及5% CO 2下培育30分鐘，以進行膠原蛋白聚合。在刺激之前，將人類VEGF (R&D Systems #293-VE-050)不與或與拮抗抗體或艾力雅一起在室溫在補充有2%胎牛血清之基礎內皮生長培養基中預培育60分鐘。藉由向球體中添加預先形成之VEGF-抗體/艾力雅複合物或單獨VEGF刺激出芽24小時。補充有2%胎牛血清而無VEGF之基礎內皮生長培養基充當對照。在固定於4%多聚甲醛中之後，將細胞充分洗滌且在含有0.2% Triton X-100之PBS中用2 µg/mL HCS-Cellmask綠(ThermoFisher Scientific, #H32714)染色隔夜。在ZEISS LSM 780共焦顯微鏡上分析球體。根據手動地且表述為積聚芽長度/球體(mm)或用Zeiss ZEN-成像軟體半自動化地且表述為球體周界(像素)之Z-堆疊之最大投影影像來定量HRMEC之三維出芽。準備資料以用GraphPad Prism (版本8)呈現且表示平均值± SEM。
視網膜電描記術
通用程序
視網膜電描記術(ERG)為評定不同視網膜神經元之光誘導之電活動之非侵襲性電生理技術，且允許定量視網膜功能之不同態樣，諸如弱光或色覺。使用Espion E3 ERG記錄系統(Diagnosys LLC)將ERG量測為角膜與參考電極之間的電勢變化。在ERG記錄之前，使動物暗適應至少2 h，且藉由i.p.注射氯胺酮(Ketanest，大約100 mg/kg)及賽拉嗪(xylazin) (Rompun，大約7 mg/kg)來麻醉。將動物置放於加熱台上以維持體溫恆定於37℃。利用局部托品卡胺及10%苯腎上腺素使瞳孔擴大。在記錄期間將一滴2%美多秀(Methocel)溶液(OmniVision)置放於角膜上以預防眼睛角膜乾燥。用金環形電極，自兩隻眼睛同時執行記錄。參考電極為用美多秀潤濕且連接於動物頰部之無齒鱷魚夾。對於電接地，將夾子連接於動物尾部。在1 kHz下取樣ERG信號且在0.15 Hz低頻及500 Hz高頻截止下進行記錄。光刺激由藉由一組發光二極體或氙氣燈泡(對於閃光≥ 1 cd·s/m 2)遞送之全場閃光(持續時間~ 4 ms)組成。所有閃光藉由Ganzfeld刺激器(ColorDome；Diagnosys)在黑暗中或在背景光上產生。
ERG方案
ERG反應首先自暗適應動物記錄(以分離視桿驅動之反應)，之後自適應紅色背景光(50 cd/m 2，以分離UV視錐驅動之ERG反應)及最後適應綠-藍色背景光(25.5 cd/m 2，以分離M視錐驅動之ERG反應)之動物記錄。
在暗適應ERG之情況下，反應藉由在1·10 -5至100 cd·s/m 2範圍內之一系列閃光誘發。對於亮度為1·10 -5及3·10 -5cd·s/m 2之閃光，對20個試驗之反應求平均。對於在1·10 -4至0.05 cd·s/m 2之間的閃光，對10個試驗之反應求平均；對於0.1 cd·s/m 2之閃光，對8個試驗之反應求平均；且對於1 cd·s/m 2之閃光，對5個試驗求平均。最後的10 cd·s/m 2閃光，吾人記錄3個試驗之反應，且對於最終閃光100 cd·s/m 2，記錄單一閃光。
個別閃光之間的間隔經選擇以確保視網膜自各次閃光完全恢復(無閃光誘發之反應幅度減小或隱含時間縮短之指示)。基於此等標準，對於1·10 -5及3·10 -5cd·s/m 2閃光，閃光間間隔為2秒，對於1·10 -4至0.05 cd·s/m 2之間的閃光為5秒，對於0.1 cd·s/m 2之閃光為10秒，且對於1 cd·s/m 2之閃光為20 s。在10 cd·s/m 2及100 cd·s/m 2之單一閃光之後，分別存在30 s及120 s之恢復時間。
對於UV視錐驅動及M視錐驅動之反應之記錄而言，首先使動物光適應紅色背景光2 min，且之後適應綠色背景光。光反應係藉由0.02、0.04、0.08、0.17、0.35、0.83、1.66、2.90及4.15 µW/m 2之UV閃光及分別藉由0.1直至110 cd·s/m 2閃光之M視錐閃光誘發。對所有10個試驗之反應求平均，其中閃光間間隔為3 s。
動物及STZ治療
雄性Brown Norway大鼠(BN大鼠)係獲自Charles River (德國)。藉由i.p.注射STZ (65 mg/kg體重)誘發高血糖症。在STZ施用後第7天，無反應或反應不良之動物不包括於研究中，亦即血糖濃度＜ 20 mM之動物。有規律地監測體重及血糖含量。在玻璃體內給藥之前大約3週，投與STZ。
給藥及玻璃體內注射
對於玻璃體內注射，大鼠用2.5%-3%異氟醚(Forene；Abbvie)麻醉。投與一滴4 mg/ml鹽酸奧布卡因(oxybuprocainhydrochlorid) (Novesine；Omnivision)以用於局部麻醉。經由34號(gauge)針(裝配在10 μl Hamilton玻璃注射器上)將5 µL注射至恰好在各眼睛中之角膜緣後的玻璃體中。
資料分析
使用Espion E3 ERG記錄系統(Diagnosys LLC)將ERG量測為角膜與參考電極之間的電勢變化。
在用Matlab軟體計算之前，證明不同組之各ERG閃光在計算來自各閃光之平均曲線之前為一致的。
為了測定ERG a/b波幅度，ERG資料使用MATLAB軟體(版本R2014a；MathWorks)處理且分析。在吾人之情況下，吾人用單獨的巨集分類資料且為吾人之Matlab例程準備檔案。
自a波反應之底部至b波峰之峰值計算b波幅度。b波隱含時間量測為在閃光刺激之後達到b波峰值所需的時間。
藉由使用最小平方擬合程序(GraphPad Prism，版本6.01及隨後GraphPad Prism之更高版本)擬合作為刺激強度之函數之b波幅度。自基線(零基線)至負a波反應計算a波幅度。
藉由單向ANOVA進行統計分析。
實例 1 ：
識別人類 VEGF 及人類 TrkB 之結合分子之總體設計
圖 1
本發明人已研發出結合VEGF及TrkB且分別充當VEGF拮抗劑及TrkB促效劑之結合分子。所用之分子設計具有對目標抗原具有特異性之IgG抗體(稱為「主抗體」)，以及與重鏈C端偶合之具有不同特異性之scFv。設計之示意圖顯示於圖1中。較佳地，結合分子為雙特異性且四價的。
雙特異性分子含有在scFv之可變重鏈(VH)與可變輕鏈(VL)域之間的可撓性肽序列，且scFv域經由其他系列連接子與主IgG抗體連接。在一個組態中，scFv經定向以使得VL域形成scFv之「N端」末端，且因此與主抗體之重鏈的C端融合，而VH形成scFv之C端且實際上形成完整重鏈多肽。然而，可瞭解，此「N-VL-VH-C」結構可顛倒，亦即「N-VH-VL-C」。
為了測試此概念之可行性，製備基於圖1中描繪之格式之多種不同雙特異性分子，且自系列1開始至系列4歷經若干個分子設計週期而經進一步最佳化。
以下實例解釋用於生成結合VEGF及TrkB之不同系列的雙特異性分子以及此等分子之格式及生物活性的變體。
實例 2 ：
識別 VEGF 及 TrkB 之結合域之製備
圖 1
如可瞭解，為了製備與人類VEGF及TrkB結合之雙特異性分子，需要獲得與其個別目標抗原結合之可變域。
出於此目的，免疫球蛋白(Ig) VH及VL基因係獲自不同VEGF及TrkB結合劑且經格式化為本發明之雙特異性分子。總計三個不同VEGF結合域係獲自個別VEGF結合劑，稱為B20、G6及蘭尼單抗。為了與TrkB結合，結合域係獲自個別TrkB結合劑，稱為C2 (WO2010086828)。
個別結合劑格式化為本發明之雙特異性分子係藉由熟習此項技術者已知之常規方法進行。簡言之，為了構築編碼scFv之基因區段，藉由編碼肽序列GGSEGKSSGSGSESKSTGGS (SEQ ID NO:221)之可撓性連接子之基因區段，將編碼可變域之VL及VH基因對接合。所得scFv編碼基因區段轉而框內選殖至編碼人類IgG抗體之重鏈之基因的3'端。此等編碼區段係藉由重疊PCR方法合成且選殖至表現載體pTT5中。
接著，將編碼Fab (2)部分之VL及VH基因對形式化為實例1中概述之雙特異性格式。將VH基因在編碼人類Igγ之基因之5'端以框內融合物選殖至pTT5表現載體中。將編碼scFv結合劑之基因框內選殖在相同Igγ編碼區段之3'端處。類似地，將VL基因以與編碼人類IgG κ輕鏈之基因框內融合物形式選殖至pTT5表現載體中。
在以上用於VH及VL基因之定向選殖的程序中使用In-Fusion® HD選殖套組(Clonetech, U.S.A.)。合成具有與線性化載體之末端互補之15 bp延伸部分的用於VL/VH之PCR引子。使用製造商標準方案進行PCR且擴增子經純化或用選殖增強子處理，接著選殖至適當載體中。接著根據製造商說明書(Clonetech, U.S.A.)將大腸桿菌轉形。對DNA mini-prep定序。
各表現載體含有鏈編碼基因(編碼訊號序列及重鏈或輕鏈之基因)之真核啟動子元件、原核選擇標記基因(諸如安比西林(ampicillin))之表現卡匣及複製起點。使此等DNA質體在抗安比西林性大腸桿菌菌落中繁殖且純化。
將表現載體轉染至CHO-E細胞中。在搖瓶中在140 rpm攪動下在37℃及5% CO 2下培養在無血清培養基中懸浮生長之經轉染之CHO-E細胞且保持在指數生長之條件下。在轉染當天，細胞經1 mg輕鏈質體及0.5 mg重鏈質體化學轉染。接著，以1至2×10 6個細胞/毫升將其接種於1 L之Gibco® FreeStyle™ CHO表現培養基(LifeTechnologies, NY, US)中。接著在軌道振盪下將細胞培育10至12天，其中一次饋送150 ml市售進料溶液以允許表現蛋白質。根據製造商說明書，使用Octet®儀(Pall ForteBio, CA, US)及protA生物感測器尖端測定細胞培養上清液中之結合分子效價。
藉由蛋白A親和層析，使用MabSelect™ SuRe™ (Cytiva)，隨後尺寸排阻層析(Superdex 200, Cytiva)或陽離子交換層析(POROS™ 50 HS, ThermoFisher)中之一者自培養上清液純化重組結合分子，且儲存於60 mM NaOAc緩衝液、100 mM NaCl (pH 5.0)中，藉由質譜分析及分析型尺寸排阻層析來評定樣品之純度及不均勻度。所有樣品在功能測試之前確認單體含量≥90%且含有＜10%雜質。
此導致經由如下表3中所示且在下文中亦稱為多普單抗(DMab)之不同系列1至系列4產生雙特異性、四價結合分子(亦參見Vekataramani等人, Biochemical and Biophysical Research Communications,第504卷,第1期, 2018年9月26日, 第19-24頁)。
表3：
   Fab ScFv/ 定向 連接子 系列 修飾
TPP-11735 C2 B20 VH-VL 20L3 1   
TPP-11736 C2 B20 VL-VH 20L3 1   
TPP-11737 C2 G6 VH-VL 20L3 1   
TPP-11738 C2 G6 VL-VH 20L3 1   
TPP-14936 C2 蘭尼單抗VH-VL 20L3 1   
TPP-14937 C2 蘭尼單抗VL-VH 20L3 1   
TPP-16061 C2 B20 VL-VH 20L1 1   
TPP-16062 C2 B20 VL-VH 15L1 1   
TPP-16063 C2 B20 VL-VH 10L1 1   
TPP-16064 C2 B20 VL-VH 6GS 1   
TPP-19984 C2 蘭尼單抗VH-VL 10L1 1   
TPP-19985 C2 蘭尼單抗VH-VL 20L1 1   
TPP-14938 B20 C2 VH-VL 20L3 2   
TPP-14939 B20 C2 VL-VH 20L3 2   
TPP-14940 蘭尼單抗 C2 VH-VL 20L3 2   
TPP-14941 蘭尼單抗 C2 VL-VH 20L3 2   
TPP-19986 蘭尼單抗 C2 VH-VL 10L1 3   
TPP-19987 蘭尼單抗 C2 VH-VL 20L1 3   
TPP-19988 蘭尼單抗 C2 VL-VH 10L1 3   
TPP-19989 蘭尼單抗 C2 VL-VH 20L1 3   
TPP-22171 蘭尼單抗 C2 VH-VL 10L1 4 CC
TPP-22173 蘭尼單抗 C2 VL-VH 10L1 4 CC
TPP-22180 蘭尼單抗 C2 VH-VL 10L1 4 1Q6Q70G
TPP-22187 蘭尼單抗 C2 VL-VH 10L1 4 1Q
TPP-22188 蘭尼單抗 C2 VL-VH 10L1 4 6Q
TPP-22189 蘭尼單抗 C2 VL-VH 10L1 4 70G
TPP-22190 蘭尼單抗 C2 VL-VH 10L1 4 1Q70G
TPP-22191 蘭尼單抗 C2 VL-VH 10L1 4 6Q70G
TPP-22192 蘭尼單抗 C2 VL-VH 10L1 4 1Q6Q70G
TPP-22204 蘭尼單抗 C2 VH-VL 10L1 4 CC1Q6Q70G
TPP-22211 蘭尼單抗 C2 VL-VH 10L1 4 CC1Q
TPP-22212 蘭尼單抗 C2 VL-VH 10L1 4 CC6Q
TPP-22213 蘭尼單抗 C2 VL-VH 10L1 4 CC70G
TPP-22214 蘭尼單抗 C2 VL-VH 10L1 4 CC1Q70G
TPP-22215 蘭尼單抗 C2 VL-VH 10L1 4 CC6Q70G
TPP-22216 蘭尼單抗 C2 VL-VH 10L1 4 CC1Q6Q70G
TPP-23457 蘭尼單抗 TPP-6830 VH-VL 10L1 4   
TPP-23459 蘭尼單抗 TPP-6830 VL-VH 10L1 4   
簡言之，進行以下設計活動：
系列 1
在系列1中，產生具有在雙特異性結合分子中作為TrkB結合部分之抗原結合片段(Fab)之結合分子。將VEGF結合部分為scFv (2)，且評估不同VEGF結合劑，例如B20、G6或蘭尼單抗。此外，測試不同VL-VH或VH-VL定向，且在結合分子之設計中使用若干連接子，諸如20L3、20L1、15L1、10L1、6GS。
系列 2
在系列2中，產生具有在雙特異性結合分子中作為VEGF結合部分之抗原結合片段(Fab)之結合分子，且再次評估不同VEGF結合劑。此時，將TrkB結合部分格式化為scFv (2)，且測試不同VL-VH或VH-VL定向。
系列 3
在系列3中，基於蘭尼單抗，產生在雙特異性結合分子中作為抗原結合片段(Fab)及VEGF結合部分之結合分子。將TrkB結合部分再次格式化為scFv (2)，且係基於C2 TrkB結合劑。測試VL-VH或VH-VL定向及不同連接子之排列。
系列 4
在最終系列4中，將不同突變引入蘭尼單抗結合部分中，諸如VHE1Q、VHE6Q及/或VLD70G，且分析CC橋在TrkB結合scFv部分中之穩定效果。
此等設計活動之結果及其對於特性及生物活性之影響現在以下實例中更詳細地描述。
實例 3 ：
C2 、 BDNF 以 及四種第一系列之 多普單抗 TPP-11735 、 736 、 737 及 738 進行 之人類 TrkB 活化的比較
圖 2A 至圖 2B
將穩定表現人類TrkB之CHO細胞與增加濃度之天然TrkB配體BDNF、C2抗體、IgG1同型對照或四種多普單抗TPP-11735、TPP-11736、TPP-11737、TPP-11738一起培育。藉由量測(A) Y706/707上之TrkB磷酸化或(B) TrkB下游之分別T202/Y204 (ERK1)及T185/Y187 (ERK2)上之ERK1/2磷酸化評定TrkB活化。最低化合物濃度為僅溶劑。
結果：
藉由DMab進行之TrkB活化幾乎與親本C2分子一致。此外，DMab顯示與親本C2分子相同的特性，且在約~40%-50%之BDNF (pTrkB)下充當部分TrkB促效劑，具有TrkB活化之功效。儘管DMab確實併入親本C2抗體之整個(Fab) 2部分而不改變序列或定向/佈局，此為極令人鼓舞的結果，因為其顯示，格式化為此特異性格式並不會不利地影響TrkB結合劑活化TrkB及TrkB下游傳訊之能力。如所預期，同型對照並不會活化TrkB。
實例 4 ：
藉由 C2 、 BDNF 及第一系列之 多普單抗 TPP-11735/736 進行之 石蟹獼猴 / 兔 / 大鼠 / 小鼠 TrkB 活化之比較
圖 3A 至圖 3D
將穩定表現(A)石蟹獼猴TrkB、(B)兔TrkB、(C)大鼠TrkB或(D)小鼠TrkB之CHO細胞與增加濃度之天然TrkB配體BDNF、C2抗體、或多普單抗TPP-11735或TPP-11736一起培育。藉由量測Y706/707上之TrkB磷酸化評定TrkB活化。最低化合物濃度為僅溶劑。資料表示平均值+/- SEM。
結果：
同樣，藉由DMab進行之TrkB活化幾乎與親本C2分子一致，且活化與人類TrkB受體之活化相當。此外，在此分析中，DMab顯示與親本C2分子相同的特性，且在約~40%-50%之BDNF (pTrkB)下充當部分TrkB促效劑，具有TrkB活化之功效。
實例 5 ：
TPP-11735/736/737/738 介導之 TrkB 活化之選擇性
圖 4A 至圖 4C
將穩定表現(A)人類TrkA、(B)人類TrkB或(C)人類TrkC之CHO細胞與增加濃度之C2抗體或四種多普單抗TPP-11735、TPP-11736、TPP-11737、TPP-11738一起培育。藉由量測Y706/707上之受體磷酸化評定Trk受體之活化。與增加濃度之TrkA (NGF)、TrkB (BDNF)及TrkC (NT-3)之天然配體一起培育用作對照。最低化合物濃度為僅溶劑。資料表示平均值+/- SEM。
結果：
所測試多普單抗中無一者活化TrkA或TrkC。所有多普單抗對於TrkB極具特異性/選擇性。
實例 6 ：
C2 、 TPP-11736 及 / 或 BDNF 誘導之人類 TrkB 受體之內化之比較
圖 5A 至圖 5B
(A)將穩定表現人類TrkB之CHO細胞與增加濃度之天然TrkB配體BDNF、或1 nM BDNF與增加濃度之C2抗體或多普單抗TPP-11736一起培育。(B)藉由在不滲透細胞之情況下對表面TrkB受體進行免疫螢光染色，隨後共焦顯微分析來評定TrkB內化。熱圖之深色及淺色場分別表示高於螢光臨限值之高及低百分比的細胞。
結果：
BDNF誘導TrkB受體內化(泳道1+2；熱圖場自上而下變得更暗)。
抗體C2及TPP-11736降低BDNF誘導之TrkB受體之內化(泳道3-5及6-8；應注意熱圖場由下至上變得更暗)。
實例 7 ：
在存在或不存在人類 VEGF 下 藉由 C2 及 TPP-11736 ( 第一系列 ) 進行 之人類 TrkB 活化之比較
圖 6
在未預培育或與200 ng/mL人類VEGF-A (hVEGF)一起預培育之情況下，將穩定表現人類TrkB之CHO細胞與增加濃度之C2工具抗體或多普單抗TPP-11736一起培育。藉由量測TrkB下游之T202/Y204 (ERK1)及T185/Y187 (ERK2)上之ERK1/2磷酸化評定TrkB活化。在無抗體之情況下與增加濃度之人類VEGF-A一起培育充當對照。最低化合物濃度為僅溶劑。資料表示平均值。為了清晰起見，省略誤差桿。
結果：
與單獨人類VEGF一起培育並不會改變ERK1/2磷酸化。
此外，與人類VEGF一起預培育既不會實質上改變C2或TPP-11736之效能亦不會實質上改變其進行ERK1/2磷酸化之功效。
實例 8 ：
STZ 誘導之糖尿病大鼠中之 DMab 11736 及 C2 之神經保護功效
圖 7
使用IVT注射促效TrkB工具抗體(C2)以及多普單抗TPP-11736，糖尿病誘導之視網膜神經退化大鼠模型中之TrkB活化之神經保護功能。動物用STZ處理以誘導高血糖症。藉由在治療前後進行視網膜電描記術(ERG)評定視網膜功能。糖尿病誘導導致在STZ治療後3週內延遲隱含時間。在此時間點，對動物玻璃體內給藥同型對照抗體(抗TNP)或C2 (各19 µg/5 µl)、或等莫耳量之TPP-11736 (25 µg/5 µl)。在治療兩週之後，重複ERG記錄且分析。在即將玻璃體內施用抗體之前及其兩週後之視桿驅動之B波隱含時間延遲顯示於圖7中；平均值+/- SEM； n.s.p＞0.05，不顯著；**p＜0.01；***p＜0.001；單向Anova與Tukey多比較測試。
結果：
在投與兩週之後，相較於在抗TNP治療之前之時間點，抗TNP抗體治療並不會降低糖尿病誘導之視桿驅動之b波隱含時間(在t = 2週時，15.4 ms；相對於在t = 0時，13.3 ms；p＞0.05，不顯著)。
在投與兩週之後，相較於在抗體治療之前之時間點，TPP-11736及C2處理之動物顯示糖尿病誘導之視桿驅動之b波隱含時間延遲顯著降低(C2：在t = 2週時，8.62 ms；相對於在t = 0時，14.4 ms；***p＜0.01；TPP-11736：在t = 2週時，10.3 ms；相對於在t = 0時，16.1 ms；**p＜0.01)。
與TrkB活化之活體外分析中之早先量測一致，C2及TPP-11736顯示類似的活體內神經保護功效。
實例 9 ：
藉由艾力雅及第一系列之四種 多普單抗 TPP-11735 、 736 、 737 及 738 進行 之人類 VEGF-A 清除之比較 -- VEGF 誘導之 VEGFR2 磷酸化之抑制
圖 8A 至圖 8B
使人類視網膜微血管內皮細胞(HRMEC)饑餓，且接著在與增加濃度之指示結合分子或艾力雅一起預培育或未預培育之情況下，與50 ng/mL人類VEGF一起培育。
藉由量測Y1175上之VEGF受體2 (VEGFR2)磷酸化評定VEGF-A清除。(A)多普單抗TPP-11735、TPP-736、TPP-737及TPP-738之比較。(B) TPP-11736及TPP-11738與艾力雅之比較。未刺激細胞(基礎)及無抗體處理之50 ng/ml人類VEGF充當對照。資料表示平均值+/- SEM。
結果：
TPP-11737與TPP-11738：此等分子均具有G6抗VEGF分子作為scFv。737呈VH-VL定向連接，而738具有VL-VH定向。結果表明，基於G6抗VEGF抗體，VL-VH定向好很多地起作用。
TPP-11735與TPP-11736：此等分子均具有B20抗VEGF分子作為scFv。對於此分析中之B20 VEGF抗體，兩個定向之間不存在許多效能差異。
TPP-11736與TPP-11738：此等分子具有B20 (VL-VH)或G6 (VL-VH)抗VEGF分子作為scFv。兩種結合分子顯示類似效能(IC50 ~4 nM)，但TPP-11736更有效。
相較於TPP-11736或TPP-11738 (~4 nM)，艾力雅(IC50 = 0.7 nM)強效許多。
實例 10 ：
藉由艾力雅及第一系列之四種 多普單抗 TPP-11735 、 736 、 737 及 738 進行 之人類 VEGF-A 清除之比較 -- VEGF 誘導之 ERK1/2 磷酸化之抑制
圖 9A 至圖 9B
使人類視網膜微血管內皮細胞(HRMEC)饑餓，且接著在與增加濃度之指示抗體或艾力雅一起預培育或未預培育之情況下，與50 ng/mL人類VEGF一起培育。
VEGF-A清除係藉由量測T202/Y204 (ERK1)及T185/Y187 (ERK2)上之ERK1/2磷酸化評定之TrkB活化評定。(A)多普單抗TPP-11735、TPP-736、TPP-737及TPP-738之比較。(B) TPP-11736、TPP-738與艾力雅之比較。未刺激細胞(基礎)及無抗體處理之50 ng/ml人類VEGF充當對照。資料表示平均值+/- SEM。
結果：
TPP-11737與TPP-11738：此等分子均具有G6抗VEGF分子作為scFv。737呈VH-VL定向連接，而738具有VL-VH定向。結果表明，基於G6抗VEGF抗體，VL-VH定向好很多地起作用。
TPP-11735與TPP-11736：此等分子均具有B20抗VEGF分子作為scFv。對於此分析中之B20 VEGF抗體，兩個定向之間不存在許多效能差異。
TPP-11736與TPP-11738：此等分子具有B20 (VL-VH)或G6 (VL-VH)抗VEGF分子作為scFv。兩種結合分子顯示類似效能(IC50 ~4 nM)，但TPP-11736更有效。
相較於TPP-11736或TPP-11738 (~10 nM)，艾力雅(IC50 = 2 nM)強效許多。
實例 11 ：
藉由艾力雅及第一系列之多普單抗 TPP-11736 進行 之人類 VEGF-A 清除之比較 -- VEGF 誘導之 p38 MAPK 磷酸化之抑制
圖 10
使人類視網膜微血管內皮細胞(HRMEC)饑餓，且接著在與增加濃度之TPP-11736或艾力雅一起預培育或未預培育之情況下，與50 ng/mL人類VEGF一起培育。藉由量測T180/Y182上之p38 MAPK磷酸化評定VEGF-A清除。未刺激細胞(基礎)及無抗體處理之50 ng/ml人類VEGF充當對照。資料表示平均值+/- SEM。
結果：
艾力雅(IC 50= ~0.74 nM)比TPP-11736 (~7.4 nM)更強效約10倍。
實例 12 ：
藉由第一系列之四種 多普單抗 TPP-11735 、 736 、 737 及 738 以 及艾力雅 進行 之人類 VEGF-A 清除之比較 -- VEGF 誘導之 HRMEC 增殖之抑制
圖 11A 至圖 11E
使人類視網膜微血管內皮細胞(HRMEC)饑餓，且接著在與增加濃度之指示結合分子或艾力雅一起預培育或未預培育之情況下，與10 ng/mL人類VEGF一起培育。分子濃度以mol/L為單位給出。藉由自動化基於影像之HRMEC細胞數目定量(IncuCyte)評定VEGF-A清除。每四個小時記錄影像，持續總共96小時之時段。顯示相對細胞數目。將在t = 0時之細胞數目設定為一。未刺激細胞充當對照(基礎)。資料表示平均值+/- SEM。
結果：
TPP-11737與TPP-11738：此等分子均具有G6抗VEGF分子作為scFv。TPP-11737呈VH-VL定向連接，而TPP-11738具有VL-VH定向。顯然，在G6之情況下，VL-VH定向好很多地起作用。TPP-11737幾乎無效果。
TPP-11735 (VH-VL)與TPP-11736 (VL-VH)：此等分子均具有B20抗VEGF分子作為scFv。同樣，VL-VH定向表現得更好。
736與738：B20 (VL-VH)與G6 (VL-VH)：在此分析中，TPP-11736 (B20)明顯更有效。
最後，艾力雅比TPP-11736更有效。
系列1：TPP-11735、TPP-11736、TPP-11737、TPP-11738之發現之概述
TrkB活化：
藉由DMab進行之TrkB活化幾乎與親本C2分子一致。此並非出人意料的，因為C2 TrkB結合劑之整個(Fab) 2部分併入DMab中而不改變序列或定向/佈局。此外，所有多普單抗(及C2)僅為部分TrkB促效劑。
VEGF清除：
明顯地，對於G6及B20作為VEGF結合劑，VL-VH定向更佳地起作用，且B20 (VL-VH)比G6 (VL-VH)更有效。此外，兩種多普單抗(B20及G6)活體外均不如艾力雅。
基於此等初始發現，本發明人打算在以下實例中產生及測試呈VL-VH定向之B20的不同連接子，以改良多普單抗(TPP-16061至TPP-16064)之VEGF清除。
實例 13 ：
藉由 C2 、 BDNF 及第一系列之四種 多普單抗 TPP- 16061 、 16062 、 16063 及 16064 進行 之人類 TrkB 活化之比較 ； TrkB 磷酸化
圖 12
將穩定表現人類TrkB之CHO細胞與增加濃度之天然TrkB配體BDNF、C2抗體、TPP-11736 (B20，scFv，20L3，VL-VH)或以下具有不同連接子之四種多普單抗一起培育：TPP-16061 (B20，scFv，20L1，VL-VH)、TPP-16062 (B20，scFv，15L1，VL-VH)、TPP-16063 (B20，scFv，10L1，VL-VH)、TPP-16064 (B20，scFv，6GS，VL-VH)。藉由量測Y706/707上之TrkB磷酸化評定TrkB活化。最低化合物濃度為僅溶劑。資料表示平均值。為了清晰起見，省略誤差桿。
結果：
藉由DMab TPP-16061至16064進行之TrkB活化幾乎與親本C2分子及TPP-11736一致。TrkB活化似乎很大程度上與蛋白質之Fc與scFv (抗VEGF)部分之間的連接子變體無關。儘管此為預期的—因為連接子位於蛋白質之Fc與scFv (抗VEGF)部分之間的TrkB (Fab) 2片段遠端—但此仍為可在不影響結合分子之活性之情況下採用不同連接子的良好確認。最後，所有顯示之結合分子僅顯示部分TrkB促效活性。
實例 14 ：
藉由 BDNF 、 TPP-11736 及第一系列之兩種 多普單抗 TPP- 16061 及 16062 進行 之人類 TrkB 活化之比較 ； ERK1/2 磷酸化
圖 13
將穩定表現人類TrkB之CHO細胞與增加濃度之天然TrkB配體BDNF、TPP-11736 (B20，scFv，20L3，VL-VH)或具有不同連接子之兩種多普單抗TPP-16061 (B20，scFv，20L1，VL-VH)及TPP-16062 (B20，scFv，15L1，VL-VH)一起培育。藉由量測T202/Y204 (ERK1)及T185/Y187 (ERK2)上之ERK1/2磷酸化評定TrkB活化。最低化合物濃度為僅溶劑。資料表示平均值+/- SEM。
結果：
藉由DMab TPP-16061及16062進行之TrkB活化幾乎與TPP-11736一致。本文中亦顯示，TrkB活化很大程度上與連接子變體無關，且所顯示之結合分子僅顯示部分TrkB促效活性。
實例 15 ：
藉由第一系列之四種 多普單抗 TPP-16061 、 062 、 063 及 064 與 TPP-11736 進行 之人類 VEGF-A 清除之比較 -- (A) VEGF 誘導之 VEGFR2 磷酸化之抑制 ， (B) ERK1/2 磷酸化
圖 14A 至圖 14B
使人類視網膜微血管內皮細胞(HRMEC)饑餓，且接著在與增加濃度之以下指示抗體一起預培育或未預培育之情況下，與50 ng/mL人類VEGF一起培育：TPP-11736 (B20，scFv，20L3，VL-VH)；或以下具有不同連接子之四種多普單抗：TPP-16061 (B20，scFv，20L1，VL-VH)、TPP-16062 (B20，scFv，15L1，VL-VH)、TPP-16063 (B20，scFv，10L1，VL-VH)、TPP-16064 (B20，scFv，6GS，VL-VH)。藉由分別量測(A) Y1175上之VEGF受體2 (VEGFR2)磷酸化或(B) T202/Y204 (ERK1)及T185/Y187 (ERK2)上之ERK1/2磷酸化評定VEGF-A清除。未刺激細胞(基礎)及無抗體處理之50 ng/ml人類VEGF充當對照。資料表示平均值+/- SEM。
結果：
連接子之變化對於VEGF清除之效能或功效幾乎無影響。此為略微出人意料的—鑒於連接子位於VEGF結合位點附近—但進一步確認，可在不影響結合分子之活性之情況下採用不同連接子。
實例 16 ：
藉由第一系列之四種 多普單抗 TPP-16061 、 062 、 063 及 064 進行 之人類 VEGF-A 清除之比較 -- VEGF 誘導之 HRMEC 增殖之抑制
圖 15
使人類視網膜微血管內皮細胞(HRMEC)饑餓，且接著在與0.5 nM多普單抗或1 nM艾力雅一起預培育或未預培育之情況下，與10 ng/mL人類VEGF一起培育。藉由自動化基於影像之HRMEC細胞數目定量(IncuCyte)評定VEGF-A清除。每四個小時記錄影像，持續總共96小時之時段。顯示相對細胞數目。將在t = 0時之細胞數目設定為一。未刺激細胞充當對照(基礎)。資料表示平均值+/- SEM。
結果：
類似於實例15中顯示之磷酸化分析，相較於親本分子TPP-11736，連接子變體並不會表現得更好(或更差)。艾力雅係以1 nM使用，因為推測艾力雅為單價分子，而多普單抗為二價。在此等條件下，艾力雅在VEGF誘導之HRMEC之增殖之抑制中表現得更好。
實例 17 ：
藉由艾力雅、 TPP-11736 及第一系列之四種 多普單抗 TPP-16061 、 062 、 063 及 064 進行 之人類 VEGF-A 清除之比較 -- VEGF 誘導之 HRMEC 出芽之抑制
圖 16
人類視網膜微血管內皮細胞(HRMEC)之球體包埋於膠原蛋白基質中。藉由在與2.5 nM之指示多普單抗或5 nM艾力雅一起預培育或未預培育之情況下，與50 ng/mL人類VEGF一起培育24小時，來誘導內皮出芽24小時。內皮出芽藉由共焦顯微術評定且顯示獲自Z-堆疊之最大投影的球體周界。未刺激細胞充當對照(基礎)。資料表示平均值+/- SEM。相對於50 ng/mL hVEGF + 2.5 nM TPP-11736，n.s. p＞0.05不顯著。
結果：
類似於實例15中顯示之磷酸化分析，相較於親本分子TPP-11736，連接子變體並不會表現得更好(或更差)。艾力雅係以1 nM使用，因為推測艾力雅為單價分子，而多普單抗為二價。在此等條件下，艾力雅在VEGF誘導之HRMEC之增殖之抑制中表現得更好。
系列1：TPP-16061、TPP-16062、TPP-16063、TPP-16064之發現之概述
TrkB活化：相較於親本分子TPP-11736，未觀測到差異/改善。
VEGF清除：相較於親本分子TPP-11736，無差異/改善。
基於此等發現，本發明人打算比較TPP-11736 (B20作為scFv)與TPP-13788 (B20 IgG)之VEGF清除，以測試再格式化作為Fab之B20是否將改善VEGF清除。
實例 18 ：
藉由 TPP-11736 及 TPP-13788 (B20 IgG) 進行 之人類 VEGF-A 清除之比較 -- VEGF 誘導之 VEGFR2 、 ERK1/2 及 p38 MAPK 之磷酸化的抑制
圖 17A 至圖 17C
使人類視網膜微血管內皮細胞(HRMEC)饑餓，且接著在未預培育或與增加濃度之多普單抗TPP-11736 (B20抗VEGF作為scFv)或TPP-13788 (B20 IgG)一起預培育之情況下，與50 ng/mL人類VEGF一起培育。藉由量測(A) Y1175上之VEGF受體2 (VEGFR2)磷酸化、(B) T202/Y204 (ERK1)及T185/Y187 (ERK2)上之ERK1/2磷酸化或(C) T180/Y182上之p38 MAPK磷酸化評定VEGF-A清除。無分子處理之50 ng/ml人類VEGF充當對照。資料表示平均值+/- SEM。下表4報導對應最佳擬合IC 50值(非線性回歸；log(促效劑)相對於反應(三個參數))。
表4：
   TPP-11736 TPP-13788
IC 50(VEGFR2磷酸化) 2.6 nM 1.0 nM
IC 50(ERK1/2磷酸化) 9.1 nM 3.0 nM
IC 50(p38 MAPK磷酸化) 7.7 nM 2.4 nM
結果：
相對於TPP-11736，所測試之B20 IgG TPP-13788顯示VEGF-A清除效能增加大致3倍
實例 19 ：
藉由 TPP-11736 及 TPP-13788 (B20 IgG) 進行 之人類 VEGF-A 清除之比較 -- VEGF 誘導之 HRMEC 出芽之抑制
圖 18
人類視網膜微血管內皮細胞(HRMEC)之球體包埋於膠原蛋白基質中。藉由在未預培育或與2.5 nM之多普單抗TPP-11736或2.5 nM TPP-13788 (B20 IgG)一起預培育之情況下，與50 ng/mL人類VEGF一起培育，來誘導內皮出芽24小時。內皮出芽藉由共焦顯微術評定且顯示獲自Z-堆疊之最大投影的球體周界。未刺激細胞充當對照(基礎)。資料表示平均值+/- SEM。相對於50 ng/mL hVEGF + 2.5 nM TPP-11736，n.s. p＞0.05不顯著。
結果：
儘管在VEGFR2、ERK1/2及p38 MAPK磷酸化分析中VEGF清除改善，但TPP-13788 (B20 IgG)介導之VEGF誘導之出芽的抑制不比TPP-11736之抑制好。
實例 20 ：
藉由 BDNF 、 TPP-11736 及第一系列之兩種 多普單抗 TPP- 14936 及 TPP-14937 進行 之人類 TrkB 活化之比較 ； TrkB 及 ERK1/2 磷酸化
圖 19A 至圖 19C
將穩定表現人類TrkB之CHO細胞與增加濃度之天然TrkB配體BDNF、TPP-11736 (B20，scFv，20L3，VL-VH)或兩種多普單抗TPP-13936 (蘭尼單抗，scFv，20L3，VH-VL)或TPP-14937 (蘭尼單抗，scFv，20L3，VL-VH)一起培育。藉由量測(A) Y706/707上之TrkB磷酸化、(B及C)分別T202/Y204 (ERK1)及T185/Y187 (ERK2)上之ERK1/2磷酸化評定TrkB活化。最低化合物濃度為僅溶劑。資料表示平均值+/- SEM。
結果：
藉由DMab TPP-14936及TPP-14937進行之TrkB活化幾乎與TPP-11736一致。此為預期的，因為結合分子之TrkB結合組分始終為作為Fab片段之C2。
實例 21 ：
藉由 BDNF 、 TPP-11736 及多普單抗 TPP- 14936 進行 之石蟹獼猴及大鼠 TrkB 活化之比較 ； TrkB 磷酸化
圖 20A 至圖 20B
將穩定表現(A)石蟹獼猴TrkB或(B)大鼠TrkB之CHO細胞與增加濃度之天然TrkB配體BDNF、TPP-11736 (B20，scFv，20L3，VL-VH)或TPP-14936 (蘭尼單抗，scFv，20L3，VH-VL)一起培育。藉由量測Y706/707上之TrkB磷酸化評定TrkB活化。最低化合物濃度為僅溶劑。資料表示平均值+/- SEM。
結果：
藉由DMab TPP-14936進行之TrkB活化幾乎與TPP-11736一致。同樣，此為預期的，因為兩種分子之TrkB結合組分在兩種情況下均為作為Fab片段之C2。
實例 22 ：
藉由 TPP-11736 、 TPP-14936 或 TPP-14937 進行 之人類 VEGF-A 清除之比較 -- VEGF 誘導之 VEGFR2 、 ERK1/2 及 Src 之磷酸化的抑制
圖 21A 至圖 21C
使人類視網膜微血管內皮細胞(HRMEC)饑餓，且接著在與增加濃度之多普單抗TPP-11736 (B20，scFv，20L3，VL-VH)、TPP-14936 (蘭尼單抗，scFv，20L3，VH-VL)或TPP-14937 (蘭尼單抗，scFv，20L3，VL-VH)一起預培育或未預培育之情況下，與50 ng/mL人類VEGF一起培育。藉由量測(A) Y1175上之VEGF受體2 (VEGFR2)磷酸化、(B) T202/Y204及T185/Y187上之ERK1/2磷酸化或(C) Y419上之Src磷酸化評定VEGF-A清除。無抗體處理之50 ng/ml人類VEGF充當對照。資料表示平均值+/- SEM。下表5分別報導對應最佳擬合IC 50值及絕對功效值(底部平線區) (非線性回歸；log(促效劑)相對於反應(三個參數))。
表5：
   TPP-11736 TPP-14936 TPP-14937
IC 50(VEGFR2磷酸化) 2.4 nM 1.9 nM 4.3 nM
底部平線區 (VEGFR2磷酸化；計數) 482 -1097 -1407
IC 50(ERK1/2磷酸化) 5.6 nM 3.5 nM 5.6 nM
底部平線區 (ERK1/2磷酸化，計數) 3688 -340,8 -926,9
IC 50(Src磷酸化) 4.0 nM 3.4 nM 5.8 nM
底部平線區 (Src磷酸化，計數) 6300 4654 4571
結果：
TPP-11736與TPP-14936/TPP-14937之間的VEGF清除之效能(IC 50)類似。
藉由TPP-14936進行之VEGF清除之效能(IC 50)比TPP-14937略微更佳à蘭尼單抗scFv之VH-VL比VL-VH定向更佳。
藉由TPP-14936及TPP-14937進行之VEGF清除比TPP-11736更有效(底部值較小)。
實例 23 ：
藉由 TPP-11736 及 多普單抗 TPP-14936 及 TPP-14937 進行 之人類 VEGF-A 清除之比較 -- VEGF 誘導之 HRMEC 出芽之抑制
圖 22
人類視網膜微血管內皮細胞(HRMEC)之球體包埋於膠原蛋白基質中。藉由在與2.5 nM之多普單抗TPP-11736 (B20，scFv，20L3，VL-VH)、TPP-14936 (蘭尼單抗，scFv，20L3，VH-VL)或TPP-14937 (蘭尼單抗，scFv，20L3，VL-VH)一起預培育或未預培育之情況下，與50 ng/mL人類VEGF一起培育來誘導內皮出芽24小時。內皮出芽藉由共焦顯微術評定且顯示獲自Z-堆疊之最大投影的球體周界。未刺激細胞充當對照(基礎)。資料表示平均值+/- SEM。n.s. p＞0.05，不顯著，****p＜0.0001。
結果：
儘管藉由TPP-14936及TPP-14937進行之VEGF清除在VEGFR2/ERK1_2/Src磷酸化分析中類似，但在VEGF誘導之出芽之抑制中存在顯著差異。然而，TPP-11736與TPP-14937之間無顯著差異，藉由TPP-14936進行之VEGF誘導之HRMEC出芽的抑制比TPP-14937或TPP-11736更有效許多。
此出人意料的發現指示，抗VEGF scFv之VH-VL定向對於此分析中之效能至關重要：VH-VL比VL-VH好許多。有趣的是，在TPP-11735與736 (B20)之情況下，VL-VH定向比VH-VL更佳，且在TPP-11737與738 (G6)之情況下亦如此。
實例 24 ：
藉由 多普單抗 TPP-11736 、 TPP-14936 及 TPP-14937 、以及艾力雅進行之人類 VEGF-A 清除之比較 -- VEGF 誘導之 HRMEC 增殖之抑制
圖 23A 至圖 23D
使人類視網膜微血管內皮細胞(HRMEC)饑餓，且接著在與增加濃度之指示結合分子或艾力雅一起預培育或未預培育之情況下，與10 ng/mL人類VEGF一起培育。結合分子/艾力雅濃度以mol/L為單位給出。藉由自動化基於影像之HRMEC細胞數目定量(IncuCyte)評定VEGF-A清除。每四個小時記錄影像，持續總共84小時之時段。顯示相對細胞數目。將在t = 0時之細胞數目設定為一。未刺激細胞充當對照(基礎)。資料表示平均值+/- SEM。
結果：
相較於TPP-11736，TPP-14936及TPP-14937顯示VEGF誘導之HRMEC增殖之抑制的效能及尤其功效更佳。TPP-14936比TPP-14937更強效。
極其出人意料地，TPP-14936及TPP-14937比艾力雅更有效。兩種多普單抗均降低增殖，甚至低於基線。與艾力雅相比，其顯示完全抑制VEGF誘導之增殖。然而，艾力雅仍比TPP-14936及14937更強效。
系列1：TPP-14936/14937之發現之概述
TrkB活化：相較於TPP-11736，未觀測到差異/改善。因為兩種結合分子均具有C2結合劑作為Fab片段，因此此在預期之中。
VEGF清除：
磷酸化分析：在TPP-11736與TPP-14936/TPP-14937之間，VEGF清除之效能(IC 50)類似。藉由TPP-14936及TPP-14937進行之VEGF清除比TPP-11736(底部值)更有效。
出芽分析：TPP-11736與TPP-14937之間無顯著差異。TPP-14936對VEGF誘導之HRMEC出芽的抑制比TPP-14937或TPP-11736更有效許多。出乎意料地，抗VEGF蘭尼單抗之VH-VL定向比VL-VH好許多。
增殖分析：相較於TPP-11736，TPP-14936及TPP-14937顯示VEGF誘導之HRMEC增殖之抑制的效能及尤其功效更佳。TPP-14936比TPP-14937更強效，且TPP-14936及TPP-14937均比艾力雅更有效。
基於此等發現，本發明人打算更好地瞭解多普單抗之逆向佈局，且嘗試蘭尼單抗/B20作為Fab以改善VEGF清除之效能(功效)及C2 TrkB結合劑作為scFv。現在以下實例中產生且測試以下結合分子(系列2)：TPP-14938 (B20 Fab)、TPP-14939 (B20 Fab)、TPP-14940 (蘭尼單抗Fab)、TPP-14941 (蘭尼單抗Fab)。
實例 25 ：
藉由 BDNF 、 TPP-11736 及四種第二系列之 多普單抗 TPP- 14938 、 TPP- 14939 、 TPP- 14940 及 TPP- 14941 進行 之人類 TrkB 活化之比較 ； TrkB 及 ERK1/2 磷酸化
圖 24A 至圖 24B 及圖 25
將穩定表現人類TrkB之CHO細胞與增加濃度之天然TrkB配體BDNF、TPP-11736 (C2作為Fab)或四種第二系列之多普單抗TPP-14938 (C2作為scFv，20L3，VH-VL)、TPP-14939 (C2作為scFv，20L3，VL-VH)、TPP-14940 (C2作為scFv，20L3，VH-VL)及TPP-14941 (C2作為scFv，20L3，VL-VH)一起培育。藉由(A)量測Y706/707上之TrkB磷酸化或藉由(B)分別量測T202/Y204 (ERK1)及T185/Y187 (ERK2)上之ERK1/2磷酸化評定TrkB活化。最低化合物濃度為僅溶劑。資料表示平均值+/- SEM。
結果：
TPP-11736含有C2 CDR作為Fab。四種多普單抗TPP-14938、TPP-14939、TPP-14940及TPP-14941含有C2作為scFv。
與TPP-11736或初始C2抗體(兩者均為部分TrkB受體促效劑)形成強烈對比，所有四種新多普單抗現在均顯示完全TrkB受體促效劑活性。藉由彼等多普單抗進行之TrkB活化現與天然配體BDNF一樣有效。此完全為出人意料的，因為初始C2抗體僅顯示部分TrkB受體促效劑。不希望受理論所束縛，似乎VEGF誘導之與單一結合分子聚類以及結合分子之空間形成可為造成所觀測到之TrkB活化之功效及效能增加的原因(亦參見圖25)。
相較於TPP-14939及TPP-14941，利用多普單抗TPP-14938及TPP-14940進行之TrkB活化之效能亦略微更佳。因此C2 scFv之「VH-VL」定向顯示更佳的TrkB活化效能。
實例 26 ：
藉由 BDNF 、 TPP-11736 及四種第二系列之 多普單抗 TPP- 14938 、 TPP- 14939 、 TPP- 14940 及 TPP- 14941 進行 之石蟹獼猴 / 大鼠 TrkB 活化之比較 ； TrkB 及 ERK1/2 磷酸化
圖 26A 至圖 26B
將穩定表現(A)石蟹獼猴TrkB或(B)大鼠TrkB之CHO細胞與增加濃度之天然TrkB配體BDNF、TPP-11736 (C2作為Fab)或兩種第二系列之多普單抗TPP-14940 (C2作為scFv，20L3，VH-VL)及TPP-14941 (C2作為scFv，20L3，VL-VH)一起培育。藉由量測Y706/707上之TrkB磷酸化評定TrkB活化。最低化合物濃度為僅溶劑。資料表示平均值+/- SEM。
結果：
實例25利用人類TrkB之結果可在石蟹獼猴及大鼠模型中再現。同樣在此處，與TPP-11736形成強烈對比，新多普單抗為完全TrkB受體促效劑。藉由彼等多普單抗進行之TrkB活化與天然配體BDNF一樣有效。
同樣，相較於TPP-14941，利用多普單抗TPP-14940之TrkB活化之效能略微更佳。因此C2 scFv之VH-VL定向顯示更佳的TrkB活化效能。
實例 27 ：
在存在或不存在人類 VEGF 下 ， 藉由 C2 、 TPP-14940 及 TPP-14941 ( 第二系列 ) 進行 之人類 TrkB 活化 (TrkB 磷酸化 ) 之比較 -- 協同效應
圖 27A 至圖 27C
在與200 ng/mL人類VEGF-A (hVEGF)一起預培育或未預培育之情況下，將穩定表現人類TrkB之CHO細胞與增加濃度之多普單抗(A) TPP-14940、(B) TPP-14941或(C) C2一起培育。藉由量測Y706/707上之TrkB磷酸化評定TrkB活化。最低化合物濃度為僅溶劑。資料表示平均值+/- SEM。
結果：
出人意料地，與人類VEGF一起預培育顯著改善藉由TPP-14941 (C2作為scFv，20L3，VL-VH)進行之TrkB磷酸化(TrkB活化)之效能。
相較於TPP-14940，對於TPP-14941而言，VEGF對於TrkB磷酸化(TrkB活化)之效能的影響更大。因此，儘管兩種分子對於TrkB磷酸化之效能均顯示協同效應，但似乎多普單抗(scFv VL-VH與scFv VH-VL與Fab)之TrkB活化部分之定向/幾何結構似乎對於協同效應具有影響，其中具有VL-VH定向之scFv為較佳的。
VEGF預培育並不會影響藉由C2 (對照)進行之TrkB磷酸化(TrkB活化)的效能。
實例 28 ：
在存在或不存在人類 VEGF 下 ， 藉由 C2 、 TPP-14940 及 TPP-14941 ( 第二系列 ) 進行 之人類 TrkB 活化 (ERK1/2 磷酸化 ) 之比較 -- 協同效應
圖 28A 至圖 28C
在與200 ng/mL人類VEGF-A (hVEGF)一起預培育或未預培育之情況下，將穩定表現人類TrkB之CHO細胞與增加濃度之多普單抗(A) TPP-14940、(B) TPP-14941或(C) C2一起培育。藉由量測TrkB下游之T202/Y204 (ERK1)及T185/Y187 (ERK2)上之ERK1/2磷酸化評定TrkB活化。最低化合物濃度為僅溶劑。資料表示平均值+/- SEM。
結果：
此處亦出人意料地，與人類VEGF一起預培育顯著改善藉由TPP-14941 (C2作為scFv，20L3，VL-VH)進行之ERK1/2磷酸化(TrkB活化)之效能。
同樣在此處，相較於TPP-14940，對於TPP-14941而言，VEGF對於ERK1/2磷酸化(TrkB活化)之效能的影響更大。同樣，兩種分子對於TrkB磷酸化之效能均顯示協同效應，但似乎多普單抗(scFv VL-VH與scFv VH-VL與Fab)之TrkB活化部分之定向/幾何結構似乎對於協同效應具有影響，其中具有VL-VH定向之scFv為較佳的。
如先前所示，VEGF預培育亦確實不會影響藉由TPP-11736 (系列1，C2作為Fab)進行之ERK1/2磷酸化(TrkB活化)之效能。最後，VEGF預培育並不會影響藉由C2 (對照)進行之ERK1/2磷酸化(TrkB活化)的效能。
實例 29 ：
藉由單獨 VEGF 及與 BDNF 組合進行之人類 TrkB 活化 (TrkB/ERK 磷酸化 ) 之比較 -- 協同效應之對照實驗
圖 29A 至圖 29B
在具有或不具有200 ng/mL固定濃度之hVEGF之情況下，將穩定表現人類TrkB之CHO細胞與增加濃度之單獨人類VEGF-A (hVEGF)或增加濃度之BDNF一起培育。藉由量測(A) Y706/707上之TrkB磷酸化或(B)TrkB下游之分別T202/Y204 (ERK1)及T185/Y187 (ERK2)上之ERK1/2磷酸化評定TrkB活化。最低化合物濃度為僅溶劑。資料表示平均值+/- SEM。
結果：
單獨hVEGF並不會誘導TrkB或ERK1/2磷酸化。
BDNF劑量-反應曲線很大程度上與hVEGF無關。
實例 30 ：
在存在或不存在人類 VEGF 下 ， 藉由 C2 、 TPP-14940 及 TPP-14941 ( 第二系列 ) 進行 之石蟹獼猴 TrkB 活化 (TrkB 磷酸化 ) 之比較 -- 協同效應
圖 30A 至圖 30C
在與200 ng/mL人類VEGF-A (hVEGF)一起預培育或未預培育之情況下，將穩定表現石蟹獼猴TrkB之CHO細胞與增加濃度之多普單抗(A) TPP-14940、(B) TPP-14941或(C) C2一起培育。藉由量測Y706/707上之TrkB磷酸化評定TrkB活化。最低化合物濃度為僅溶劑。資料表示平均值+/- SEM。
結果：
同樣在此模型中，與人類VEGF一起預培育顯著改善藉由TPP-14941 (C2作為scFv，20L3，VL-VH)進行之TrkB磷酸化(TrkB活化)之效能。VEGF對於藉由TPP-14940 (C2作為scFv，20L3，HL)進行之TrkB磷酸化(TrkB活化)之效能的影響較小。
實例 31 ：
在存在或不存在人類 VEGF 下 ， 藉由 C2 、 TPP-14940 及 TPP-14941 ( 第二系列 ) 進行 之石蟹獼猴 TrkB 活化 (ERK1/2 磷酸化 ) 之比較 -- 協同效應
圖 31A 至圖 31C
在與200 ng/mL人類VEGF-A (hVEGF)一起預培育或未預培育之情況下，將穩定表現石蟹獼猴TrkB之CHO細胞與增加濃度之多普單抗(A) TPP-14940、(B) TPP-14941或(C) C2一起培育。藉由量測TrkB下游之T202/Y204 (ERK1)及T185/Y187 (ERK2)上之ERK1/2磷酸化評定TrkB活化。最低化合物濃度為僅溶劑。資料表示平均值+/- SEM。
結果：
同樣在此模型中，與人類VEGF一起預培育顯著改善藉由TPP-14941 (C2作為scFv，20L3，VL-VH)進行之ERK1/2磷酸化(TrkB活化)之效能。VEGF對於藉由TPP-14940 (C2作為scFv，20L3，HL)進行之ERK1/2磷酸化(TrkB活化)之效能的影響較小。
實例 32 ：
藉由 TPP-11736 (B20 作為 scFv) 、 TPP-14938 (B20 作為 Fab) 或 TPP-14939 (B20 作為 Fab) 進行 之人類 VEGF-A 清除之比較 -- VEGF 誘導之 VEGFR2 、 ERK1/2 及 Src 之磷酸化的抑制
圖 32A 至圖 32C
使人類視網膜微血管內皮細胞(HRMEC)饑餓，且接著在與增加濃度之多普單抗TPP-11736 (B20作為scFv)、TPP-14938 (B20作為Fab)或TPP-14939 (B20作為Fab)一起預培育或未預培育之情況下，與50 ng/mL人類VEGF一起培育。藉由量測(A) Y1175上之VEGF受體2 (VEGFR2)磷酸化、(B) T202/Y204 (ERK1)及T185/Y187 (ERK2)上之ERK1/2磷酸化或(C) Y419上之Src磷酸化評定VEGF-A清除。無抗體處理之50 ng/ml人類VEGF充當對照。資料表示平均值+/- SEM。下表6分別報導對應最佳擬合IC 50值及絕對功效值(底部平線區) (非線性回歸；log(促效劑)相對於反應(三個參數))。
表6：
   TPP-11736 TPP-14938 TPP-14939
IC 50(VEGFR2磷酸化) 2.36 nM 1.02 nM 0.742 nM
底部平線區 (VEGFR2磷酸化，計數) 482 129 242
IC 50(ERK1/2磷酸化) 5.59 nM 2.71 nM 2.51 nM
底部平線區 (ERK1/2磷酸化，計數) 3688 1331 1144
IC 50(Src磷酸化) 3.97 nM 1.80 nM 1.16 nM
底部平線區 (Src磷酸化，計數) 6300 5485 5538
結果：
藉由TPP-14938/39進行之VEGF清除之效能(IC 50)比TPP-11736略微更好。
藉由TPP-14938及TPP-14939進行之VEGF清除比TPP-11736更有效(底部值較小)。
總之，B20 scFv與B20 Fab之間的差異相當小且充分對應於圖17/18中顯示之先前結果：TPP-11736與TPP-13788 (B20 IgG)。總之，B20明顯相對較佳地耐受自Fab重新格式化為scFv。
實例 33 ：
藉由 TPP-11736 (B20 scFv) 、 TPP-14938 (B20 Fab) 或 TPP-14939 (B20 Fab) 進行 之人類 VEGF-A 清除之比較 -- VEGF 誘導之 HRMEC 增殖之抑制
圖 33A 至圖 33C
使人類視網膜微血管內皮細胞(HRMEC)饑餓，且接著在與增加濃度之指示結合分子一起預培育或未預培育之情況下，與10 ng/mL人類VEGF一起培育。分子濃度以mol/L為單位給出。藉由自動化基於影像之HRMEC細胞數目定量(IncuCyte)評定VEGF-A清除。每四個小時記錄影像，持續總共84小時之時段。顯示相對細胞數目。將在t = 0時之細胞數目設定為一。未刺激細胞充當對照(基礎)。資料表示平均值+/- SEM。
結果：
在增殖分析中，將B20 scFv (TPP-11736)重新格式化為B20 Fab (TPP-14938及TPP-14939)既不會改善VEGF-A清除之效能亦不會改善其功效。實際上，基於B20 Fab之抗體似乎略微比TPP-11736不太強效/有效。
實例 34 ：
藉由 TPP-14936 ( 蘭尼單抗 ， scFv ， HL) 或 TPP-14937 ( 蘭尼單抗 ， scFv ， LH) 與 TPP-14940 及 TPP-14941 ( 蘭尼單抗 Fab) 進行 之人類 VEGF-A 清除之比較 -- VEGF 誘導之 VEGFR2 、 ERK1/2 及 Src 之磷酸化的抑制
圖 34A 至圖 34C
使人類視網膜微血管內皮細胞(HRMEC)饑餓，且接著在與增加濃度之多普單抗TPP-11736 (B20作為scFv)、TPP-14936 (蘭尼單抗作為scFv，VH-VL)、TPP-14937 (蘭尼單抗作為scFv，VL-VH)、TPP-14940 (蘭尼單抗作為Fab)或TPP-14941 (蘭尼單抗作為Fab)一起預培育或未預培育之情況下，與50 ng/mL人類VEGF一起培育。藉由量測(A) Y1175上之VEGF受體2 (VEGFR2)磷酸化、(B) T202/Y204 (ERK1)及T185/Y187 (ERK2)上之ERK1/2磷酸化或(C) Y419上之Src磷酸化評定VEGF-A清除。無抗體處理之50 ng/ml人類VEGF充當對照。資料表示平均值+/- SEM。下表7分別報導對應最佳擬合IC 50值及絕對功效值(底部平線區) (非線性回歸；log(促效劑)相對於反應(三個參數))。
表7.
   TPP-11736 TPP-14936 TPP-14937 TPP-14940 TPP-14941
IC 50(VEGFR2磷酸化) 2.36 nM 1.90 nM 4.29 nM 0.373 nM 0.292 nM
底部平線區(VEGFR2磷酸化，計數) 482 -1097 -1407 -567 -763
IC 50(ERK1/2磷酸化) 5.59 nM 3.49 nM 5.58 nM 0.802 nM 0.430 nM
底部平線區(ERK1/2磷酸化，計數) 3688 -340 -926 438 1147
IC 50(Src磷酸化) 3.97 nM 3.40 nM 5.83 nM 0.276 nM 0.393 nM
底部平線區(Src磷酸化，計數) 6300 4654 4571 4771 4367
結果：
在全部三個分析中，將蘭尼單抗自scFv重新格式化為Fab顯著改善VEGF清除之效能(IC 50比蘭尼單抗scFv或參考分子TPP-11736好10倍)。
藉由基於蘭尼單抗之分子進行之VEGF清除之功效比TPP-11736好許多(底部值)。
然而，蘭尼單抗並不極好地耐受自Fab重新格式化為scFv (與B20相反，參見先前實例)。
實例 35 ：
藉由 TPP-14936 ( 蘭尼單抗作為 scFv ， VH-VL) 或 TPP-14937 ( 蘭尼單抗作為 scFv ， VL-VH) 與 TPP-14940 及 TPP-14941 ( 蘭尼單抗 Fab) 進行 之人類 VEGF-A 清除之比較 -- VEGF 誘導之 HRMEC 增殖之抑制
圖 35A 至圖 35D
使人類視網膜微血管內皮細胞(HRMEC)饑餓，且接著在與增加濃度之指示結合分子一起預培育或未預培育之情況下，與10 ng/mL人類VEGF一起培育。分子濃度以mol/L為單位給出。藉由自動化基於影像之HRMEC細胞數目定量(IncuCyte)評定VEGF-A清除。每四個小時記錄影像，持續總共84小時之時段。顯示相對細胞數目。將在t = 0時之細胞數目設定為一。未刺激細胞充當對照(基礎)。資料表示平均值+/- SEM。
結果：
在增殖分析中，將蘭尼單抗作為scFv (TPP-11736/TPP-14937)重新格式化為蘭尼單抗Fab (TPP-14940及TPP-14941)顯著改善VEGF-A清除之效能。
在TPP-14940及TPP-14941之情況下，已在0.25 nM之濃度下發現完全VEGF抑制，而完全抑制分別需要1 nM TPP-14936及4 nM TPP-14937。
在所有四種分子中，VEGF-A抑制之功效類似(全部完全抑制劑)。
實例 36 ：
藉由 TPP-14938 或 TPP-14939 (B20 Fab) 與 TPP-14940 及 TPP-14941 ( 蘭尼單抗 Fab ) 進行 之人類 VEGF-A 清除之比較 -- VEGF 誘導之 VEGFR2 、 ERK1/2 及 Src 之磷酸化的抑制
圖 36A 至圖 36C
使人類視網膜微血管內皮細胞(HRMEC)饑餓，且接著在與增加濃度之多普單抗TPP-11736 (B20作為scFv)、TPP-13938 (B20作為Fab)或TPP-13939 (B20作為Fab)、TPP-14940 (蘭尼單抗作為Fab)或TPP-14941 (蘭尼單抗作為Fab)一起預培育或未預培育之情況下，與50 ng/mL人類VEGF一起培育。藉由量測(A) Y1175上之VEGF受體2 (VEGFR2)磷酸化、(B) T202/Y204 (ERK1)及T185/Y187 (ERK2)上之ERK1/2磷酸化或(C) Y419上之Src磷酸化評定VEGF-A清除。無分子處理之50 ng/ml人類VEGF充當對照。資料表示平均值+/- SEM。下表8分別報導對應最佳擬合IC 50值及絕對功效值(底部平線區) (非線性回歸；log(促效劑)相對於反應(三個參數))。
表8：
   TPP-11736 TPP-14938 TPP-14939 TPP-14940 TPP-14941
IC 50(VEGFR2磷酸化) 2.36 nM 1.02 nM 0.742 nM 0.373 nM 2.92 nM
底部平線區(VEGFR2磷酸化，計數) 482 129 242 -567 -763
IC 50(ERK1/2磷酸化) 5.59 nM 2.71 nM 2.51 nM 0.802 nM 0.430 nM
底部平線區(ERK1/2磷酸化，計數) 3688 1331 1144 438 1147
IC 50(Src磷酸化) 3.97 nM 1.80 nM 1.16 nM 0.276 nM 0.393 nM
底部平線區(Src磷酸化，計數) 6300 5485 5538 4771 4367
結果：
在所有三個分析中，具有蘭尼單抗Fab之多普單抗顯示VEGF清除之效能明顯比基於B20 Fab之多普單抗更佳。
在所有三個分析中，具有蘭尼單抗Fab之多普單抗顯示VEGF清除之功效明顯比基於B20 Fab之多普單抗更佳(底部值)。
實例 37 ：
藉由 TPP-14938 或 TPP-14939 (B20 作為 Fab) 與 TPP-14940 及 TPP-14941 ( 蘭尼單抗作為 Fab ) 進行 之人類 VEGF-A 清除之比較 -- VEGF 誘導之 HRMEC 增殖之抑制
圖 37A 至圖 37D
使人類視網膜微血管內皮細胞(HRMEC)饑餓，且接著在與增加濃度之指示結合分子一起預培育或未預培育之情況下，與10 ng/mL人類VEGF一起培育。分子濃度以mol/L為單位給出。藉由自動化基於影像之HRMEC細胞數目定量(IncuCyte)評定VEGF-A清除。每四個小時記錄影像，持續總共84小時之時段。顯示相對細胞數目。將在t = 0時之細胞數目設定為一。未刺激細胞充當對照(基礎)。資料表示平均值+/- SEM。
結果：
相較於基於B20 Fab之分子TPP-14938及TPP-14939，藉由基於蘭尼單抗Fab之分子TPP-14940及TPP-14941抑制VEGF誘導之增殖之效能及功效明顯更優。
即使在最高濃度(16 nM)下，TPP-14938及TPP-14939未能充分抑制VEGF誘導之出芽。
相比之下，TPP-14940及TPP-14941已在低64倍的0.25 nM濃度下充分抑制VEGF誘導之增殖。
實例 38 ：
藉由 多普單抗 TPP-11736 (B20 作為 scFv) 、 TPP-14936 ( 蘭尼單抗作為 scFv ， VH-VL) 、 TPP-14937 ( 蘭尼單抗作為 scFv ， VL-VH) 、 TPP-14938 (B20 作為 Fab) 或 TPP-14939 (B20 Fab) 、 TPP-14940 ( 蘭尼單抗作為 Fab) 、 TPP-14941 ( 蘭尼單抗作為 Fab) 或艾力雅進行之人類 VEGF-A 清除之比較 -- VEGF 誘導之 HRMEC 出芽的抑制
圖 38
人類視網膜微血管內皮細胞(HRMEC)之球體包埋於膠原蛋白基質中。藉由在與2.5 nM之多普單抗TPP-11736 (B20 scFv)、TPP-14936 (蘭尼單抗scFv，VH-VL)、TPP-14937 (蘭尼單抗scFv，VL-VH)、TPP-14938 (B20 Fab)、TPP-14939 (B20 Fab)、TPP-14940 (蘭尼單抗Fab)、TPP-14941 (蘭尼單抗Fab)或5nM艾力雅一起預培育或未預培育之情況下，與50 ng/mL人類VEGF一起培育來誘導內皮出芽24小時。內皮出芽藉由共焦顯微術評定且顯示獲自Z-堆疊之最大投影的球體周界。未刺激細胞充當對照(基礎)。資料表示平均值+/- SEM。n.s. p＞0.05無顯著差異；相較於50 ng/mL hVEGF， §p＜0.0001；相較於50 ng/mL hVEGF，#p＞0.05無顯著差異。***p＜0.001；單向Anova與Tukey多比較測試。
結果：
在此分析中，基於蘭尼單抗Fab之多普單抗TPP-14940及TPP-14941明顯為最佳VEGF清除劑。與艾力雅相比，TPP-14940及TPP-14941充分抑制VEGF誘導之出芽；在不存在VEGF (基礎)下之內皮出芽與50 ng/mL hVEGF (與2.5 nM TPP-14940或TPP-14941一起預培育)之內皮出芽之間未發現統計學上顯著差異。
藉由TPP-14940及TPP-14941抑制VEGF誘導之EC出芽顯著比藉由任何其他多普單抗抑制更好。
藉由TPP-14940及TPP-14941抑制VEGF誘導之EC出芽顯著比藉由艾力雅抑制更好。
此外，在用50 ng/mL hVEGF與50 ng/mL hVEGF (與艾力雅一起預培育)刺激之內皮出芽之間不存在統計學上顯著差異。
實例 39 ：
藉由多普單抗 TPP-11940 及艾力雅進行之人類 VEGF-A 清除之比較 -- 在 Brown Norway 大鼠中 ， 人類 VEGF-A 誘導之視網膜高滲透性之抑制
圖 39A 至圖 39B
TPP-14940 (但並非艾力雅)防止大鼠視網膜中之人類VEGF-A誘導之高滲透性。(A)顯示實驗程序之時間方案。在玻璃體內(ivt)投與抗VEGF化合物(每隻眼睛13或26 pmol之艾力雅或TPP-14940)或對照(26 pmol TPP-11737)之後十五分鐘，藉由ivt注射每隻眼睛投與13 pmol人類VEGF-A。PBS注射充當對照。二十四小時後，在分離及固定眼睛之前藉由靜脈內(iv)注射投與1 mL/kg伊凡氏藍(Evans Blue；EB)溶液(45 mg/mL於0.9%鹽水中)30分鐘。在相同時間點收集血漿樣品以確認相等全身性EB暴露。(B)藉由利用共焦顯微術量測視網膜鋪片中之EB外滲來定量Brown Norway大鼠之視網膜中之VEGF-A誘導的高滲透性。沿著鋸齒緣切割眼睛，移除晶狀體及玻璃體，且將眼杯固定在4℃下之多聚甲醛(4%)中1 h且接著轉移至在4℃之PBS隔夜。將視網膜與外部區段(鞏膜及脈絡膜)分開，且轉移至載玻片並切割四次以達成平坦三葉草樣結構。組織用封固劑(含有DNA染料DAPI之Vectashield H-1200)覆蓋且將蓋玻片置於頂部上以獲得視網膜鋪片。樣品在639 nm波長下激發，且用LSM 700共焦雷射掃描顯微鏡(Carl Zeiss, Jena；放大率800，雷射強度2%，60 µm之5個堆疊)記錄伊凡氏藍在669 nm下的發射，且獲得具有最大強度投影之視網膜鋪片的影像。在臨限值為30之程式ImageJ中打開影像之後，進行螢光強度總和之分析。***p＜0.001；*p＜0.05；n.s.p＞0.05；相對於TPP-11737 + PBS，#p＞0.05不顯著。單向Anova與Tukey多比較測試，n = 9-17。
結果：
在對照條件下，玻璃體內VEGF-A注射增加血管滲透性約60%。TPP-11737用作對照抗體，因為其該與TPP-14940相同的分子格式(多普單抗)，但在先前活體外分析中，該化合物並不清除VEGF。
在1:1及2:1分子比之結合分子與VEGF下，TPP-14940完全阻斷血管高滲透性。然而，在急劇對比中，艾力雅在相同條件下且甚至在倍增濃度下未能顯著降低血管滲漏。
系列2：TPP-14938、TPP-14939、TPP-14940、TPP-14941之發現之概述
TrkB活化：
與TPP-11736形成強烈對比，所有四種新多普單抗均為完全TrkB受體促效劑。藉由彼等多普單抗進行之TrkB活化與天然配體BDNF一樣有效。
相對於TPP-14939及TPP-14941，具有「VH-VL」定向之多普單抗TPP-14938/40中之TrkB活化之效能略微更好。
出人意料地，與人類VEGF一起預培育顯著改善藉由TPP-14941 [C2，scFv，20L3，VL-VH]進行之TrkB磷酸化(TrkB活化)的效能，從而指出協同效應。
與TPP-14941相比，VEGF對於藉由TPP-14940 [C2，scFv，20L3，VH-VL]進行之TrkB磷酸化(TrkB活化)之效能的影響相對較地更小。
VEGF清除：
在增殖分析中，將B20 scFv (TPP-11736)重新格式化為B20 Fab (TPP-14938及TPP-14939)既不會改善VEGF-A清除之效能亦不會改善其功效。
在增殖分析中，將蘭尼單抗scFv (TPP-11736/TPP-14937)重新格式化為蘭尼單抗Fab (TPP-14940及TPP-14941)顯著改善VEGF-A清除之效能。
在TPP-14940及TPP-14941之情況下，已在低至0.25 nM之濃度下發現完全VEGF抑制。
相較於基於B20 Fab之分子TPP-14938及TPP-14939，藉由基於蘭尼單抗Fab之分子TPP-14940及TPP-14941抑制VEGF誘導之增殖之效能及功效更優。
因為本發明人觀測到結合分子中之連接子截割(clipping) (資料未顯示)，所以在以下實例中，基於以下衍生其他分子：TPP-14940：TPP-19986 (VH-VL，10L1)、TPP-19987 (VH-VL，20L1)；及基於TPP-14941：TPP-19988 (VL-VH，10L1)、TPP-19989 (VL-VH，20L1)，其全部均基於蘭尼單抗作為Fab及C2作為scFv。
實例 40 ：
藉由 BDNF 、 TPP- 14940 [C2 ， scFv ， 20L3 ， VH-VL] 或其連接子變體 TPP-19986 [C2 ， scFv ， 10L1 ， VH-VL] 或 TPP-19987 [C2 ， scFv ， 20L1 ， VH-VL] 、或 TPP- 14941 [C2 ， scFv ， 20L3 ， VL-VH] 及其連接子變體 TPP- 19988 [C2 ， scFv ， 10L1 ， VL-VH] 或 TPP- 19989 [C2 ， scFv ， 20L1 ， VL-VH] 進行 之人類 TrkB 活化之比較 ； TrkB 及 ERK1/2 磷酸化 -- 系列 3
圖 40A 至圖 40D
將穩定表現人類TrkB之CHO細胞與增加濃度之天然TrkB配體BDNF、TPP-14940 [C2，scFv，20L3，VH-VL]或其連接子變體TPP-19986 [C2，scFv，10L1，VH-VL]或TPP-19987 [C2，scFv，20L1，VH-VL]、或TPP-14941 [C2，scFv，20L3，V-VH]及其連接子變體TPP-19988 [C2，scFv，10L1，VL-VH]或TPP-19989 [C2，scFv，20L1，VL-VH]一起培育。藉由(A及B)量測Y706/707上之TrkB磷酸化或藉由(C及D)分別量測T202/Y204 (ERK1)及T185/Y187 (ERK2)上之ERK1/2磷酸化評定TrkB活化。最低化合物濃度為僅溶劑。資料表示平均值+/- SEM。下表9及10分別報導TrkB及ERK1/2磷酸化之對應最佳擬合EC 50值(非線性回歸；log(促效劑)相對於反應(三個參數))。
表9：
   BDNF TPP-14940 TPP-19986 TPP-19987
EC 50(pTrkB) 1.22 nM 3.21 nM 2.00 nM 2.16 nM
EC 50(pERK) 0.507 nM 0.475 nM 0.406 nM 0.381 nM
表10：
   BDNF TPP-14941 TPP-19988 TPP-19989
EC 50(pTrkB) 1.28 nM 6.28 nM 7.83 nM 7.37 nM
EC 50(pERK) 0.282  nM 1.29 nM 2.05 nM 1.77 nM
結果：
親本分子與各別連接子變體之間不存在顯著差異。TrkB及ERK1/2磷酸化之效能及功效幾乎一致。此為值得注意的，因為連接子位於TrkB結合位點附近，但並不會影響結合分子之生物活性。
所有所測試分子均為完全TrkB促效劑。
同樣，如先前所示，相較於TPP-14941分子及其連接子變體(VL-VH定向)，TPP-14940分子及其連接子變體(VH-VL定向)之TrkB/ERK磷酸化的效能更好。
實例 41 ：
藉由 BDNF 、 TPP- 14940 [C2 ， scFv ， 20L3 ， VH-VL] 或 TPP- 14941 [C2 ， scFv ， 20L3 ， VL-VH] 及連接子變體 TPP- 19988 [C2 ， scFv ， 10L1 ， VL-VH] 或 TPP- 19989 [C2 ， scFv ， 20L1 ， VL-VH] 進行 之人類TrkB 內化之比較 -- 系列3
圖 41A 至圖 41B
將穩定表現石蟹獼猴TrkB之CHO細胞與增加濃度之天然TrkB配體BDNF、或1 nM BDNF與增加濃度之第一系列之多普單抗TPP-14940 [C2，scFv，20L3，VH-VL]或TPP-14941 [C2，scFv，20L3，VL-VH]及連接子變體TPP-19988 [C2，scFv，10L1，VL-VH]或TPP-19989 [C2，scFv，20L1，VL-VH]一起培育。藉由在不滲透細胞之情況下對表面TrkB受體進行免疫螢光染色，隨後共焦顯微分析來評定TrkB內化。熱圖之深色及淺色場分別表示高於螢光臨限值之高及低百分比的細胞。
結果：
BDNF誘導TrkB受體內化。儘管TPP-14940、TPP-14941、TPP-19988及TPP-19989為完全TrkB受體促效劑，但多普單抗中無一者增加BDNF誘導之受體內化而實際上降低BDNF誘導之TrkB受體的內化(注意：熱圖場由下至上變得更暗)。
實例 42 ：
藉由 TPP-14940 及其連接子變體 TPP-19986 、及 TPP-14941 及其連接子變體 TPP-19988 進行 之人類 VEGF-A 清除之比較 -- VEGF 誘導之 VEGFR2 之磷酸化的抑制 -- 系列 3
圖 42
使人類視網膜微血管內皮細胞(HRMEC)饑餓，且接著在與增加濃度之多普單抗TPP-14940及其連接子變體TPP-19986、及TPP-14941及其連接子變體TPP-19988一起預培育或未預培育之情況下，與50 ng/mL人類VEGF一起培育。藉由量測Y1175上之VEGF受體2 (VEGFR2)磷酸化評定VEGF-A清除。無分子處理之50 ng/ml人類VEGF充當對照。資料表示平均值+/- SEM。下表11報導VEGFR2磷酸化之抑制之對應最佳擬合IC 50值(非線性回歸；log(促效劑)相對於反應(三個參數))。
表11：
   TPP-14940 TPP-19986 TPP-19987 TPP-14941 TPP-19988 TPP-19989
IC 50(VEGFR2磷酸化) 0.280 nM 0.142 nM 0.188 nM 0.225 nM 0.281 nM 0.268 nM
結果：
親本分子TPP-14940/TPP-14941與各別連接子變體之間不存在顯著差異。VEGF誘導之VEGFR2磷酸化之抑制之效能及功效幾乎一致。
實例 43 ：
藉由 多普單抗 TPP- 14940 [C2 ， scFv ， 20L3 ， VH-VL] 或其連接子變體 TPP-19986 [C2 ， scFv ， 10L1 ， VH-VL] 或 TPP-19987 [C2 ， scFv ， 20L1 ， VH-VL] 、或 TPP- 14941 [C2 ， scFv ， 20L3 ， VL-VH] 及其連接子變體 TPP- 19988 [C2 ， scFv ， 10L1 ， VL-VH] 或 TPP- 19989 [C2 ， scFv ， 20L1 ， VL-VH] 進行 之人類 VEGF-A 清除之比較 -- VEGF 誘導之 HRMEC 出芽的抑制 -- 系列 3
圖 43
人類視網膜微血管內皮細胞(HRMEC)之球體包埋於膠原蛋白基質中。藉由在與2.5 nM之多普單抗TPP-11736 (B20 scFv)、TPP-14940 [C2，scFv，20L3，VH-VL]或其連接子變體TPP-19986 [C2，scFv，10L1，VH-VL]或TPP-19987 [C2，scFv，20L1，VH-VL]、或TPP-14941 [C2，scFv，20L3，VL-VH]及其連接子變體TPP-19988 [C2，scFv，10L1，VL-VH]或TPP-19989 [C2，scFv，20L1，VL-VH]一起預培育或未預培育之情況下，與50 ng/mL人類VEGF一起培育來誘導內皮出芽24小時。內皮出芽藉由共焦顯微術評定且顯示獲自Z-堆疊之最大投影的球體周界。未刺激細胞充當對照(基礎)。資料表示平均值+/- SEM。n.s. p＞0.05無顯著差異；相較於50 ng/mL hVEGF， §p＜0.0001；相較於50 ng/mL hVEGF，#p＞0.05無顯著差異。***p＜0.001；單向Anova與Tukey多比較測試。
結果：
親本分子TPP-14940/TPP-14941與各別連接子變體之間未觀測到顯著差異。所有分子均充分抑制VEGF誘導之HRMEC出芽。
系列3：TPP-19986、19987、19988、19989之發現之概述
TrkB活化：
在親本分子(TPP-14940/14941)與各別連接子變體之間未觀測到顯著差異。
所有所測試結合分子均為完全TrkB受體促效劑。VH-VL定向及其連接子變體仍然更強效。
未觀測到受體內化之變化。考慮到新多普單抗類似於BDNF為完全TrkB受體促效劑，此為極其出人意料。
VEGF清除：
在親本分子(TPP-14940/14941)與各別連接子變體之間未觀測到顯著差異。
CMC特性：
在使用連接子10L1及20L1連接子之情況下，不再觀測到連接子截割(資料未顯示)。
作為下一步驟，設計最後一個系列之結合分子(系列4)，以改善結合分子之CMC以及生物物理學特性，但始終嘗試保留本發明之結合分子的優良生物功能。
實例 44 ：
藉由在 TrkB scFv 部分中不具有或具有二硫橋鍵 (CC) 之多普單抗進行 之人類 TrkB 活化之比較 ； TrkB 磷酸化 -- 系列 4
圖 44A 至圖 44D
將穩定表現人類TrkB之CHO細胞與增加濃度之在抗TrkB scFv部分中具有/不具有CC橋鍵之指示多普單抗一起培育。(A) TPP-22180與TPP-22204；(B) TPP-22192與TPP-22216；(C) TPP-22190與TPP-22214；(D) TPP-22191與TPP-22215。藉由量測Y706/707上之TrkB磷酸化評定TrkB活化。最低化合物濃度為僅溶劑。資料表示平均值+/- SEM。下表12分別報導TrkB活化之對應最佳擬合EC 50值及絕對或相對功效值(頂部平線區) (非線性回歸；log(促效劑)相對於反應(三個參數))。
表12：
TPP 圖 描述 TrkB 磷酸化效能 (EC 50 ， nM) TrkB 磷酸化功效 (AlphaLISA 計數 ) 相對於無 CC 橋鍵之親本純系之 TrkB 磷酸化功效 (%)
TPP-22180 A (1Q6Q70G_TrkB-C2-VH-VL_10L1) 8.09 6642 100
TPP-22204 A (1Q6Q70G_TrkB-C2-VH-VL_10L1, CC) 3.88 7613 115
TPP-22192 B (1Q6Q70G_TrkB-C2-VL-VH_10L1) 12.2 5642 100
TPP-22216 B (1Q6Q70G_TrkB-C2-VL-VH_10L1, CC) 4.33 8407 149
TPP-22190 C (1Q70G_TrkB-C2-VL-VH_10L1) 9.95 4225 100
TPP-22214 C (1Q70G_TrkB-C2-VL-VH_10L1, CC) 2.18 5102 121
TPP-22191 D (6Q70G_TrkB-C2-VL-VH_10L1) 5.49 4848 100
TPP-22215 D (6Q70G_TrkB-C2-VL-VH_10L1, CC) 1.12 5793 119
結果：
引入二硫橋鍵主要為了改善結合分子之CMC特性。出人意料地，藉由在scFv抗TrkB部分中包括二硫橋鍵，進一步改善TrkB活化之效能及功效。在具有VL-VH定向之結合分子中觀測到較大影響。
實例 45 ：
藉由在 TrkB scFv 部分中具有或不具有二硫橋鍵 (CC) 之多普單抗進行 之大鼠 TrkB 活化之比較 ； TrkB 磷酸化 -- 系列 4
圖 45A 至圖 45B
將穩定表現大鼠TrkB之CHO細胞與增加濃度之在抗TrkB scFv部分中具有/不具有CC橋鍵之指示多普單抗一起培育。(A) TPP-22180與TPP-22204；(B) TPP-22192與TPP-22216。藉由量測Y706/707上之TrkB磷酸化評定TrkB活化。最低化合物濃度為僅溶劑。資料表示平均值+/- SEM。下表13分別報導TrkB活化之對應最佳擬合EC 50值及絕對或相對功效值(頂部平線區) (非線性回歸；log(促效劑)相對於反應(三個參數))。
表13：
TPP 圖 描述 TrkB 磷酸化效能 (EC 50 ， nM) TrkB 磷酸化功效 (AlphaLISA 計數 ) 相對於無 CC 橋鍵之親本純系之 TrkB 磷酸化功效 (%)
TPP-22180 A (1Q6Q70G_TrkB-C2-VH-VL_10L1) 4.21 19676 100
TPP-22204 A (1Q6Q70G_TrkB-C2-VH-VL_10L1, CC) 2.01 21787 111
TPP-22192 B (1Q6Q70G_TrkB-C2-VL-VH_10L1) 18.9 21213 100
TPP-22216 B (1Q6Q70G_TrkB-C2-VL-VH_10L1, CC) 3.31 25808 122
結果：
在scFv抗TrkB部分中包括二硫橋鍵改善TrkB活化之效能及功效。同樣，對於VL-VH定向之結合分子之影響似乎較大。總體而言，資料與針對人類TrkB所獲得之資料良好一致。
實例 46 ：
TPP-22204/22214 介導之 TrkB 活化之選擇性
圖 46
將穩定表現(A)人類TrkA、(B)人類TrkB或(C)人類TrkC之CHO細胞與增加濃度之C2抗體或多普單抗TPP-22204或TPP-22214一起培育。藉由量測Y706/707上之受體磷酸化評定Trk受體之活化。與增加濃度之TrkA (NGF)、TrkB (BDNF)及TrkC (NT-3)之天然配體一起培育用作對照。最低化合物濃度為僅溶劑。資料表示平均值+/- SEM。
結果：
兩種多普單抗對於TrkB均極具特異性/選擇性--其中無一者活化TrkA或TrkC。
實例 47 ：
TPP-22214 對於 BDNF 誘導之 TrkB 活化之影響
圖 47A 至圖 47B
在具有或不具有0.3 nM、1 nM或3 nM恆定濃度之BDNF之情況下，將穩定表現人類TrkB受體之CHO細胞與增加濃度之(A) C2抗體或(B)多普單抗TPP-22214一起培育。藉由量測Y706/707上之受體磷酸化評定TrkB之活化。資料表示平均值+/- SEM。
結果：
與C2形成強烈對比，TPP-22214並不會限制BDNF誘導之TrkB活化。
實例 48 ：
在存在或不存在人類 VEGF 下 ， 藉由 TPP-22214 進行 之人類 TrkB 活化 (TrkB 磷酸化 ) 之比較
圖 48A 至圖 48D
在與(A) 200 ng/mL人類VEGF-A (hVEGF)、(B) 50 ng/mL hVEGF、(C) 10 ng/mL hVEGF或(D) 2 ng/mL hVEGF一起預培育或未預培育之情況下，將穩定表現人類TrkB之CHO細胞與增加濃度之多普單抗TPP-22214一起培育。藉由量測Y706/707上之TrkB磷酸化評定TrkB活化。最低化合物濃度為僅溶劑。資料表示平均值+/- SEM。
結果：
如之前所示，與200 ng/mL人類VEGF一起預培育改善藉由TPP-22214進行之TrkB磷酸化(TrkB活化)之效能。更重要的是，此協同效應在50、10及甚至2 ng/mL hVEGF下很大程度上保留。在諸如石蟹獼猴之其他物種中亦獲得類似效果(資料未顯示)。
實例 49 ：
在存在或不存在人類 VEGF 下 ， 藉由 TPP-22214 進行 之人類 TrkB 活化 (ERK 磷酸化 ) 之比較
圖 49A 至圖 49D
在與(A) 200 ng/mL人類VEGF-A (hVEGF)、(B) 50 ng/mL hVEGF、(C) 10 ng/mL hVEGF或(D) 2 ng/mL hVEGF一起預培育或未預培育之情況下，將穩定表現人類TrkB之CHO細胞與增加濃度之多普單抗TPP-22214一起培育。藉由量測TrkB下游之T202/Y204 (ERK1)及T185/Y187 (ERK2)上之ERK1/2磷酸化評定TrkB活化。最低化合物濃度為僅溶劑。資料表示平均值+/- SEM。
結果：
同樣，與200 ng/mL人類VEGF一起預培育亦改善藉由TPP-22214進行之TrkB活化下游之ERK磷酸化的效能。同樣在此分析中，協同效應在低至2 ng/mL hVEGF之濃度下很大程度上保留。在諸如石蟹獼猴之其他物種中亦獲得類似效果(資料未顯示)。
實例 50 ：
VEGF 結合加強 TrkB 活化研究所提出之機制
圖 50
藉由以所描述之莫耳比(1:1、4:1或20:1)，將樣品一起混合在1x杜氏PBS (Dulbecco's PBS)中來製備TPP-22214與hVEGF之複合物。在分析之前，在室溫培育樣品1小時。與迷你DAWN TREOS及Optilab REX串聯使用Agilent 1200。使樣品以0.6 ml/min之流速在作為移動相之1x杜氏PBS中運行。將100 μl複合物或單獨TPP-22214注射至Superose 6 Increase管柱(30 cm × 10 mm)上，其中分子藉由流體動力學體積進行分離。接著使用Astra 6.1.1.17分析資料。
結果：
在VEGF-A存在下，TPP-22214形成複合物，其中最大複合物在1:1莫耳比下形成。此等複合物表明多普單抗及VEGF在超出1:1比率外複合。此等較大複合物可導致TrkB受體在細胞表面上聚類。實驗資料支持所提出之機制。
實例 51 ：
藉由增加濃度之 BDNF 或 TPP-22214 ， 及在 1 nM BDNF 存在下增加濃度之 TPP-22214 進行 之人類 TrkB 內化之比較
圖 51A 至圖 51C
將穩定表現人類TrkB之CHO細胞與(A)增加濃度之天然TrkB配體BDNF、(B)增加濃度之TPP-22214或(C) 1 nM BDNF與增加濃度之TPP-22214一起培育。藉由在不滲透細胞之情況下對表面TrkB受體進行免疫螢光染色，隨後共焦顯微分析來評定TrkB內化。資料表示表面TrkB染色強度高於臨限值之細胞百分比；平均值+/- SEM。
結果：
(A)與BDNF一起培育誘導TrkB受體內化。
(B) TPP-22214並不會誘導TrkB受體內化。
(C)藉由增加TPP-22214之濃度，BDNF誘導之受體內化降低/消除。
實例 52 ：
STZ 誘導之糖尿病大鼠中之 TPP-22214 及 C2 之神經保護功效
圖 52
使用IVT注射促效TrkB抗體(C2)以及多普單抗TPP-22214，糖尿病誘導之視網膜神經退化大鼠模型中之TrkB活化之神經保護功能。動物用STZ處理以誘導高血糖症。藉由在治療前後進行視網膜電描記術(ERG)評定視網膜功能。糖尿病誘導導致在STZ治療後3週內延遲隱含時間。在此時間點，對動物玻璃體內給藥同型對照抗體(抗TNP)或C2 (各19 µg/5 µl)、或等莫耳量之TPP-22214 (25 µg/5 µl)。描繪在即將玻璃體內施用分子之前及其兩週後之視桿驅動之B波隱含時間延遲；平均值+/- SEM； n.s.p＞0.05；不顯著(n.s.)，****p＜0.0001；單向Anova與Tukey多比較測試。
結果：
在投與之後兩週，相較於在抗TNP治療之前之時間點，抗TNP抗體治療並不會降低糖尿病誘導之視桿驅動之b波隱含時間。實際上，相較於在抗TNP抗體施用之前之時間點，隱含時間延遲甚至顯著增加(在t = 2週時，17.1 ms；相對於在t = 0週時，11.2 ms；****p＜0.0001)。此指示，STZ誘導之視網膜損傷在t = 0週時未完全確立，及抗TNP治療不能阻止隱含時間延遲進一步增加。
在投與之後兩週，C2抗體治療阻斷隱含時間延遲之進一步增加。然而，相較於在C2治療之前之時間點，C2抗體治療並不會顯著降低糖尿病誘導之視桿驅動之b波隱含時間(在t = 2週時，10.3 ms；相對於在t = 0週時，12.8 ms， n.s.p＞0.05；不顯著)。
在投與之後兩週，相較於在TPP-22214治療之前之時間點，TPP-22214抗體治療阻斷隱含時間延遲之進一步增加，且甚至顯著降低糖尿病誘導之視桿驅動之b波隱含時間超過40% (在t = 2週時，8.3 ms；相對於在t = 0週時，14.2 ms，****p＜0.0001)。
實例 53 ：
藉由不具有或具有二硫橋鍵 (CC) 之多普單抗以 及親本分子 TPP-14940/TPP-14941 進行 之人類 VEGF-A 清除之比較 -- VEGF 誘導之 VEGFR2 之磷酸化的抑制
圖 53A 至圖 53B
藉由量測Y1175上之VEGF受體2 (VEGFR2)磷酸化評定VEGF-A清除。無分子處理之50 ng/ml人類VEGF充當對照。資料表示平均值+/- SEM。下表14報導對應最佳擬合IC 50值(非線性回歸；log(促效劑)相對於反應(三個參數))。
表14：
TPP 圖 描述 VEGF誘導之VEGFR2磷酸化之抑制(IC 50，nM)
TPP-14941 A (TrkB-C2-VL-VH,_20L3) 0.225
TPP-22180 A (1Q6Q70G_TrkB-C2-VH-VL_10L1) 0.210
TPP-22204 A (1Q6Q70G_TrkB-C2-VH-VL_10L1, CC) 0.199
TPP-22192 A (1Q6Q70G_TrkB-C2-VL-VH_10L1) 0.264
TPP-22216 A (1Q6Q70G_TrkB-C2-VL-VH_10L1, CC) 0.331
TPP-14940 B TrkB-C2-VH-VL,_20L3) 0.165
TPP-14941 B (TrkB-C2-VL-VH,_20L3) 0.173
TPP-22190 B (1Q70G_TrkB-C2-VL-VH_10L1) 0.235
TPP-22214 B (1Q70G_TrkB-C2-VL-VH_10L1, CC) 0.242
TPP-22191 B (6Q70G_TrkB-C2-VL-VH_10L1) 0.233
TPP-22215 B (6Q70G_TrkB-C2-VL-VH_10L1, CC) 0.195
結果：
在親本分子TPP-14940/TPP-14941與具有或不具有二硫橋鍵之各別多普單抗變體之間不存在顯著差異。VEGF誘導之VEGFR2磷酸化之抑制之效能及功效幾乎一致。
實例 54 ：
藉由 TPP-22214 或艾力雅進行之人類 VEGF-A 清除之比較 -- Y1175 上及 ERK1/2 之 VEGF 誘導之 VEGFR2 磷酸化之抑制 ( 兩者均與 EC 增殖相關 )
圖 54A 至圖 54B
使人類視網膜微血管內皮細胞(HRMEC)饑餓，且接著在與增加濃度之TPP-22214或艾力雅一起預培育或未預培育之情況下，與50 ng/mL人類VEGF一起培育。藉由量測(A) Y1175上之VEGF受體2 (VEGFR2)磷酸化或(B) T202/Y204 (ERK1)及T185/Y187 (ERK2)上之ERK1/2磷酸化評定VEGF-A清除。無分子處理之50 ng/ml人類VEGF充當對照。資料表示平均值+/- SEM。下表15報導形成非線性回歸之對應最佳擬合值(log(促效劑)相對於反應(三個參數))。在艾力雅與TPP-22214之間顯著不同(P＜0.05)之最佳擬合值以粗體顯示。P值亦在表15中報導。
表15：
VEGF誘導之VEGFR2磷酸化之抑制(Y1175) 圖 艾力雅 TPP-22214 P值
頂部平線區(AlphaLISA計數) A 17523 18104 0.4629
IC 50(nM) A 0.339 0.186 -
LogIC 50 A -9.470 -9.731 0.0245
底部平線區 (AlphaLISA 計數 ) A 4031 -761.9 ＜0.0001
  
VEGF誘導之ERK1/2磷酸化之抑制(T202/Y204 (ERK1)及T185/Y187 (ERK2)) 圖 艾力雅 TPP-22214 P值
頂部平線區(AlphaLISA計數) B 108769 111446 0.7349
IC 50(nM) B 1.95 0.415 -
LogIC 50 B -8.709 -9.382 0.0087
底部平線區 (AlphaLISA 計數 ) B 21745 -7737 0.0024
結果：
相較於艾力雅，TPP-22214充分抑制VEGF誘導之Y1175上之VEGFR2的磷酸化及ERK1/2的磷酸化。亦可在底部平線區之值之高度顯著差異上看見TPP-22214之VEGF清除之經改善功效(參見表15)。最後，TPP-22214在VEGF清除中比艾力雅顯著更強效。
實例 55 ：
藉由 TPP-22204 、 TPP-22214 或 TPP-22216 與 艾力雅進行之人類 VEGF-A 清除之比較 -- VEGF 誘導之 HRMEC 增殖之抑制
圖 55A 至圖 55E
使人類視網膜微血管內皮細胞(HRMEC)饑餓，且接著在與增加濃度之指示結合分子：(A) TPPP-22204、(B) TPP-22214、(C) TPP-22216或(D)艾力雅一起預培育或未預培育之情況下，與10 ng/mL人類VEGF一起培育。藉由自動化基於影像之HRMEC細胞數目定量(IncuCyte)評定VEGF-A清除。每四個小時記錄影像，持續總共84小時之時段。顯示相對細胞數目。將在t = 0時之細胞數目設定為一。未刺激細胞充當對照(基礎)。資料表示平均值+/- SEM。(E)相對於艾力雅或TPP-22214之濃度之生長曲線及基礎曲線下面積之差異的曲線。下表16報導形成非線性回歸之對應最佳擬合值(log(促效劑)相對於反應(三個參數))。在艾力雅與TPP-22214之間顯著不同(P＜0.05)之最佳擬合值以粗體顯示。P值亦在表16中報導。
表16：
VEGF誘導之HRMEC增殖之抑制△ (相對於基礎之曲線下面積) 圖 艾力雅 TPP-22214 P值
頂部平線區(任意單位) E 128.9 128.3 0.9406
IC 50(pM) E 171 88.7 -
LogIC 50 E -9.767 -10.05 0.0093
底部平線區 ( 任意單位 ) E 13.3 -14.2 ＜0.0001
結果：
藉由多普單抗抑制VEGF誘導之增殖之效能及功效明顯優於艾力雅(TPP-22214與艾力雅之間的LogIC 50值及底部平線區值之高度顯著差異)。
即使在最高濃度(16 nM)下，艾力雅未能充分抑制VEGF誘導之出芽。相比之下，所有多普單抗已在降低64倍之濃度0.25 nM下充分抑制VEGF誘導之增殖。
實例 56 ：
藉由 TPP-22214 或艾力雅進行之人類 VEGF-A 清除之比較 -- Y1214 上之 VEGFR2 及 p38-MAPK 之 VEGF 誘導之 磷酸化的抑制
圖 56A 至圖 56B
使人類視網膜微血管內皮細胞(HRMEC)饑餓，且接著在與增加濃度之TPP-22214或艾力雅一起預培育或未預培育之情況下，與50 ng/mL人類VEGF一起培育。藉由量測(A) Y1214上之VEGF受體2 (VEGFR2)磷酸化或(B) T180/Y182上之p38-MAPK磷酸化評定VEGF-A清除。無分子處理之50 ng/ml人類VEGF充當對照。資料表示平均值+/- SEM。下表17報導形成非線性回歸之對應最佳擬合值(log(促效劑)相對於反應(三個參數))。在艾力雅與TPP-22214之間顯著不同(P＜0.05)之最佳擬合值以粗體顯示。P值亦在表17中報導。
表17：
VEGF誘導之VEGFR2磷酸化之抑制(Y1214) 圖 艾力雅 TPP-22214 P值
頂部平線區(AlphaLISA計數) A 7150 7275 0.7759
IC 50(nM) A 0.437 0.278 -
LogIC 50 A -9.360 -9.555 0.1991
底部平線區 (AlphaLISA 計數 ) A 1429 -245.0 ＜0.0001
  
VEGF誘導之p38-MAPK磷酸化之抑制(T180/Y182) 圖 艾力雅 TPP-22214 P值
頂部平線區(AlphaLISA計數) B 23071 25363 0.1608
IC 50(nM) B 0.748 0.472 -
LogIC 50 B -9.126 -9.326 0.4202
底部平線區 (AlphaLISA 計數 ) B 8894 -1489 ＜0.0001
結果：
與艾力雅形成強烈對比，TPP-22214充分抑制Y1214上之VEGFR2及p38-MAPK之VEGF誘導的磷酸化。根據表17中底部平線區之值之高度顯著差異可發現TPP-22214之更有效VEGF清除。此外，觀測到藉由TPP-22214進行之VEGF清除之效能比艾力雅更佳之趨勢。
實例 57 ：
藉由 TPP-22204 、 TPP-22214 、 TPP-22215 或 TPP-22216 與 艾力雅進行之人類 VEGF-A 清除之比較 -- VEGF 誘導之 HRMEC 出芽之抑制
圖 57A 至圖 57B
人類視網膜微血管內皮細胞(HRMEC)之球體包埋於膠原蛋白基質中。藉由在與2.5 nM之TPP-22204、TPP-22214、TPP-22215或TPP-22216、或5 nM艾力雅一起預培育或未預培育之情況下，與50 ng/mL人類VEGF一起培育來誘導內皮出芽24小時。(A)內皮出芽藉由共焦顯微術評定且顯示獲自Z-堆疊之最大投影的球體周界。未刺激細胞充當對照(基礎)。資料表示平均值+/- SEM。n.s. p＞0.05，不顯著，****p＜0.0001。(B)顯示在基礎條件下出芽24小時之後或在與2.5 nM TPP-22214或5 nM艾力雅一起預培育或未預培育之情況下用50 ng/mL人類VEGF刺激之後，來自球體的代表性最大投影影像。條= 100 µm。
結果：
類似於Y1214 VEGFR2磷酸化分析，多普單抗在抑制VEGF誘導之HRMEC出芽中更有效許多。此外，多普單抗能夠充分抑制VEGF誘導之內皮細胞出芽。值得注意的是，以相較於多普單抗兩倍之分子濃度使用艾力雅，且仍不能夠充分抑制細胞出芽。
實例 58 ：
藉由 TPP-22214 或艾力雅進行之人類 VEGF-A 清除之比較 -- Y951 上之 VEGFR2 及 Src 之 VEGF 誘導之 磷酸化的抑制
圖 58A 至圖 58B
使人類視網膜微血管內皮細胞(HRMEC)饑餓，且接著在與增加濃度之TPP-22214或艾力雅一起預培育或未預培育之情況下，與50 ng/mL人類VEGF一起培育。藉由量測(A) Y951上之VEGF受體2 (VEGFR2)磷酸化或(B) Y419上之Src磷酸化評定VEGF-A清除。無抗體處理之50 ng/ml人類VEGF充當對照。資料表示平均值+/- SEM。下表18報導形成非線性回歸之對應最佳擬合值(log(促效劑)相對於反應(三個參數))。在艾力雅與TPP-22214之間顯著不同(P＜0.05)之最佳擬合值以粗體顯示。P值亦在表18中報導。
表18：
VEGF誘導之VEGFR2磷酸化之抑制(Y951) 圖 艾力雅 TPP-22214 P值
頂部平線區(AlphaLISA計數) A 20491 20757 0.8567
IC50 (nM) A 0.540 0.340 -
LogIC 50 A -9.268 -9.469 0.2856
底部平線區 (AlphaLISA 計數 ) A 5133 -743.9 ＜0.0001
  
VEGF誘導之Src磷酸化之抑制(Y419) 圖 艾力雅 TPP-22214 P值
頂部平線區(AlphaLISA計數) B 3425 3405 0.8832
IC 50(nM) B 0.933 0.426 -
LogIC 50 B -9.370 -9.030 0.2219
底部平線區 (AlphaLISA 計數 ) B 2207 1629 ＜0.0001
結果：
與艾力雅形成強烈對比，TPP-22214充分抑制Y951上之VEGFR2及Y419上之Src之VEGF誘導的磷酸化。根據底部平線區之值之高度顯著差異可發現TPP-22214之更有效VEGF清除(表18)。
實例 59 ：
藉由多普單抗 TPP-22214 及艾力雅進行之人類 VEGF-A 清除之比較 -- 在 Brown Norway 大鼠中 ， 人類 VEGF-A 誘導之視網膜高滲透性之抑制
圖 59A 至圖 59B
TPP-22214防止大鼠視網膜中之人類VEGF-A誘導的高滲透性。(A)顯示實驗程序之時間方案。在玻璃體內(ivt)投與抗VEGF化合物(每隻眼睛13或26 pmol之艾力雅或TPP-14940)或對照(26 pmol TPP-11737)之後十五分鐘，藉由ivt注射每隻眼睛投與13 pmol人類VEGF-A。PBS注射充當對照。二十四小時後，在分離及固定眼睛之前藉由靜脈內(iv)注射投與1 mL/kg伊凡氏藍(Evans Blue；EB)溶液(45 mg/mL於0.9%鹽水中)30分鐘。在相同時間點收集血漿樣品以確認相等全身性EB暴露。(B)藉由利用共焦顯微術量測視網膜鋪片中之EB外滲來定量Brown Norway大鼠之視網膜中之VEGF-A誘導的高滲透性。沿著鋸齒緣切割眼睛，移除晶狀體及玻璃體，且將眼杯固定在4℃下之多聚甲醛(4%)中1 h且接著轉移至在4℃之PBS隔夜。將視網膜與外部區段(鞏膜及脈絡膜)分開，且轉移至載玻片並切割四次以達成平坦三葉草樣結構。組織用封固劑(含有DNA染料DAPI之Vectashield H-1200)覆蓋且將蓋玻片置於頂部上以獲得視網膜鋪片。樣品在639 nm波長下激發，且用LSM 700共焦雷射掃描顯微鏡(Carl Zeiss, Jena；放大率800，雷射強度2%，60 µm之5個堆疊)記錄伊凡氏藍在669 nm下的發射，且獲得具有最大強度投影之視網膜鋪片的影像。在臨限值為30之程式ImageJ中打開影像之後，進行螢光強度總和之分析。***p＜0.001；*p＜0.05；n.s. p＞0.05。單向Anova與Tukey多比較測試，n = 9-17。顯示與67:1莫耳比之艾力雅:VEGF一起之培育以用於比較。
結果：
在對照條件下，玻璃體內VEGF-A注射增加血管滲透性約60%。注意：TPP-11737用作對照分子，因為其具有與TPP-22214相同的分子格式(多普單抗)，但在先前活體外分析中，並不清除VEGF (參見上文)。
在1:1分子比之結合分子與VEGF下，TPP-22214完全阻斷血管高滲透性。然而，在急劇對比中，艾力雅在相同條件下且甚至在倍增濃度下未能顯著降低血管滲漏。僅在67:1之極高分子比率下，艾力雅能夠抑制人類VEGF誘導之血管滲漏。
實例 60 ：
TrkB 結合對於藉由 TPP-22214 進行 之 VEGF 清除之影響 -- 在存在或不存在 TrkB 胞外域下藉由 TPP-22214 進行 之人類 VEGF-A 清除之比較
圖 60A 至圖 60B
(A) TkrB胞外域(TrkB-ECD)之功能特徵。將穩定表現人類TrkB之CHO細胞與增加濃度之天然配體BDNF或10 nM BDNF與增加濃度之TrkB-ECD一起培育。藉由量測Y706/707上之TrkB磷酸化評定TrkB活化。最低化合物濃度為僅溶劑。資料表示平均值+/- SEM。
(B) TPP-22214之TrkB-ECD結合對於抑制VEGF誘導之VEGFR2磷酸化的影響。使人類視網膜微血管內皮細胞(HRMEC)饑餓，且接著與50 ng/mL人類VEGF、50 ng/mL人類VEGF及增加濃度之TPP-22214、或50 ng/mL人類VEGF及增加濃度之TPP-22214及100 nm TrkB-ECD一起培育。在具有或不具有50 ng/mL VEGF之情況下，HRMEC與增加濃度之TrkB-ECD一起培育以及未刺激之細胞(基礎)充當對照。藉由量測Y1175上之VEGF受體2 (VEGFR2)磷酸化評定VEGF-A清除。資料表示平均值+/- SEM。
結果：
圖(A)：BDNF與增加濃度之TrkB-ECD一起預培育顯著降低TrkB受體之活化。此顯示，TrkB-ECD能夠結合且清除BDNF，此可自功能性TrkB-ECD預期。
圖(B)：藉由TPP-22214進行之VEGF清除與TrkB-ECD之存在與否無關。兩個曲線幾乎一致。此指示，TPP-22214之TrkB結合本身確實不限制多普單抗之VEGF清除，表明多普單抗可同時活化TrkB受體及清除VEGF。
實例 61 ：
為了改善系列 3 至系列 4 之 CMC 特性之工程改造工作
評定來自系列3及系列4之分子之生理特性。在分子製備期間，使用分析型尺寸排阻層析測試藉由單體百分比來量測之蛋白A後的品質。此外，在10 mM組胺酸pH 6.0中評定各分子之熱穩定性及聚集起始。使用熱位移分析來量測熱穩定性，該熱位移分析使用Sypro橙染料量測蛋白質隨溫度之去摺疊。各T m計算為在整個溫度中螢光訊號之一階導數之最大峰值。使用動態光散射來量測聚集起始，以量測作為溫度之函數之流體力學半徑。最後，藉由量測在40℃或5℃2週後之聚集測試各種多普單抗之儲存穩定性。使用分析型尺寸排阻層析來量測聚集。
分子模型化用於鑑別可潛在地提高蘭尼單抗之Fv部分之pI且因此潛在地提高其溶解性而不影響其構形穩定性的單點突變。此計算設計工作建議三個構架突變，即VH E1→Q、VH E6→Q及VL D70G，其中VH及VL分別係指蘭尼單抗Fv中之重鏈及輕鏈之可變部分。重鏈中之突變VH E1→Q及VH E6→Q對應於此等位置處之人類生殖系殘基。預期輕鏈中之突變VL D70→G將破壞蘭尼單抗Fv之溶劑暴露的帶負電小塊。
工程改造工作已增加多普單抗之總體生理特性且轉換成整個分子之改良的CMC特性。對於大部分所測試分子，發現在蛋白A後單體百分比增加。此改良分子之總體可製造性。T m1及T agg中所見之改良指示工程改造改良分子之構形及膠體穩定性。此進一步轉換成在40℃及5℃下更佳的穩定性概況。
表19：
      TPP-19988 TPP-22173 TPP-22204 TPP-22192 TPP-22216 TPP-22190 TPP-22214
   TrkB-C2-VL-VH TrkB-C2-VL-VH-CC 1Q6Q70G_TrkB-C2-VH-VL_10L1_CC 1Q6Q70G_TrkB-C2-VL-VH_10L1 1Q6Q70G_TrkB-C2-VL-VH_10L1_CC 1Q70G_TrkB-C2-VL-VH_10L1 1Q70G_TrkB-C2-VL-VH_10L1_CC
蛋白 A 後之品質 單體% 70.9 91.49 87.5 74.6 87.2 78.7 87.3
熱轉移分析 T m1 ( ℃ ) 60 62.7 60.2 60.1 63.0 59.8 61.9
T m2 ( ℃ ) 66.7 69.7 70.8 71.4 70.1 68.3 70.8
聚集起始溫度 T agg( ℃ ) 54 61 58.0 53.0 62.0 53.0 60.0
在50 mg/mL 下之2 週 穩定性 在 40 ℃ 下之∆ 單體% 9.46 0.32 0.1 6.2 0.1 1.6 0.1
在 5 ℃ 下之∆ 單體% 5.08 0.12 0.0 0.6 0.1 0.8 0.1
實例 62 ：
TPP-22214 之玻璃體半衰期之測定
新西蘭雌性白兔接受雙側玻璃體內投與TPP-22214或貝伐單抗(Bevacizumab)。在不同時間點收集玻璃體樣品，且藉由ELISA測定TPP-22214或貝伐單抗之濃度。在玻璃體內投與之前及之後以規律間隔，使動物進行眼部檢查。
表20：
目標 TrkB 及 VEGF VEGF
分子 TPP-22214 貝伐單抗 貝伐單抗 蘭尼單抗 阿柏西普(Aflibercept)
格式 多普單抗 IgG IgG Fab 融合蛋白
分子量(kDa) 202 149 149 48 115
玻璃體半衰期 (天) 6.7 4.3 4.3 2.9 3.9
公開案 以實驗方式測定 以實驗方式測定 Bakri, S., Ophthalmology 2007, 114 (5): 855-859 Bakri, S., Ophthalmology 2007, 114 (12): 2179-82 Park, S., IOVS, 2016, 57 (6), 2613
表20顯示以實驗方式測定之TPP-22214及貝伐單抗之玻璃體半衰期之結果，且比較貝伐單抗、蘭尼單抗及阿柏西普之內部以實驗方式測定的值與已知文獻值。所報導之貝伐單抗半衰期與內部/以實驗方式得到之值一致，確認所應用方法之準確度及資料集之可比較性。顯示TPP-22214在兔中具有相較於例如貝伐單抗高大致50%之活體內半衰期(6.7天相對於4.3天)。
表21：
眼部VEGF ( 水狀液 ， 濕性AMD 患者)
公開案 Hsu, M., Sci Rep 2016, 6:34631 Sato T, Sci Rep 2018; 8:1098 Hata M, IOVS 2017, 58 (1): 292-298 Cabral T, Int J Retin Vitr 2017, 3:6
VEGF濃度 pg/mL pM pg/mL pM pg/mL pM pg/mL pM
546 28 228 12 90.0 4.7 180 9.4
表21報導濕性年齡相關之黃斑變性(wAMD)患者中之眼部VEGF濃度之文獻值。
表22：
TPP-22214 之給藥間隔(基於貝伐單抗之人類t 1/2計算)
物種 人類
眼睛體積(mL) 4.5
在0.05 mL中之目標劑量(mg) 2
谷值濃度(pM) 400
高於谷值濃度之數目t 1/2 12.4
來自文獻之貝伐單抗人類t 1/2(天) 9.7
高於谷值濃度之天數 121
給藥間隔(月) 3.95
基於表21中顯示之值，且僅藉由使用貝伐單抗之人類玻璃體內半衰期(t 1/2) (9.7天；Hutton-Smith, L., Mol. Pharmaceutics, 2016, 13, 2941-2950)，計算TPP-22214之人類給藥頻率之保守估計(表21)。在2 mg/眼之劑量下，4個月之給藥間隔似乎合理。
實例 63 ：
藉由 BDNF 、 TPP-6830 及兩種 多普單抗 TPP- 23457 及 TPP- 23459 進行之 人類 TrkB 活化之比較
圖 61A 至圖 61B
將穩定表現人類TrkB之CHO細胞與增加濃度之天然TrkB配體BDNF、TPP-6830 (另一單株TrkB抗體)或兩種多普單抗TPP-23457 (TPP-6380作為scFv，10L1，VH-VL；蘭尼單抗作為Fab)及TPP-23459 (TPP6380作為scFv，10L1，VL-VH；蘭尼單抗作為Fab)一起培育。
新的多普單抗分子現基於不同TrkB結合劑(TPP-6830)，以評估在基於C2 TrkB結合劑之多普單抗之情況下觀測到之效果是否亦可在不同TrkB結合劑之情況下再現。
結果：
同樣，與TPP-6830 (初始TrkB抗體，為部分TrkB受體促效劑)形成強烈對比，兩種新的多普單抗：TPP-23457及TPP-23459多普單抗現顯示完全TrkB受體促效劑活性。藉由彼等多普單抗進行之TrkB活化至少與天然配體BDNF一樣有效。
此進一步支持以下理論：結合分子之空間形成可為所觀測到之功效增加與特定TrkB結合劑無關的原因。
實例 64 ：
在存在或不存在人類 VEGF 下 ， 藉由 TPP-6830 (TrkB 單株抗體 ) 及兩種 多普單抗 TPP-23457 及 TPP-23459 進行 之人類 TrkB 活化 (TrkB 磷酸化 ) 之比較
圖 62A 至圖 62C
在與200 ng/mL人類VEGF-A (hVEGF)一起預培育或未預培育之情況下，將穩定表現人類TrkB之CHO細胞與增加濃度之多普單抗(A) TPP-23457、(B) TPP-23459或(C)TPP-6830一起培育。藉由量測Y706/707上之TrkB磷酸化評定TrkB活化。最低化合物濃度為僅溶劑。資料表示平均值+/- SEM。
結果：
同樣，與人類VEGF一起預培育顯著改善藉由TPP-23457 (TPP-6830作為scFv，10L1，VH-VL；蘭尼單抗作為Fab)及TPP-23459 (TPP-6380作為scFv，10L1，VL-VH；蘭尼單抗作為Fab)進行之TrkB磷酸化(TrkB活化)之效能。
VEGF預培育並不會影響藉由TPP-6830 (對照)進行之TrkB磷酸化(TrkB活化)的效能。
此進一步支持以下理論：所觀測到之效能增加與特定TrkB結合劑無關。
實例 65 ：
在存在或不存在人類 VEGF 下 ， 藉由 TPP-6830 (TrkB 單株抗體 ) 及兩種 多普單抗 TPP-23457 及 TPP-23459 進行 之人類 TrkB 活化 (ERK 磷酸化 ) 之比較
圖 63A 至圖 63C
在與200 ng/mL人類VEGF-A (hVEGF)一起預培育或未預培育之情況下，將穩定表現人類TrkB之CHO細胞與增加濃度之多普單抗(A) TPP-23457、(B) TPP-23459或(C)TPP-6830一起培育。藉由量測TrkB下游之T202/Y204 (ERK1)及T185/Y187 (ERK2)上之ERK1/2磷酸化評定TrkB活化。最低化合物濃度為僅溶劑。資料表示平均值+/- SEM。
結果：
此處同樣，與人類VEGF一起預培育顯著改善藉由TPP-23457 (TPP-6830作為scFv，10L1，VH-VL；蘭尼單抗作為Fab)及TPP-23459 (TPP-6380作為scFv，10L1，VL-VH；蘭尼單抗作為Fab)進行之ERK1/2磷酸化(TrkB活化)之效能。
如先前所示，VEGF預培育並不會影響藉由TPP-6830 (對照)進行之ERK1/2磷酸化(TrkB活化)之效能，從而進一步支持以下理論：所觀測到之效能增加與特定TrkB結合劑無關。
實例 66 ：
TPP-23457 對於 BDNF 誘導之 TrkB 活化 (TrkB 磷酸化 ) 之影響
圖 64A 至圖 64B
在具有或不具有0.3 nM、1 nM或3 nM恆定濃度之BDNF之情況下，將穩定表現人類TrkB受體之CHO細胞與增加濃度之(A) C2抗體或(B)多普單抗TPP-23457一起培育。藉由量測Y706/707上之受體磷酸化評定TrkB之活化。資料表示平均值+/- SEM。
結果：
與C2形成強烈對比，TPP-23457並不會限制BDNF誘導之TrkB活化。
實例 67 ：
TPP-23457 對於 BDNF 誘導之 TrkB 活化 (Erk 磷酸化 ) 之影響
圖 65A 至圖 65B
在具有或不具有0.3 nM、1 nM或3 nM恆定濃度之BDNF之情況下，將穩定表現人類TrkB受體之CHO細胞與增加濃度之(A) C2抗體或(B)多普單抗TPP-23457一起培育。藉由量測TrkB下游之T202/Y204 (ERK1)及T185/Y187 (ERK2)上之ERK1/2磷酸化評定TrkB之活化。資料表示平均值+/- SEM。
結果：
與C2形成強烈對比，TPP-23457並不會限制TrkB下游BDNF誘導之Erk磷酸化。
實例 68 ：
藉由 TPP-22214 、 TPP -23457 或 TPP-23459 進行之人類 VEGF-A 清除之比較 -- Y1175 上 及 ERK1/2 之 VEGF 誘導之 VEGFR2 磷酸化之抑制 ( 兩者均與 EC 增殖相關 )
圖 66A 至圖 66B
使人類視網膜微血管內皮細胞(HRMEC)饑餓，且接著在與增加濃度之TPP-22214、TPP-23457或TPP23459一起預培育或未預培育之情況下，與50 ng/mL人類VEGF一起培育。藉由量測(A) Y1175上之VEGF受體2 (VEGFR2)磷酸化或(B) T202/Y204 (ERK1)及T185/Y187 (ERK2)上之ERK1/2磷酸化評定VEGF-A清除。無分子處理之50 ng/ml人類VEGF充當對照。資料表示平均值+/- SEM。
結果：
多普單抗TPP-23457及TPP-23459之VEGF清除幾乎與TPP-22215一致。
如所預期，基於不同TrkB scFv結合劑之多普單抗(TPP-6830且非C2)亦不會對Fab之VEGF清除功能具有任何影響。
圖 1 ：系列1至系列4之VEGF-TrkB單一結合分子之設計說明。
圖 2A 至圖 2B ：在與增加濃度之指示分子一起培育之後，在穩定表現人類TrkB之CHO細胞中量測(A) TrkB磷酸化(Y706/707)或(B) ERK1/2磷酸化(T202/Y204-ERK1) (T185/Y187-ERK2)。資料表示平均值+/- SEM。
圖 3 A 至圖 3 D：在與增加濃度之指示分子一起培育之後，在穩定表現(A)石蟹獼猴TrkB、(B)兔TrkB、(C)大鼠TrkB或(D)小鼠TrkB之CHO細胞中量測TrkB磷酸化(Y706/707)。資料表示平均值+/- SEM。
圖 4 A 至圖 4C：在與增加濃度之指示分子一起培育之後，在穩定表現(A)人類TrkA、(B)人類TrkB或(C)人類TrkC之CHO細胞中量測Trk磷酸化(Y706/707)。TrkA之天然配體NGF、TrkB之天然配體BDNF及TrkC之天然配體NT-3用作對照。資料表示平均值+/- SEM。
圖 5A 至圖 5B ：(A)將穩定表現人類TrkB之CHO細胞與指示濃度之天然TrkB配體BDNF (重複兩次)、1 nM BDNF +指示濃度之促效TrkB抗體C2 (重複三次)或1 nM BDNF + 指示濃度之多普單抗(Doppelmab) TPP-11736 (重複三次)一起培育。(B)藉由表面TrkB受體之免疫螢光染色，隨後共焦顯微分析來評定TrkB內化。熱圖之深色及淺色場分別表示高於螢光臨限值之高及低百分比的細胞。
圖 6 ：在200 ng/mL人類VEGF-A預培育或未預培育之情況下，在與增加濃度之指示分子一起培育之後，在穩定表現人類TrkB之CHO細胞中量測ERK1/2磷酸化(T202/Y204-ERK1) (T185/Y187-ERK2)。僅與VEGF-A之培育充當對照。資料表示平均值。為了清晰起見，省略誤差桿。
圖 7 ：糖尿病誘發之視網膜神經退化之大鼠模型中之TrkB活化的神經保護性功能。動物用STZ處理以誘導高血糖症。接著，藉由在即將玻璃體內施用促效TrkB抗體C2或多普單抗TPP-11736之前及其兩週後進行視網膜電描記術(ERG)及視桿驅動之B波隱含時間延遲來評定視網膜功能；平均值+/- SEM； n.s.p＞0.05，不顯著；**p＜0.01；***p＜0.001；單向Anova與Tukey多比較測試。抗TNP充當同型對照抗體。
圖 8A 至圖 8B ：藉由量測VEGF受體2磷酸化(Y1175-VEGFR2)評定VEGF-A清除。出於此目的，使人類視網膜微血管內皮細胞(human retinal microvascular endothelial cell；HRMEC)饑餓，且接著在與增加濃度之指示分子一起預培育或未預培育之情況下，與50 ng/mL人類VEGF一起培育。(A)多普單抗TPP-11735、TPP-736、TPP-737及TPP-738之比較。(B) TPP-11736及TPP-11738與艾力雅之比較。未刺激細胞(基礎)及無抗體處理之50 ng/ml人類VEGF充當對照。資料表示平均值+/- SEM。
圖 9A 至圖 9B ：藉由ERK1/2磷酸化(T202/Y204-ERK1) (T185/Y187-ERK2)評定VEGF-A清除。出於此目的，使人類視網膜微血管內皮細胞(HRMEC)饑餓，且接著在與增加濃度之指示分子一起預培育或未預培育之情況下，與50 ng/mL人類VEGF一起培育。(A)多普單抗TPP-11735、TPP-736、TPP-737及TPP-738之比較。(B) TPP-11736、TPP-738與艾力雅之比較。未刺激細胞(基礎)及無抗體處理之50 ng/ml人類VEGF充當對照。資料表示平均值+/- SEM。
圖 10 ：藉由量測p38 MAPK磷酸化(T180/Y182)評定VEGF-A清除。出於此目的，使人類視網膜微血管內皮細胞(HRMEC)饑餓，且接著在與增加濃度之指示分子一起預培育或未預培育之情況下，與50 ng/mL人類VEGF一起培育。未刺激細胞(基礎)及無抗體處理之50 ng/ml人類VEGF充當對照。資料表示平均值+/- SEM。
圖 11 A 至圖 11 E ：使人類視網膜微血管內皮細胞(HRMEC)饑餓，且接著在與增加濃度之指示分子：(A) TPP-11735、(B) TPP-11736、(C)艾力雅、(D) TPP-11737、(E) TPP-11738一起預培育或未預培育之情況下，與10 ng/mL人類VEGF一起培育。分子濃度以mol/L為單位給出。藉由基於影像之HRMEC細胞數目之定量來評定VEGF-A清除。顯示相對細胞數目。將在t = 0時之細胞數目設定為一。未刺激細胞充當對照(基礎)。資料表示平均值+/- SEM。
圖 12 ：在與增加濃度之指示分子一起培育之後，在穩定表現人類TrkB之CHO細胞中量測TrkB磷酸化(Y706/707)。資料表示平均值+/- SEM。
圖 13 ：在與增加濃度之指示分子一起培育之後，在穩定表現人類TrkB之CHO細胞中量測ERK1/2磷酸化(T202/Y204-ERK1) (T185/Y187-ERK2)。資料表示平均值+/- SEM。
圖 14 A 至圖 14 B ：藉由量測(A) VEGF受體2磷酸化(Y1175)或(B) ERK1/2磷酸化(T202/Y204 - ERK1) (T185/Y187 - ERK2)評定VEGF-A清除。出於此目的，使人類視網膜微血管內皮細胞(HRMEC)饑餓，且接著在與增加濃度之指示分子一起預培育或未預培育之情況下，與50 ng/mL人類VEGF一起培育。未刺激細胞(基礎)及無分子處理之50 ng/ml人類VEGF充當對照。資料表示平均值+/- SEM。
圖 15 ：藉由基於影像之HRMEC細胞數目之定量來評定VEGF-A清除。出於此目的，使人類視網膜微血管內皮細胞(HRMEC)饑餓，且接著在與0.5 nM多普單抗或1 nM艾力雅一起預培育或未預培育之情況下，與10 ng/mL人類VEGF一起培育。每四個小時記錄影像，持續總共96小時之時段。顯示相對細胞數目。將在t = 0時之細胞數目設定為一。未刺激細胞充當對照(基礎)。資料表示平均值+/- SEM。
圖 16 ：內皮出芽藉由共焦顯微術評定且顯示獲自Z-堆疊之最大投影的球體周界。出於此目的，人類視網膜微血管內皮細胞(HRMEC)之球體包埋於膠原蛋白基質中。藉由在與2.5 nM之指示多普單抗或5 nM艾力雅一起預培育或未預培育之情況下，與50 ng/mL人類VEGF一起培育24小時，來誘導內皮出芽24小時。未刺激細胞充當對照(基礎)。資料表示平均值+/- SEM。
圖 17 A 至圖 17 C ：藉由量測(A) VEGF受體2磷酸化(Y1175)、(B) ERK1/2磷酸化(T202/Y204 - ERK1) (T185/Y187 - ERK2)或(C) p38 MAPK磷酸化(T180/Y182)評定VEGF-A清除。出於此目的，使人類視網膜微血管內皮細胞(HRMEC)饑餓，且接著在與增加濃度之多普單抗TPP-11736或TPP-13788 (B20 IgG)一起預培育或未預培育之情況下，與50 ng/mL人類VEGF一起培育。無抗體處理之50 ng/ml人類VEGF充當對照。資料表示平均值+/- SEM。
圖 18 ：內皮出芽藉由共焦顯微術評定且顯示獲自Z-堆疊之最大投影的球體周界。出於此目的，人類視網膜微血管內皮細胞(HRMEC)之球體包埋於膠原蛋白基質中。藉由在與2.5 nM之多普單抗TPP-11736或2.5 nM TPP-13788 (B20 IgG)一起預培育或未預培育之情況下，與50 ng/mL人類VEGF一起培育，來誘導內皮出芽24小時。未刺激細胞充當對照(基礎)。資料表示平均值+/- SEM。
圖 19 A 至圖 19 C ：在與增加濃度之指示分子一起培育之後，在穩定表現人類TrkB之CHO細胞中量測(A) TrkB磷酸化(Y706/707)或(B及C) ERK1/2磷酸化(T202/Y204-ERK1) (T185/Y187-ERK2)。資料表示平均值+/- SEM。
圖 20A 至圖 20B ：在與增加濃度之指示分子一起培育之後，在穩定表現(A)石蟹獼猴TrkB或(B)大鼠TrkB之CHO細胞中量測TrkB磷酸化(Y706/707)。資料表示平均值+/- SEM。
圖 21A 至圖 21C ：藉由量測(A) VEGF受體2磷酸化(Y1175)、(B) ERK1/2磷酸化(T202/Y204 - ERK1) (T185/Y187 - ERK2)或(C) Src磷酸化(Y419)評定VEGF-A清除。出於此目的，使人類視網膜微血管內皮細胞(HRMEC)饑餓，且接著在與增加濃度之指示分子一起預培育或未預培育之情況下，與50 ng/mL人類VEGF一起培育。無抗體處理之50 ng/ml人類VEGF充當對照。資料表示平均值+/- SEM。
圖 22 ：內皮出芽藉由共焦顯微術評定且顯示獲自Z-堆疊之最大投影的球體周界。出於此目的，人類視網膜微血管內皮細胞(HRMEC)之球體包埋於膠原蛋白基質中。藉由在與2.5 nM之指示分子一起預培育或未預培育之情況下，與50 ng/mL人類VEGF一起培育，來誘導內皮出芽24小時。未刺激細胞充當對照(基礎)。資料表示平均值+/- SEM。n.s. p＞0.05，不顯著，****p＜0.0001。
圖 23A 至圖 23D：藉由基於影像之HRMEC細胞數目之定量來評定VEGF-A清除。於此目的，使人類視網膜微血管內皮細胞(HRMEC)饑餓，且接著在與增加濃度之指示分子：(A) TPP-11736、(B) TPP-14936、(C) TPP-14937或(D)艾力雅一起預培育或未預培育之情況下，與10 ng/mL人類VEGF一起培育。結合分子/艾力雅濃度以mol/L為單位給出。每四個小時記錄影像，持續總共84小時之時段。顯示相對細胞數目。將在t = 0時之細胞數目設定為一。未刺激細胞充當對照(基礎)。資料表示平均值+/- SEM。
圖 24A 至圖 24B ：在增加濃度之所指示之第二系列分子與一起培育之後，在穩定表現人類TrkB之CHO細胞中量測(A) TrkB磷酸化(Y706/707)或(B) ERK1/2磷酸化(T202/Y204 - ERK1) (T185/Y187 - ERK2)。資料表示平均值+/- SEM。
圖 25 ：描繪所提出之VEGF誘導之與單一結合分子之聚類的潛在作用，導致TrkB活化之功效及效能增加的草圖。
圖 26A 至圖 26B ：在與增加濃度之所指示之第二系列分子一起培育之後，在穩定表現(A)石蟹獼猴TrkB或(B)大鼠TrkB之CHO細胞中量測TrkB磷酸化(Y706/707)。資料表示平均值+/- SEM。
圖 27A 至圖 27C：在與200 ng/mL人類VEGF-A一起預培育或未預培育之情況下，在與增加濃度之多普單抗(A) TPP-14940、(B)TPP-14941或(C) C2抗體一起培育之後，在穩定表現人類TrkB之CHO細胞中量測TrkB磷酸化(Y706/707)。資料表示平均值+/- SEM。
圖 28 A 至圖 28 C ：在與200 ng/mL人類VEGF-A一起預培育或未預培育之情況下，在與增加濃度之多普單抗((A) TPP-14940、(B) TPP-14941或(C) C2抗體一起培育之後，在穩定表現人類TrkB之CHO細胞中量測ERK1/2磷酸化(T202/Y204 - ERK1) (T185/Y187 - ERK2)。資料表示平均值+/- SEM。
圖 29A 至圖 29B ：在與增加濃度之人類VEGF-A、或與增加濃度之單獨BDNF或增加濃度之BDNF與200 ng/mL固定濃度之hVEGF一起培育之後，在穩定表現人類TrkB之CHO細胞中量測(A) TrkB磷酸化(Y706/707)或(B) ERK1/2磷酸化(T202/Y204 - ERK1) (T185/Y187 - ERK2)。資料表示平均值+/- SEM。
圖 30A 至圖 30C ：在與200 ng/mL人類VEGF-A一起預培育或未預培育之情況下，在與增加濃度之多普單抗(A) TPP-14940、(B) TPP-14941或(C) C2抗體一起培育之後，在穩定表現石蟹獼猴TrkB之CHO細胞中量測TrkB磷酸化(Y706/707)。資料表示平均值+/- SEM。
圖 31 A 至圖 31 C ：在與200 ng/mL人類VEGF-A一起預培育或未預培育之情況下，在與增加濃度之多普單抗(A) TPP-14940、(B) TPP-14941或(C) C2抗體一起培育之後，在穩定表現石蟹獼猴TrkB之CHO細胞中量測ERK1/2磷酸化(T202/Y204 - ERK1) (T185/Y187 - ERK2)。資料表示平均值+/- SEM。
圖 32A 至圖 32C ：藉由量測(A) VEGF受體2磷酸化(Y1175)、(B) ERK1/2磷酸化(T202/Y204 - ERK1) (T185/Y187 - ERK2)或(C) Src磷酸化(Y419)評定VEGF-A清除。出於此目的，使人類視網膜微血管內皮細胞(HRMEC)饑餓，且接著在與增加濃度之指示分子一起預培育或未預培育之情況下，與50 ng/mL人類VEGF一起培育。無抗體處理之50 ng/ml人類VEGF充當對照。資料表示平均值+/- SEM。
圖 33A 至圖 33C ：使人類視網膜微血管內皮細胞(HRMEC)饑餓，且接著在與增加濃度之指示分子：(A) TPP-11736、(B) TPP-14938、(C) TPP-14939一起預培育或未預培育之情況下，與10 ng/mL人類VEGF一起培育。分子濃度以mol/L為單位給出。藉由基於影像之HRMEC細胞數目之定量來評定VEGF-A清除。顯示相對細胞數目。將在t = 0時之細胞數目設定為一。未刺激細胞充當對照(基礎)。資料表示平均值+/- SEM。
圖 34A 至圖 34C ：藉由量測(A) VEGF受體2磷酸化(Y1175)、(B) ERK1/2磷酸化(T202/Y204 - ERK1) (T185/Y187 - ERK2)或(C) Src磷酸化(Y419)評定VEGF-A清除。出於此目的，使人類視網膜微血管內皮細胞(HRMEC)饑餓，且接著在與增加濃度之指示分子一起預培育或未預培育之情況下，與50 ng/mL人類VEGF一起培育。無抗體處理之50 ng/ml人類VEGF充當對照。資料表示平均值+/- SEM。
圖 35A 至圖 35 D ：藉由基於影像之HRMEC細胞數目之定量來評定VEGF-A清除。於此目的，使人類視網膜微血管內皮細胞(HRMEC)饑餓，且接著在與增加濃度之指示分子：(A) TPP-14936、(B) TPP-14937、(C) TPP-14940或(D) TPP-14941一起預培育或未預培育之情況下，與10 ng/mL人類VEGF一起培育。分子濃度以mol/L為單位給出。每四個小時記錄影像，持續總共84小時之時段。顯示相對細胞數目。將在t = 0時之細胞數目設定為一。未刺激細胞充當對照(基礎)。資料表示平均值+/- SEM。
圖 36A 至圖 36C ：藉由量測(A) VEGF受體2磷酸化(Y1175)、(B) ERK1/2磷酸化(T202/Y204 - ERK1) (T185/Y187 - ERK2)或(C) Src磷酸化(Y419)評定VEGF-A清除。出於此目的，使人類視網膜微血管內皮細胞(HRMEC)饑餓，且接著在與增加濃度之指示分子一起預培育或未預培育之情況下，與50 ng/mL人類VEGF一起培育。無抗體處理之50 ng/ml人類VEGF充當對照。資料表示平均值+/- SEM。
圖 37A 至圖 37 D ：藉由基於影像之HRMEC細胞數目之定量來評定VEGF-A清除。於此目的，使人類視網膜微血管內皮細胞(HRMEC)饑餓，且接著在與增加濃度之指示分子：(A) TPP-14938、(B) TPP-14939、(C) TPP-14940或(D) TPP-14941一起預培育或未預培育之情況下，與10 ng/mL人類VEGF一起培育。分子濃度以mol/L為單位給出。每四個小時記錄影像，持續總共84小時之時段。顯示相對細胞數目。將在t = 0時之細胞數目設定為一。未刺激細胞充當對照(基礎)。資料表示平均值+/- SEM。
圖 38 ：內皮出芽藉由共焦顯微術評定且顯示獲自Z-堆疊之最大投影的球體周界。出於此目的，人類視網膜微血管內皮細胞(HRMEC)之球體包埋於膠原蛋白基質中。藉由在與2.5 nM之指示分子一起預培育或未預培育之情況下，與50 ng/mL人類VEGF一起培育，來誘導內皮出芽24小時。未刺激細胞充當對照(基礎)。資料表示平均值+/- SEM。n.s. p＞0.05無顯著差異；相較於50 ng/mL hVEGF， §p＜0.0001；相較於50 ng/mL hVEGF，#p＞0.05無顯著差異。***p＜0.001；單向Anova與Tukey多比較測試。
圖 39A 至圖 39B ：(A)顯示實驗程序之時間方案。在玻璃體內(ivt)投與抗VEGF化合物(每隻眼睛13或26 pmol之艾力雅或TPP-14940)或對照(26 pmol TPP-11737)之後十五分鐘，藉由ivt注射每隻眼睛投與13 pmol人類VEGF-A。PBS注射充當對照。二十四小時後，在分離及固定眼睛之前藉由靜脈內(iv)注射投與1 mL/kg伊凡氏藍(Evans Blue；EB)溶液(45 mg/mL於0.9%鹽水中)30分鐘。在相同時間點收集血漿樣品以確認相等全身性EB暴露。(B)藉由利用共焦顯微術量測視網膜鋪片中之EB外滲來定量Brown Norway大鼠之視網膜中之VEGF-A誘導的高滲透性。沿著鋸齒緣切割眼睛，移除晶狀體及玻璃體，且將眼杯固定在4℃下之多聚甲醛(4%)中1 h且接著轉移至在4℃之PBS隔夜。將視網膜與外部區段(鞏膜及脈絡膜)分開，且轉移至載玻片並切割四次以達成平坦三葉草樣結構。組織用封固劑(含有DNA染料DAPI之Vectashield H-1200)覆蓋且將蓋玻片置於頂部上以獲得視網膜鋪片。樣品在639 nm波長下激發，且用LSM 700共焦雷射掃描顯微鏡(Carl Zeiss, Jena；放大率800，雷射強度2%，60 µm之5個堆疊)記錄伊凡氏藍在669 nm下的發射，且獲得具有最大強度投影之視網膜鋪片的影像。在臨限值為30之程式ImageJ中打開影像之後，進行螢光強度總和之分析。***p＜0.001；*p＜0.05；n.s.p＞0.05；相對於TPP-11737 + PBS，#p＞0.05不顯著。單向Anova與Tukey多比較測試，n = 9-17。
圖 40A 至圖 40D ：在與增加濃度之BDNF或增加濃度之指示分子一起培育之後，在穩定表現人類TrkB之CHO細胞中量測(A及B) TrkB磷酸化(Y706/707)或(C及D) ERK1/2磷酸化(T202/Y204 - ERK1) (T185/Y187 - ERK2)。
圖 41A 至圖 41B ：(A)將穩定表現人類TrkB之CHO細胞與指示濃度之天然TrkB配體BDNF (重複兩次)或1 nM BDNF與指示濃度之多普單抗(各重複三次)一起培育。(B)藉由表面TrkB受體之免疫螢光染色，隨後共焦顯微分析來評定TrkB內化。熱圖之深色及淺色場分別表示高於螢光臨限值之高及低百分比的細胞。
圖42：藉由量測VEGF受體2磷酸化(Y1175)評定VEGF-A清除。出於此目的，使人類視網膜微血管內皮細胞(HRMEC)饑餓，且接著在與增加濃度之指示分子一起預培育或未預培育之情況下，與50 ng/mL人類VEGF一起培育。無分子處理之50 ng/ml人類VEGF充當對照。資料表示平均值+/- SEM。
圖 43 ：內皮出芽藉由共焦顯微術評定且顯示獲自Z-堆疊之最大投影的球體周界。出於此目的，人類視網膜微血管內皮細胞(HRMEC)之球體包埋於膠原蛋白基質中。藉由在與2.5 nM之指示分子一起預培育或未預培育之情況下，與50 ng/mL人類VEGF一起培育，來誘導內皮出芽24小時。未刺激細胞充當對照(基礎)。資料表示平均值+/- SEM。n.s. p＞0.05無顯著差異；相較於50 ng/mL hVEGF， §p＜0.0001；相較於50 ng/mL hVEGF，#p＞0.05無顯著差異。***p＜0.001；單向Anova與Tukey多比較測試。
圖 44A 至圖 44D ：在與增加濃度之多普單抗(A) TPP-22180與TPP-22204、(B) TPP-22192與TPP-22216、(C) TPP-22190與TPP-22214、(D) TPP-22191與TPP-22215一起培育之後，在穩定表現人類TrkB之CHO細胞中量測TrkB磷酸化(Y706/707)。資料表示平均值+/- SEM。
圖 45A 至圖 45B ：在與增加濃度之多普單抗(A) TPP-22180與TPP-22204、(B) TPP-22192與TPP-22216一起培育之後，在穩定表現大鼠TrkB之CHO細胞中量測TrkB磷酸化(Y706/707)。資料表示平均值+/- SEM。
圖 46A 至圖 46C ：在與增加濃度之C2抗體或多普單抗TPP-22204或TPP-22214一起培育之後，在穩定表現(A)人類TrkA、(B)人類TrkB或(C)人類TrkC之CHO細胞中量測Trk磷酸化(Y706/707)。TrkA之天然配體NGF、TrkB之天然配體BDNF及TrkC之天然配體NT-3用作對照。資料表示平均值+/- SEM。
圖 47A 至圖 47B ：在(A)在具有或不具有0.3 nM、1 nM或3 nM恆定濃度之BDNF之情況下，與增加濃度之C2抗體一起培育；或(B)在具有或不具有0.3 nM、1 nM或3 nM恆定濃度之BDNF之情況下，與增加濃度之多普單抗TPP-22214一起培育之後，在穩定表現人類TrkB受體之CHO細胞中量測TrkB磷酸化(Y706/707)。資料表示平均值+/- SEM。
圖 48A 至圖 48D ：在與(A) 200 ng/mL人類VEGF-A (hVEGF)、(B) 50 ng/mL hVEGF、(C) 10 ng/mL hVEGF或(D) 2 ng/mL hVEGF一起預培育或未預培育之情況下，在與增加濃度之多普單抗TPP-22214一起培育之後，在穩定表現人類TrkB受體之CHO細胞中量測TrkB磷酸化(Y706/707)。資料表示平均值+/- SEM。
圖 49 A 至圖 49 D ：在與(A) 200 ng/mL人類VEGF-A (hVEGF)、(B) 50 ng/mL hVEGF、(C) 10 ng/mL hVEGF或(D) 2 ng/mL hVEGF一起預培育或未預培育之情況下，在與增加濃度之多普單抗TPP-22214一起培育之後，在穩定表現人類TrkB之CHO細胞中量測ERK1/2磷酸化(T202/Y204 - ERK1) (T185/Y187 - ERK2)。資料表示平均值+/- SEM。
圖 50 ：使用尺寸排阻層析與多角度光散射偵測器組合來評定多普單抗複合物之大小。在自尺寸排阻管柱溶離出蛋白質所花費之時間上，監測差示折射率(黑色、深灰色、淺灰色及虛線)及光散射。使用光散射資料來判定各點處之莫耳質量。各峰中點處之莫耳質量由星形指示且使用右軸來量測。研究單獨TPP-22214(虛線)或呈各種比率之與VEGF的複合物(黑色20:1、深灰色4:1、淺灰色1:1)。A至D表示基於所量測莫耳質量之可能的複合物示意圖。
圖 51A 至圖 51C ：藉由在不滲透細胞之情況下對表面TrkB受體進行免疫螢光染色，隨後共焦顯微分析來評定TrkB內化。將穩定表現人類TrkB之CHO細胞與(A)增加濃度之天然TrkB配體BDNF、(B)增加濃度之TPP-22214或(C) 1 nM BDNF與增加濃度之TPP-22214一起培育。資料表示表面TrkB染色強度高於臨限值之細胞百分比；平均值+/- SEM。
圖 52 ：糖尿病誘發之視網膜神經退化之大鼠模型中之TrkB活化的神經保護性功能。動物用STZ處理以誘導高血糖症。接著，藉由在即將玻璃體內施用促效TrkB抗體C2或多普單抗TPP-22214之前及其兩週後進行視網膜電描記術(ERG)及視桿驅動之B波隱含時間延遲來評定視網膜功能；平均值+/- SEM； n.s.p＞0.05；不顯著(n.s.)，****p＜0.0001；單向Anova與Tukey多比較測試。抗TNP充當同型對照抗體。
圖 53A 至 53B ：藉由量測VEGF受體2磷酸化(Y1175)評定VEGF-A清除。出於此目的，使人類視網膜微血管內皮細胞(HRMEC)饑餓，且接著在與增加濃度之指示分子一起預培育或未預培育之情況下，與50 ng/mL人類VEGF一起培育。(A)多普單抗TPP-14941、TPP-22216、TPP-22192、TPP-22204及TPP-22180之比較。(B)多普單抗TPP-14940、TPP-14941、TPP-22190、TPP-22214、TPP-22191及TPP-22215之比較。未刺激細胞(基礎)及無分子處理之50 ng/ml人類VEGF充當對照。資料表示平均值+/- SEM。
圖 54A 至圖 54B ：藉由量測(A) VEGF受體2 (VEGFR2)磷酸化(Y1175)或(B) ERK1/2磷酸化(T202/Y204 - ERK1) (T185/Y187 - ERK2)評定VEGF-A清除。出於此目的，使人類視網膜微血管內皮細胞(HRMEC)饑餓，且接著在與增加濃度之TPP-22214或艾力雅一起預培育或未預培育之情況下，與50 ng/mL人類VEGF一起培育。無分子處理之50 ng/ml人類VEGF充當對照。資料表示平均值+/- SEM。
圖 55A 至圖 55E ：使人類視網膜微血管內皮細胞(HRMEC)饑餓，且接著在與增加濃度之指示分子：(A) TPPP-22204、(B) TPP-22214c、(C) TPP-22216或(D)艾力雅一起預培育或未預培育之情況下，與10 ng/mL人類VEGF一起培育。分子濃度以mol/L為單位給出。藉由基於影像之HRMEC細胞數目之定量來評定VEGF-A清除。每四個小時記錄影像，持續總共84小時之時段。顯示相對細胞數目。將在t = 0時之細胞數目設定為一。未刺激細胞充當對照(基礎)。資料表示平均值+/- SEM。(E)顯示相對於艾力雅或TPP-22214之濃度之生長曲線及基礎曲線下面積之差異的曲線。
圖 56A 至圖 56B ：藉由量測(A) VEGF受體2磷酸化(Y1214)或(B) p38-MAPK磷酸化(T180/Y182)評定VEGF-A清除。出於此目的，使人類視網膜微血管內皮細胞(HRMEC)饑餓，且接著在與增加濃度之TPP-22214或艾力雅一起預培育或未預培育之情況下，與50 ng/mL人類VEGF一起培育。無分子處理之50 ng/ml人類VEGF充當對照。資料表示平均值+/- SEM。
圖 57A 至圖 57B ：人類視網膜微血管內皮細胞(HRMEC)之球體包埋於膠原蛋白基質中。藉由在與2.5 nM之TPP-22204、TPP-22214、TPP-22215、TPP-22216或5 nM艾力雅一起預培育或未預培育之情況下，與50 ng/mL人類VEGF一起培育，來誘導內皮出芽24小時。(A)內皮出芽藉由共焦顯微術評定且顯示獲自Z-堆疊之最大投影的球體周界。未刺激細胞充當對照(基礎)。資料表示平均值+/- SEM。n.s. p＞0.05，不顯著，****p＜0.0001。(B)顯示在基礎條件下出芽24小時之後或在未預培育或與2.5 nM TPP-22214或5 nM艾力雅一起預培育之情況下用50 ng/mL人類VEGF刺激之後，來自球體的代表性最大投影影像。條(Bar) = 100 µm。
圖 58A 至圖 58B ：藉由量測(A) VEGF受體2磷酸化(Y951)或(B) Src磷酸化(Y419)評定VEGF-A清除。出於此目的，使人類視網膜微血管內皮細胞(HRMEC)饑餓，且接著在與增加濃度之TPP-22214或艾力雅一起預培育或未預培育之情況下，與50 ng/mL人類VEGF一起培育。無抗體處理之50 ng/ml人類VEGF充當對照。資料表示平均值+/- SEM。
圖 59A 至圖 59B ：TPP-22214防止大鼠視網膜中之人類VEGF-A誘導的高滲透性。(A)顯示實驗程序之時間方案。在玻璃體內(ivt)投與抗VEGF化合物(每隻眼睛13或26 pmol之艾力雅或TPP-14940)或對照(26 pmol TPP-11737)之後十五分鐘，藉由ivt注射每隻眼睛投與13 pmol人類VEGF-A。PBS注射充當對照。二十四小時後，在分離及固定眼睛之前藉由靜脈內(iv)注射投與1 mL/kg伊凡氏藍(Evans Blue；EB)溶液(45 mg/mL於0.9%鹽水中)30分鐘。在相同時間點收集血漿樣品以確認相等全身性EB暴露。(B)藉由利用共焦顯微術量測視網膜鋪片中之EB外滲來定量Brown Norway大鼠之視網膜中之VEGF-A誘導的高滲透性。沿著鋸齒緣切割眼睛，移除晶狀體及玻璃體，且將眼杯固定在4℃下之多聚甲醛(4%)中1 h且接著轉移至在4℃之PBS隔夜。將視網膜與外部區段(鞏膜及脈絡膜)分開，且轉移至載玻片並切割四次以達成平坦三葉草樣結構。組織用封固劑(含有DNA染料DAPI之Vectashield H-1200)覆蓋且將蓋玻片置於頂部上以獲得視網膜鋪片。樣品在639 nm波長下激發，且用LSM 700共焦雷射掃描顯微鏡(Carl Zeiss, Jena；放大率800，雷射強度2%，60 µm之5個堆疊)記錄伊凡氏藍在669 nm下的發射，且獲得具有最大強度投影之視網膜鋪片的影像。在臨限值為30之程式ImageJ中打開影像之後，進行螢光強度總和之分析。***p＜0.001；*p＜0.05；n.s. p＞0.05。單向Anova與Tukey多比較測試，n = 9-17。顯示與67:1莫耳比之艾力雅:VEGF一起之培育以用於比較。
圖 60A 至圖 60B ：(A) TkrB胞外域(TrkB-ECD)之功能特徵。將穩定表現人類TrkB之CHO細胞與增加濃度之天然配體BDNF或10 nM BDNF與增加濃度之TrkB-ECD一起培育。藉由量測TrkB磷酸化(Y706/707)評定TrkB活化。(B) TPP-22214之TrkB-ECD結合對於抑制VEGF誘導之VEGFR2磷酸化的影響。使人類視網膜微血管內皮細胞(HRMEC)饑餓，且接著與50 ng/mL人類VEGF、50 ng/mL人類VEGF及增加濃度之TPP-22214、或50 ng/mL人類VEGF及增加濃度之TPP-22214及100 nm TrkB-ECD一起培育。在具有或不具有50 ng/mL VEGF之情況下，HRMEC與增加濃度之TrkB-ECD一起培育以及未刺激之細胞(基礎)充當對照。藉由量測VEGF受體2磷酸化(Y1175)評定VEGF-A清除。資料表示平均值+/- SEM。
圖 61A 至圖 61B ：在與增加濃度之指示分子一起培育之後，在穩定表現人類TrkB之CHO細胞中量測(A) TrkB磷酸化(Y706/707)或(B) ERK1/2磷酸化(T202/Y204-ERK1) (T185/Y187-ERK2)。資料表示平均值+/- SEM。
圖 62A 至圖 62C ：在與200 ng/mL人類VEGF-A一起預培育或未預培育之情況下，在與增加濃度之多普單抗(A) TPP-23457、(B) TPP-23459或(C) TPP-6830抗體一起培育之後，在穩定表現人類TrkB之CHO細胞中量測TrkB磷酸化(Y706/707)。資料表示平均值+/- SEM。
圖 63 A 至圖 63 C ：在與200 ng/mL人類VEGF-A一起預培育或未預培育之情況下，在與增加濃度之多普單抗(A) TPP-23457、(B) TPP-23459或(C) TPP-6830抗體一起培育之後，在穩定表現人類TrkB之CHO細胞中量測ERK1/2磷酸化(T202/Y204 - ERK1) (T185/Y187 - ERK2)。資料表示平均值+/- SEM。
圖 64A 至圖 64B ：在(A)在具有或不具有0.3 nM、1 nM或3 nM恆定濃度之BDNF之情況下，與增加濃度之C2抗體一起培育；或(B)在具有或不具有0.3 nM、1 nM或3 nM恆定濃度之BDNF之情況下，與增加濃度之多普單抗TPP-23457一起培育之後，在穩定表現人類TrkB受體之CHO細胞中量測TrkB磷酸化(Y706/707)。資料表示平均值+/- SEM。
圖 65A 至圖 65B ：在(A)在具有或不具有0.3 nM、1 nM或3 nM恆定濃度之BDNF之情況下，與增加濃度之C2抗體一起培育；或(B)在具有或不具有0.3 nM、1 nM或3 nM恆定濃度之BDNF之情況下，與增加濃度之多普單抗TPP-23457一起培育之後，在穩定表現人類TrkB受體之CHO細胞中量測ERK1/2磷酸化(T202/Y204 - ERK1) (T185/Y187 - ERK2)。資料表示平均值+/- SEM。
圖 66A 至圖 66B ：藉由量測(A) VEGF受體2 (VEGFR2)磷酸化(Y1175)或(B) ERK1/2磷酸化(T202/Y204 - ERK1) (T185/Y187 - ERK2)評定VEGF-A清除。出於此目的，使人類視網膜微血管內皮細胞(HRMEC)饑餓，且接著在與增加濃度之多普單抗TPP-22215、TPP-23457、TPP-23459或艾力雅一起預培育或未預培育之情況下，與50 ng/mL人類VEGF一起培育。無分子處理之50 ng/ml人類VEGF充當對照。資料表示平均值+/- SEM。 

          <![CDATA[<110> 德商百靈佳殷格翰國際股份有限公司 (BOEHRINGER INGELHEIM INTERNATIONAL GMBH)]]>
          <![CDATA[<120> 用於治療眼部疾病之雙特異性抗-VEGF及抗-TrkB結合分子]]>
          <![CDATA[<130> 01-3412]]>
          <![CDATA[<140> TW 110138827]]>
          <![CDATA[<141> 2021-10-20]]>
          <![CDATA[<150> EP 20203030.0]]>
          <![CDATA[<151> 2020-10-21]]>
          <![CDATA[<160> 257]]>
          <![CDATA[<170> BiSSAP 1.3.6]]>
          <![CDATA[<210> 1]]>
          <![CDATA[<211> 214]]>
          <![CDATA[<212> PRT]]>
          <![CDATA[<213> 智人]]>
          <![CDATA[<400> 1]]>
          Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly 
          1               5                   10                  15      
          Asp Arg Val Thr Ile Thr Cys Arg Thr Ser Glu Asn Val Tyr Ser Asn 
                      20                  25                  30          
          Leu Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile 
                  35                  40                  45              
          Tyr Ala Ala Ser Asn Leu Gln Ser Gly Val Pro Ser Arg Phe Ser Gly 
              50                  55                  60                  
          Ser Gly Ser Gly Thr Asp Tyr Thr Phe Thr Ile Ser Ser Leu Gln Pro 
          65                  70                  75                  80  
          Glu Asp Ile Ala Thr Tyr Tyr Cys Gln His Phe Trp Gly Ser Pro Phe 
                          85                  90                  95      
          Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys Arg Thr Val Ala Ala 
                      100                 105                 110         
          Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly 
                  115                 120                 125             
          Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala 
              130                 135                 140                 
          Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln 
          145                 150                 155                 160 
          Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser 
                          165                 170                 175     
          Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr 
                      180                 185                 190         
          Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser 
                  195                 200                 205             
          Phe Asn Arg Gly Glu Cys 
              210                 
          <![CDATA[<210> 2]]>
          <![CDATA[<211> 720]]>
          <![CDATA[<212> PRT]]>
          <![CDATA[<213> 智人]]>
          <![CDATA[<400> 2]]>
          Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala 
          1               5                   10                  15      
          Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Asn Tyr 
                      20                  25                  30          
          Asp Ile Ile Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met 
                  35                  40                  45              
          Gly Tyr Ile Asn Pro Tyr Asn Asp Gly Thr Lys Tyr Asn Glu Lys Phe 
              50                  55                  60                  
          Lys Gly Arg Val Thr Met Thr Arg Asp Thr Ser Thr Ser Thr Val Tyr 
          65                  70                  75                  80  
          Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys 
                          85                  90                  95      
          Ala Arg Leu Leu Lys Tyr Arg Arg Phe Arg Tyr Tyr Ala Ile Asp Tyr 
                      100                 105                 110         
          Trp Gly Gln Gly Thr Thr Val Thr Val Ser Ser Ala Ser Thr Lys Gly 
                  115                 120                 125             
          Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly 
              130                 135                 140                 
          Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val 
          145                 150                 155                 160 
          Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe 
                          165                 170                 175     
          Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val 
                      180                 185                 190         
          Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val 
                  195                 200                 205             
          Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys Arg Val Glu Pro Lys 
              210                 215                 220                 
          Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Ala 
          225                 230                 235                 240 
          Ala Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr 
                          245                 250                 255     
          Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val 
                      260                 265                 270         
          Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val 
                  275                 280                 285             
          Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser 
              290                 295                 300                 
          Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu 
          305                 310                 315                 320 
          Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala 
                          325                 330                 335     
          Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro 
                      340                 345                 350         
          Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln 
                  355                 360                 365             
          Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala 
              370                 375                 380                 
          Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr 
          385                 390                 395                 400 
          Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu 
                          405                 410                 415     
          Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser 
                      420                 425                 430         
          Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser 
                  435                 440                 445             
          Leu Ser Pro Gly Gly Gly Ser Glu Gly Lys Ser Ser Gly Ser Gly Ser 
              450                 455                 460                 
          Glu Ser Lys Ser Thr Gly Gly Ser Glu Val Gln Leu Val Glu Ser Gly 
          465                 470                 475                 480 
          Gly Gly Leu Val Gln Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala 
                          485                 490                 495     
          Ser Gly Phe Thr Ile Asn Ala Ser Trp Ile His Trp Val Arg Gln Ala 
                      500                 505                 510         
          Pro Gly Lys Gly Leu Glu Trp Val Gly Ala Ile Tyr Pro Tyr Ser Gly 
                  515                 520                 525             
          Tyr Thr Asn Tyr Ala Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Ala 
              530                 535                 540                 
          Asp Thr Ser Lys Asn Thr Ala Tyr Leu Gln Met Asn Ser Leu Arg Ala 
          545                 550                 555                 560 
          Glu Asp Thr Ala Val Tyr Tyr Cys Ala Arg Trp Gly His Ser Thr Ser 
                          565                 570                 575     
          Pro Trp Ala Met Asp Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser 
                      580                 585                 590         
          Ser Gly Gly Ser Glu Gly Lys Ser Ser Gly Ser Gly Ser Glu Ser Lys 
                  595                 600                 605             
          Ser Thr Gly Gly Ser Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu 
              610                 615                 620                 
          Ser Ala Ser Val Gly Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln 
          625                 630                 635                 640 
          Val Ile Arg Arg Ser Leu Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala 
                          645                 650                 655     
          Pro Lys Leu Leu Ile Tyr Ala Ala Ser Asn Leu Ala Ser Gly Val Pro 
                      660                 665                 670         
          Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile 
                  675                 680                 685             
          Ser Ser Leu Gln Pro Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Ser 
              690                 695                 700                 
          Asn Thr Ser Pro Leu Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys 
          705                 710                 715                 720 
          <![CDATA[<210> 3]]>
          <![CDATA[<211> 214]]>
          <![CDATA[<212> PRT]]>
          <![CDATA[<213> 智人]]>
          <![CDATA[<400> 3]]>
          Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly 
          1               5                   10                  15      
          Asp Arg Val Thr Ile Thr Cys Arg Thr Ser Glu Asn Val Tyr Ser Asn 
                      20                  25                  30          
          Leu Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile 
                  35                  40                  45              
          Tyr Ala Ala Ser Asn Leu Gln Ser Gly Val Pro Ser Arg Phe Ser Gly 
              50                  55                  60                  
          Ser Gly Ser Gly Thr Asp Tyr Thr Phe Thr Ile Ser Ser Leu Gln Pro 
          65                  70                  75                  80  
          Glu Asp Ile Ala Thr Tyr Tyr Cys Gln His Phe Trp Gly Ser Pro Phe 
                          85                  90                  95      
          Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys Arg Thr Val Ala Ala 
                      100                 105                 110         
          Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly 
                  115                 120                 125             
          Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala 
              130                 135                 140                 
          Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln 
          145                 150                 155                 160 
          Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser 
                          165                 170                 175     
          Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr 
                      180                 185                 190         
          Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser 
                  195                 200                 205             
          Phe Asn Arg Gly Glu Cys 
              210                 
          <![CDATA[<210> 4]]>
          <![CDATA[<211> 720]]>
          <![CDATA[<212> PRT]]>
          <![CDATA[<213> 智人]]>
          <![CDATA[<400> 4]]>
          Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala 
          1               5                   10                  15      
          Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Asn Tyr 
                      20                  25                  30          
          Asp Ile Ile Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met 
                  35                  40                  45              
          Gly Tyr Ile Asn Pro Tyr Asn Asp Gly Thr Lys Tyr Asn Glu Lys Phe 
              50                  55                  60                  
          Lys Gly Arg Val Thr Met Thr Arg Asp Thr Ser Thr Ser Thr Val Tyr 
          65                  70                  75                  80  
          Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys 
                          85                  90                  95      
          Ala Arg Leu Leu Lys Tyr Arg Arg Phe Arg Tyr Tyr Ala Ile Asp Tyr 
                      100                 105                 110         
          Trp Gly Gln Gly Thr Thr Val Thr Val Ser Ser Ala Ser Thr Lys Gly 
                  115                 120                 125             
          Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly 
              130                 135                 140                 
          Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val 
          145                 150                 155                 160 
          Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe 
                          165                 170                 175     
          Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val 
                      180                 185                 190         
          Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val 
                  195                 200                 205             
          Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys Arg Val Glu Pro Lys 
              210                 215                 220                 
          Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Ala 
          225                 230                 235                 240 
          Ala Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr 
                          245                 250                 255     
          Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val 
                      260                 265                 270         
          Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val 
                  275                 280                 285             
          Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser 
              290                 295                 300                 
          Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu 
          305                 310                 315                 320 
          Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala 
                          325                 330                 335     
          Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro 
                      340                 345                 350         
          Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln 
                  355                 360                 365             
          Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala 
              370                 375                 380                 
          Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr 
          385                 390                 395                 400 
          Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu 
                          405                 410                 415     
          Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser 
                      420                 425                 430         
          Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser 
                  435                 440                 445             
          Leu Ser Pro Gly Gly Gly Ser Glu Gly Lys Ser Ser Gly Ser Gly Ser 
              450                 455                 460                 
          Glu Ser Lys Ser Thr Gly Gly Ser Asp Ile Gln Met Thr Gln Ser Pro 
          465                 470                 475                 480 
          Ser Ser Leu Ser Ala Ser Val Gly Asp Arg Val Thr Ile Thr Cys Arg 
                          485                 490                 495     
          Ala Ser Gln Val Ile Arg Arg Ser Leu Ala Trp Tyr Gln Gln Lys Pro 
                      500                 505                 510         
          Gly Lys Ala Pro Lys Leu Leu Ile Tyr Ala Ala Ser Asn Leu Ala Ser 
                  515                 520                 525             
          Gly Val Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr 
              530                 535                 540                 
          Leu Thr Ile Ser Ser Leu Gln Pro Glu Asp Phe Ala Thr Tyr Tyr Cys 
          545                 550                 555                 560 
          Gln Gln Ser Asn Thr Ser Pro Leu Thr Phe Gly Gln Gly Thr Lys Val 
                          565                 570                 575     
          Glu Ile Lys Gly Gly Ser Glu Gly Lys Ser Ser Gly Ser Gly Ser Glu 
                      580                 585                 590         
          Ser Lys Ser Thr Gly Gly Ser Glu Val Gln Leu Val Glu Ser Gly Gly 
                  595                 600                 605             
          Gly Leu Val Gln Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser 
              610                 615                 620                 
          Gly Phe Thr Ile Asn Ala Ser Trp Ile His Trp Val Arg Gln Ala Pro 
          625                 630                 635                 640 
          Gly Lys Gly Leu Glu Trp Val Gly Ala Ile Tyr Pro Tyr Ser Gly Tyr 
                          645                 650                 655     
          Thr Asn Tyr Ala Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Ala Asp 
                      660                 665                 670         
          Thr Ser Lys Asn Thr Ala Tyr Leu Gln Met Asn Ser Leu Arg Ala Glu 
                  675                 680                 685             
          Asp Thr Ala Val Tyr Tyr Cys Ala Arg Trp Gly His Ser Thr Ser Pro 
              690                 695                 700                 
          Trp Ala Met Asp Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser 
          705                 710                 715                 720 
          <![CDATA[<210> 5]]>
          <![CDATA[<211> 214]]>
          <![CDATA[<212> PRT]]>
          <![CDATA[<213> 智人]]>
          <![CDATA[<400> 5]]>
          Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly 
          1               5                   10                  15      
          Asp Arg Val Thr Ile Thr Cys Arg Thr Ser Glu Asn Val Tyr Ser Asn 
                      20                  25                  30          
          Leu Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile 
                  35                  40                  45              
          Tyr Ala Ala Ser Asn Leu Gln Ser Gly Val Pro Ser Arg Phe Ser Gly 
              50                  55                  60                  
          Ser Gly Ser Gly Thr Asp Tyr Thr Phe Thr Ile Ser Ser Leu Gln Pro 
          65                  70                  75                  80  
          Glu Asp Ile Ala Thr Tyr Tyr Cys Gln His Phe Trp Gly Ser Pro Phe 
                          85                  90                  95      
          Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys Arg Thr Val Ala Ala 
                      100                 105                 110         
          Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly 
                  115                 120                 125             
          Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala 
              130                 135                 140                 
          Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln 
          145                 150                 155                 160 
          Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser 
                          165                 170                 175     
          Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr 
                      180                 185                 190         
          Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser 
                  195                 200                 205             
          Phe Asn Arg Gly Glu Cys 
              210                 
          <![CDATA[<210> 6]]>
          <![CDATA[<211> 719]]>
          <![CDATA[<212> PRT]]>
          <![CDATA[<213> 智人]]>
          <![CDATA[<400> 6]]>
          Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala 
          1               5                   10                  15      
          Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Asn Tyr 
                      20                  25                  30          
          Asp Ile Ile Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met 
                  35                  40                  45              
          Gly Tyr Ile Asn Pro Tyr Asn Asp Gly Thr Lys Tyr Asn Glu Lys Phe 
              50                  55                  60                  
          Lys Gly Arg Val Thr Met Thr Arg Asp Thr Ser Thr Ser Thr Val Tyr 
          65                  70                  75                  80  
          Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys 
                          85                  90                  95      
          Ala Arg Leu Leu Lys Tyr Arg Arg Phe Arg Tyr Tyr Ala Ile Asp Tyr 
                      100                 105                 110         
          Trp Gly Gln Gly Thr Thr Val Thr Val Ser Ser Ala Ser Thr Lys Gly 
                  115                 120                 125             
          Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly 
              130                 135                 140                 
          Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val 
          145                 150                 155                 160 
          Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe 
                          165                 170                 175     
          Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val 
                      180                 185                 190         
          Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val 
                  195                 200                 205             
          Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys Arg Val Glu Pro Lys 
              210                 215                 220                 
          Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Ala 
          225                 230                 235                 240 
          Ala Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr 
                          245                 250                 255     
          Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val 
                      260                 265                 270         
          Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val 
                  275                 280                 285             
          Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser 
              290                 295                 300                 
          Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu 
          305                 310                 315                 320 
          Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala 
                          325                 330                 335     
          Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro 
                      340                 345                 350         
          Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln 
                  355                 360                 365             
          Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala 
              370                 375                 380                 
          Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr 
          385                 390                 395                 400 
          Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu 
                          405                 410                 415     
          Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser 
                      420                 425                 430         
          Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser 
                  435                 440                 445             
          Leu Ser Pro Gly Gly Gly Ser Glu Gly Lys Ser Ser Gly Ser Gly Ser 
              450                 455                 460                 
          Glu Ser Lys Ser Thr Gly Gly Ser Glu Val Gln Leu Val Glu Ser Gly 
          465                 470                 475                 480 
          Gly Gly Leu Val Gln Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala 
                          485                 490                 495     
          Ser Gly Phe Thr Ile Ser Asp Tyr Trp Ile His Trp Val Arg Gln Ala 
                      500                 505                 510         
          Pro Gly Lys Gly Leu Glu Trp Val Ala Gly Ile Thr Pro Ala Gly Gly 
                  515                 520                 525             
          Tyr Thr Tyr Tyr Ala Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Ala 
              530                 535                 540                 
          Asp Thr Ser Lys Asn Thr Ala Tyr Leu Gln Met Asn Ser Leu Arg Ala 
          545                 550                 555                 560 
          Glu Asp Thr Ala Val Tyr Tyr Cys Ala Arg Phe Val Phe Phe Leu Pro 
                          565                 570                 575     
          Tyr Ala Met Asp Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser 
                      580                 585                 590         
          Gly Gly Ser Glu Gly Lys Ser Ser Gly Ser Gly Ser Glu Ser Lys Ser 
                  595                 600                 605             
          Thr Gly Gly Ser Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser 
              610                 615                 620                 
          Ala Ser Val Gly Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Asp 
          625                 630                 635                 640 
          Val Ser Thr Ala Val Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro 
                          645                 650                 655     
          Lys Leu Leu Ile Tyr Ser Ala Ser Phe Leu Tyr Ser Gly Val Pro Ser 
                      660                 665                 670         
          Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser 
                  675                 680                 685             
          Ser Leu Gln Pro Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Ser Tyr 
              690                 695                 700                 
          Thr Thr Pro Pro Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys 
          705                 710                 715                 
          <![CDATA[<210> 7]]>
          <![CDATA[<211> 214]]>
          <![CDATA[<212> PRT]]>
          <![CDATA[<213> 智人]]>
          <![CDATA[<400> 7]]>
          Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly 
          1               5                   10                  15      
          Asp Arg Val Thr Ile Thr Cys Arg Thr Ser Glu Asn Val Tyr Ser Asn 
                      20                  25                  30          
          Leu Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile 
                  35                  40                  45              
          Tyr Ala Ala Ser Asn Leu Gln Ser Gly Val Pro Ser Arg Phe Ser Gly 
              50                  55                  60                  
          Ser Gly Ser Gly Thr Asp Tyr Thr Phe Thr Ile Ser Ser Leu Gln Pro 
          65                  70                  75                  80  
          Glu Asp Ile Ala Thr Tyr Tyr Cys Gln His Phe Trp Gly Ser Pro Phe 
                          85                  90                  95      
          Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys Arg Thr Val Ala Ala 
                      100                 105                 110         
          Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly 
                  115                 120                 125             
          Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala 
              130                 135                 140                 
          Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln 
          145                 150                 155                 160 
          Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser 
                          165                 170                 175     
          Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr 
                      180                 185                 190         
          Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser 
                  195                 200                 205             
          Phe Asn Arg Gly Glu Cys 
              210                 
          <![CDATA[<210> 8]]>
          <![CDATA[<211> 719]]>
          <![CDATA[<212> PRT]]>
          <![CDATA[<213> 智人]]>
          <![CDATA[<400> 8]]>
          Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala 
          1               5                   10                  15      
          Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Asn Tyr 
                      20                  25                  30          
          Asp Ile Ile Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met 
                  35                  40                  45              
          Gly Tyr Ile Asn Pro Tyr Asn Asp Gly Thr Lys Tyr Asn Glu Lys Phe 
              50                  55                  60                  
          Lys Gly Arg Val Thr Met Thr Arg Asp Thr Ser Thr Ser Thr Val Tyr 
          65                  70                  75                  80  
          Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys 
                          85                  90                  95      
          Ala Arg Leu Leu Lys Tyr Arg Arg Phe Arg Tyr Tyr Ala Ile Asp Tyr 
                      100                 105                 110         
          Trp Gly Gln Gly Thr Thr Val Thr Val Ser Ser Ala Ser Thr Lys Gly 
                  115                 120                 125             
          Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly 
              130                 135                 140                 
          Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val 
          145                 150                 155                 160 
          Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe 
                          165                 170                 175     
          Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val 
                      180                 185                 190         
          Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val 
                  195                 200                 205             
          Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys Arg Val Glu Pro Lys 
              210                 215                 220                 
          Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Ala 
          225                 230                 235                 240 
          Ala Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr 
                          245                 250                 255     
          Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val 
                      260                 265                 270         
          Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val 
                  275                 280                 285             
          Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser 
              290                 295                 300                 
          Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu 
          305                 310                 315                 320 
          Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala 
                          325                 330                 335     
          Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro 
                      340                 345                 350         
          Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln 
                  355                 360                 365             
          Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala 
              370                 375                 380                 
          Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr 
          385                 390                 395                 400 
          Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu 
                          405                 410                 415     
          Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser 
                      420                 425                 430         
          Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser 
                  435                 440                 445             
          Leu Ser Pro Gly Gly Gly Ser Glu Gly Lys Ser Ser Gly Ser Gly Ser 
              450                 455                 460                 
          Glu Ser Lys Ser Thr Gly Gly Ser Asp Ile Gln Met Thr Gln Ser Pro 
          465                 470                 475                 480 
          Ser Ser Leu Ser Ala Ser Val Gly Asp Arg Val Thr Ile Thr Cys Arg 
                          485                 490                 495     
          Ala Ser Gln Asp Val Ser Thr Ala Val Ala Trp Tyr Gln Gln Lys Pro 
                      500                 505                 510         
          Gly Lys Ala Pro Lys Leu Leu Ile Tyr Ser Ala Ser Phe Leu Tyr Ser 
                  515                 520                 525             
          Gly Val Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr 
              530                 535                 540                 
          Leu Thr Ile Ser Ser Leu Gln Pro Glu Asp Phe Ala Thr Tyr Tyr Cys 
          545                 550                 555                 560 
          Gln Gln Ser Tyr Thr Thr Pro Pro Thr Phe Gly Gln Gly Thr Lys Val 
                          565                 570                 575     
          Glu Ile Lys Gly Gly Ser Glu Gly Lys Ser Ser Gly Ser Gly Ser Glu 
                      580                 585                 590         
          Ser Lys Ser Thr Gly Gly Ser Glu Val Gln Leu Val Glu Ser Gly Gly 
                  595                 600                 605             
          Gly Leu Val Gln Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser 
              610                 615                 620                 
          Gly Phe Thr Ile Ser Asp Tyr Trp Ile His Trp Val Arg Gln Ala Pro 
          625                 630                 635                 640 
          Gly Lys Gly Leu Glu Trp Val Ala Gly Ile Thr Pro Ala Gly Gly Tyr 
                          645                 650                 655     
          Thr Tyr Tyr Ala Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Ala Asp 
                      660                 665                 670         
          Thr Ser Lys Asn Thr Ala Tyr Leu Gln Met Asn Ser Leu Arg Ala Glu 
                  675                 680                 685             
          Asp Thr Ala Val Tyr Tyr Cys Ala Arg Phe Val Phe Phe Leu Pro Tyr 
              690                 695                 700                 
          Ala Met Asp Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser 
          705                 710                 715                 
          <![CDATA[<210> 9]]>
          <![CDATA[<211> 214]]>
          <![CDATA[<212> PRT]]>
          <![CDATA[<213> 智人]]>
          <![CDATA[<400> 9]]>
          Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly 
          1               5                   10                  15      
          Asp Arg Val Thr Ile Thr Cys Arg Thr Ser Glu Asn Val Tyr Ser Asn 
                      20                  25                  30          
          Leu Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile 
                  35                  40                  45              
          Tyr Ala Ala Ser Asn Leu Gln Ser Gly Val Pro Ser Arg Phe Ser Gly 
              50                  55                  60                  
          Ser Gly Ser Gly Thr Asp Tyr Thr Phe Thr Ile Ser Ser Leu Gln Pro 
          65                  70                  75                  80  
          Glu Asp Ile Ala Thr Tyr Tyr Cys Gln His Phe Trp Gly Ser Pro Phe 
                          85                  90                  95      
          Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys Arg Thr Val Ala Ala 
                      100                 105                 110         
          Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly 
                  115                 120                 125             
          Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala 
              130                 135                 140                 
          Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln 
          145                 150                 155                 160 
          Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser 
                          165                 170                 175     
          Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr 
                      180                 185                 190         
          Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser 
                  195                 200                 205             
          Phe Asn Arg Gly Glu Cys 
              210                 
          <![CDATA[<210> 10]]>
          <![CDATA[<211> 722]]>
          <![CDATA[<212> PRT]]>
          <![CDATA[<213> 智人]]>
          <![CDATA[<400> 10]]>
          Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala 
          1               5                   10                  15      
          Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Asn Tyr 
                      20                  25                  30          
          Asp Ile Ile Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met 
                  35                  40                  45              
          Gly Tyr Ile Asn Pro Tyr Asn Asp Gly Thr Lys Tyr Asn Glu Lys Phe 
              50                  55                  60                  
          Lys Gly Arg Val Thr Met Thr Arg Asp Thr Ser Thr Ser Thr Val Tyr 
          65                  70                  75                  80  
          Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys 
                          85                  90                  95      
          Ala Arg Leu Leu Lys Tyr Arg Arg Phe Arg Tyr Tyr Ala Ile Asp Tyr 
                      100                 105                 110         
          Trp Gly Gln Gly Thr Thr Val Thr Val Ser Ser Ala Ser Thr Lys Gly 
                  115                 120                 125             
          Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly 
              130                 135                 140                 
          Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val 
          145                 150                 155                 160 
          Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe 
                          165                 170                 175     
          Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val 
                      180                 185                 190         
          Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val 
                  195                 200                 205             
          Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys Arg Val Glu Pro Lys 
              210                 215                 220                 
          Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Ala 
          225                 230                 235                 240 
          Ala Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr 
                          245                 250                 255     
          Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val 
                      260                 265                 270         
          Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val 
                  275                 280                 285             
          Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser 
              290                 295                 300                 
          Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu 
          305                 310                 315                 320 
          Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala 
                          325                 330                 335     
          Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro 
                      340                 345                 350         
          Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln 
                  355                 360                 365             
          Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala 
              370                 375                 380                 
          Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr 
          385                 390                 395                 400 
          Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu 
                          405                 410                 415     
          Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser 
                      420                 425                 430         
          Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser 
                  435                 440                 445             
          Leu Ser Pro Gly Gly Gly Ser Glu Gly Lys Ser Ser Gly Ser Gly Ser 
              450                 455                 460                 
          Glu Ser Lys Ser Thr Gly Gly Ser Glu Val Gln Leu Val Glu Ser Gly 
          465                 470                 475                 480 
          Gly Gly Leu Val Gln Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala 
                          485                 490                 495     
          Ser Gly Tyr Asp Phe Thr His Tyr Gly Met Asn Trp Val Arg Gln Ala 
                      500                 505                 510         
          Pro Gly Lys Gly Leu Glu Trp Val Gly Trp Ile Asn Thr Tyr Thr Gly 
                  515                 520                 525             
          Glu Pro Thr Tyr Ala Ala Asp Phe Lys Arg Arg Phe Thr Phe Ser Leu 
              530                 535                 540                 
          Asp Thr Ser Lys Ser Thr Ala Tyr Leu Gln Met Asn Ser Leu Arg Ala 
          545                 550                 555                 560 
          Glu Asp Thr Ala Val Tyr Tyr Cys Ala Lys Tyr Pro Tyr Tyr Tyr Gly 
                          565                 570                 575     
          Thr Ser His Trp Tyr Phe Asp Val Trp Gly Gln Gly Thr Leu Val Thr 
                      580                 585                 590         
          Val Ser Ser Gly Gly Ser Glu Gly Lys Ser Ser Gly Ser Gly Ser Glu 
                  595                 600                 605             
          Ser Lys Ser Thr Gly Gly Ser Asp Ile Gln Leu Thr Gln Ser Pro Ser 
              610                 615                 620                 
          Ser Leu Ser Ala Ser Val Gly Asp Arg Val Thr Ile Thr Cys Ser Ala 
          625                 630                 635                 640 
          Ser Gln Asp Ile Ser Asn Tyr Leu Asn Trp Tyr Gln Gln Lys Pro Gly 
                          645                 650                 655     
          Lys Ala Pro Lys Val Leu Ile Tyr Phe Thr Ser Ser Leu His Ser Gly 
                      660                 665                 670         
          Val Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu 
                  675                 680                 685             
          Thr Ile Ser Ser Leu Gln Pro Glu Asp Phe Ala Thr Tyr Tyr Cys Gln 
              690                 695                 700                 
          Gln Tyr Ser Thr Val Pro Trp Thr Phe Gly Gln Gly Thr Lys Val Glu 
          705                 710                 715                 720 
          Ile Lys 
          <![CDATA[<210> 11]]>
          <![CDATA[<211> 214]]>
          <![CDATA[<212> PRT]]>
          <![CDATA[<213> 智人]]>
          <![CDATA[<400> 11]]>
          Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly 
          1               5                   10                  15      
          Asp Arg Val Thr Ile Thr Cys Arg Thr Ser Glu Asn Val Tyr Ser Asn 
                      20                  25                  30          
          Leu Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile 
                  35                  40                  45              
          Tyr Ala Ala Ser Asn Leu Gln Ser Gly Val Pro Ser Arg Phe Ser Gly 
              50                  55                  60                  
          Ser Gly Ser Gly Thr Asp Tyr Thr Phe Thr Ile Ser Ser Leu Gln Pro 
          65                  70                  75                  80  
          Glu Asp Ile Ala Thr Tyr Tyr Cys Gln His Phe Trp Gly Ser Pro Phe 
                          85                  90                  95      
          Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys Arg Thr Val Ala Ala 
                      100                 105                 110         
          Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly 
                  115                 120                 125             
          Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala 
              130                 135                 140                 
          Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln 
          145                 150                 155                 160 
          Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser 
                          165                 170                 175     
          Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr 
                      180                 185                 190         
          Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser 
                  195                 200                 205             
          Phe Asn Arg Gly Glu Cys 
              210                 
          <![CDATA[<210> 12]]>
          <![CDATA[<211> 722]]>
          <![CDATA[<212> PRT]]>
          <![CDATA[<213> 智人]]>
          <![CDATA[<400> 12]]>
          Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala 
          1               5                   10                  15      
          Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Asn Tyr 
                      20                  25                  30          
          Asp Ile Ile Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met 
                  35                  40                  45              
          Gly Tyr Ile Asn Pro Tyr Asn Asp Gly Thr Lys Tyr Asn Glu Lys Phe 
              50                  55                  60                  
          Lys Gly Arg Val Thr Met Thr Arg Asp Thr Ser Thr Ser Thr Val Tyr 
          65                  70                  75                  80  
          Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys 
                          85                  90                  95      
          Ala Arg Leu Leu Lys Tyr Arg Arg Phe Arg Tyr Tyr Ala Ile Asp Tyr 
                      100                 105                 110         
          Trp Gly Gln Gly Thr Thr Val Thr Val Ser Ser Ala Ser Thr Lys Gly 
                  115                 120                 125             
          Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly 
              130                 135                 140                 
          Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val 
          145                 150                 155                 160 
          Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe 
                          165                 170                 175     
          Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val 
                      180                 185                 190         
          Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val 
                  195                 200                 205             
          Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys Arg Val Glu Pro Lys 
              210                 215                 220                 
          Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Ala 
          225                 230                 235                 240 
          Ala Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr 
                          245                 250                 255     
          Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val 
                      260                 265                 270         
          Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val 
                  275                 280                 285             
          Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser 
              290                 295                 300                 
          Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu 
          305                 310                 315                 320 
          Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala 
                          325                 330                 335     
          Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro 
                      340                 345                 350         
          Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln 
                  355                 360                 365             
          Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala 
              370                 375                 380                 
          Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr 
          385                 390                 395                 400 
          Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu 
                          405                 410                 415     
          Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser 
                      420                 425                 430         
          Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser 
                  435                 440                 445             
          Leu Ser Pro Gly Gly Gly Ser Glu Gly Lys Ser Ser Gly Ser Gly Ser 
              450                 455                 460                 
          Glu Ser Lys Ser Thr Gly Gly Ser Asp Ile Gln Leu Thr Gln Ser Pro 
          465                 470                 475                 480 
          Ser Ser Leu Ser Ala Ser Val Gly Asp Arg Val Thr Ile Thr Cys Ser 
                          485                 490                 495     
          Ala Ser Gln Asp Ile Ser Asn Tyr Leu Asn Trp Tyr Gln Gln Lys Pro 
                      500                 505                 510         
          Gly Lys Ala Pro Lys Val Leu Ile Tyr Phe Thr Ser Ser Leu His Ser 
                  515                 520                 525             
          Gly Val Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr 
              530                 535                 540                 
          Leu Thr Ile Ser Ser Leu Gln Pro Glu Asp Phe Ala Thr Tyr Tyr Cys 
          545                 550                 555                 560 
          Gln Gln Tyr Ser Thr Val Pro Trp Thr Phe Gly Gln Gly Thr Lys Val 
                          565                 570                 575     
          Glu Ile Lys Gly Gly Ser Glu Gly Lys Ser Ser Gly Ser Gly Ser Glu 
                      580                 585                 590         
          Ser Lys Ser Thr Gly Gly Ser Glu Val Gln Leu Val Glu Ser Gly Gly 
                  595                 600                 605             
          Gly Leu Val Gln Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser 
              610                 615                 620                 
          Gly Tyr Asp Phe Thr His Tyr Gly Met Asn Trp Val Arg Gln Ala Pro 
          625                 630                 635                 640 
          Gly Lys Gly Leu Glu Trp Val Gly Trp Ile Asn Thr Tyr Thr Gly Glu 
                          645                 650                 655     
          Pro Thr Tyr Ala Ala Asp Phe Lys Arg Arg Phe Thr Phe Ser Leu Asp 
                      660                 665                 670         
          Thr Ser Lys Ser Thr Ala Tyr Leu Gln Met Asn Ser Leu Arg Ala Glu 
                  675                 680                 685             
          Asp Thr Ala Val Tyr Tyr Cys Ala Lys Tyr Pro Tyr Tyr Tyr Gly Thr 
              690                 695                 700                 
          Ser His Trp Tyr Phe Asp Val Trp Gly Gln Gly Thr Leu Val Thr Val 
          705                 710                 715                 720 
          Ser Ser 
          <![CDATA[<210> 13]]>
          <![CDATA[<211> 214]]>
          <![CDATA[<212> PRT]]>
          <![CDATA[<213> 智人]]>
          <![CDATA[<400> 13]]>
          Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly 
          1               5                   10                  15      
          Asp Arg Val Thr Ile Thr Cys Arg Thr Ser Glu Asn Val Tyr Ser Asn 
                      20                  25                  30          
          Leu Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile 
                  35                  40                  45              
          Tyr Ala Ala Ser Asn Leu Gln Ser Gly Val Pro Ser Arg Phe Ser Gly 
              50                  55                  60                  
          Ser Gly Ser Gly Thr Asp Tyr Thr Phe Thr Ile Ser Ser Leu Gln Pro 
          65                  70                  75                  80  
          Glu Asp Ile Ala Thr Tyr Tyr Cys Gln His Phe Trp Gly Ser Pro Phe 
                          85                  90                  95      
          Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys Arg Thr Val Ala Ala 
                      100                 105                 110         
          Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly 
                  115                 120                 125             
          Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala 
              130                 135                 140                 
          Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln 
          145                 150                 155                 160 
          Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser 
                          165                 170                 175     
          Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr 
                      180                 185                 190         
          Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser 
                  195                 200                 205             
          Phe Asn Arg Gly Glu Cys 
              210                 
          <![CDATA[<210> 14]]>
          <![CDATA[<211> 720]]>
          <![CDATA[<212> PRT]]>
          <![CDATA[<213> 智人]]>
          <![CDATA[<400> 14]]>
          Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala 
          1               5                   10                  15      
          Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Asn Tyr 
                      20                  25                  30          
          Asp Ile Ile Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met 
                  35                  40                  45              
          Gly Tyr Ile Asn Pro Tyr Asn Asp Gly Thr Lys Tyr Asn Glu Lys Phe 
              50                  55                  60                  
          Lys Gly Arg Val Thr Met Thr Arg Asp Thr Ser Thr Ser Thr Val Tyr 
          65                  70                  75                  80  
          Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys 
                          85                  90                  95      
          Ala Arg Leu Leu Lys Tyr Arg Arg Phe Arg Tyr Tyr Ala Ile Asp Tyr 
                      100                 105                 110         
          Trp Gly Gln Gly Thr Thr Val Thr Val Ser Ser Ala Ser Thr Lys Gly 
                  115                 120                 125             
          Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly 
              130                 135                 140                 
          Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val 
          145                 150                 155                 160 
          Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe 
                          165                 170                 175     
          Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val 
                      180                 185                 190         
          Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val 
                  195                 200                 205             
          Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys Arg Val Glu Pro Lys 
              210                 215                 220                 
          Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Ala 
          225                 230                 235                 240 
          Ala Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr 
                          245                 250                 255     
          Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val 
                      260                 265                 270         
          Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val 
                  275                 280                 285             
          Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser 
              290                 295                 300                 
          Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu 
          305                 310                 315                 320 
          Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala 
                          325                 330                 335     
          Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro 
                      340                 345                 350         
          Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln 
                  355                 360                 365             
          Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala 
              370                 375                 380                 
          Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr 
          385                 390                 395                 400 
          Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu 
                          405                 410                 415     
          Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser 
                      420                 425                 430         
          Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser 
                  435                 440                 445             
          Leu Ser Pro Gly Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly 
              450                 455                 460                 
          Gly Gly Ser Gly Gly Gly Gly Ser Asp Ile Gln Met Thr Gln Ser Pro 
          465                 470                 475                 480 
          Ser Ser Leu Ser Ala Ser Val Gly Asp Arg Val Thr Ile Thr Cys Arg 
                          485                 490                 495     
          Ala Ser Gln Val Ile Arg Arg Ser Leu Ala Trp Tyr Gln Gln Lys Pro 
                      500                 505                 510         
          Gly Lys Ala Pro Lys Leu Leu Ile Tyr Ala Ala Ser Asn Leu Ala Ser 
                  515                 520                 525             
          Gly Val Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr 
              530                 535                 540                 
          Leu Thr Ile Ser Ser Leu Gln Pro Glu Asp Phe Ala Thr Tyr Tyr Cys 
          545                 550                 555                 560 
          Gln Gln Ser Asn Thr Ser Pro Leu Thr Phe Gly Gln Gly Thr Lys Val 
                          565                 570                 575     
          Glu Ile Lys Gly Gly Ser Glu Gly Lys Ser Ser Gly Ser Gly Ser Glu 
                      580                 585                 590         
          Ser Lys Ser Thr Gly Gly Ser Glu Val Gln Leu Val Glu Ser Gly Gly 
                  595                 600                 605             
          Gly Leu Val Gln Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser 
              610                 615                 620                 
          Gly Phe Thr Ile Asn Ala Ser Trp Ile His Trp Val Arg Gln Ala Pro 
          625                 630                 635                 640 
          Gly Lys Gly Leu Glu Trp Val Gly Ala Ile Tyr Pro Tyr Ser Gly Tyr 
                          645                 650                 655     
          Thr Asn Tyr Ala Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Ala Asp 
                      660                 665                 670         
          Thr Ser Lys Asn Thr Ala Tyr Leu Gln Met Asn Ser Leu Arg Ala Glu 
                  675                 680                 685             
          Asp Thr Ala Val Tyr Tyr Cys Ala Arg Trp Gly His Ser Thr Ser Pro 
              690                 695                 700                 
          Trp Ala Met Asp Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser 
          705                 710                 715                 720 
          <![CDATA[<210> 15]]>
          <![CDATA[<211> 214]]>
          <![CDATA[<212> PRT]]>
          <![CDATA[<213> 智人]]>
          <![CDATA[<400> 15]]>
          Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly 
          1               5                   10                  15      
          Asp Arg Val Thr Ile Thr Cys Arg Thr Ser Glu Asn Val Tyr Ser Asn 
                      20                  25                  30          
          Leu Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile 
                  35                  40                  45              
          Tyr Ala Ala Ser Asn Leu Gln Ser Gly Val Pro Ser Arg Phe Ser Gly 
              50                  55                  60                  
          Ser Gly Ser Gly Thr Asp Tyr Thr Phe Thr Ile Ser Ser Leu Gln Pro 
          65                  70                  75                  80  
          Glu Asp Ile Ala Thr Tyr Tyr Cys Gln His Phe Trp Gly Ser Pro Phe 
                          85                  90                  95      
          Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys Arg Thr Val Ala Ala 
                      100                 105                 110         
          Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly 
                  115                 120                 125             
          Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala 
              130                 135                 140                 
          Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln 
          145                 150                 155                 160 
          Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser 
                          165                 170                 175     
          Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr 
                      180                 185                 190         
          Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser 
                  195                 200                 205             
          Phe Asn Arg Gly Glu Cys 
              210                 
          <![CDATA[<210> 16]]>
          <![CDATA[<211> 715]]>
          <![CDATA[<212> PRT]]>
          <![CDATA[<213> 智人]]>
          <![CDATA[<400> 16]]>
          Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala 
          1               5                   10                  15      
          Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Asn Tyr 
                      20                  25                  30          
          Asp Ile Ile Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met 
                  35                  40                  45              
          Gly Tyr Ile Asn Pro Tyr Asn Asp Gly Thr Lys Tyr Asn Glu Lys Phe 
              50                  55                  60                  
          Lys Gly Arg Val Thr Met Thr Arg Asp Thr Ser Thr Ser Thr Val Tyr 
          65                  70                  75                  80  
          Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys 
                          85                  90                  95      
          Ala Arg Leu Leu Lys Tyr Arg Arg Phe Arg Tyr Tyr Ala Ile Asp Tyr 
                      100                 105                 110         
          Trp Gly Gln Gly Thr Thr Val Thr Val Ser Ser Ala Ser Thr Lys Gly 
                  115                 120                 125             
          Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly 
              130                 135                 140                 
          Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val 
          145                 150                 155                 160 
          Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe 
                          165                 170                 175     
          Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val 
                      180                 185                 190         
          Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val 
                  195                 200                 205             
          Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys Arg Val Glu Pro Lys 
              210                 215                 220                 
          Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Ala 
          225                 230                 235                 240 
          Ala Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr 
                          245                 250                 255     
          Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val 
                      260                 265                 270         
          Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val 
                  275                 280                 285             
          Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser 
              290                 295                 300                 
          Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu 
          305                 310                 315                 320 
          Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala 
                          325                 330                 335     
          Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro 
                      340                 345                 350         
          Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln 
                  355                 360                 365             
          Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala 
              370                 375                 380                 
          Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr 
          385                 390                 395                 400 
          Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu 
                          405                 410                 415     
          Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser 
                      420                 425                 430         
          Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser 
                  435                 440                 445             
          Leu Ser Pro Gly Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly 
              450                 455                 460                 
          Gly Gly Ser Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala 
          465                 470                 475                 480 
          Ser Val Gly Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Val Ile 
                          485                 490                 495     
          Arg Arg Ser Leu Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys 
                      500                 505                 510         
          Leu Leu Ile Tyr Ala Ala Ser Asn Leu Ala Ser Gly Val Pro Ser Arg 
                  515                 520                 525             
          Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser 
              530                 535                 540                 
          Leu Gln Pro Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Ser Asn Thr 
          545                 550                 555                 560 
          Ser Pro Leu Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys Gly Gly 
                          565                 570                 575     
          Ser Glu Gly Lys Ser Ser Gly Ser Gly Ser Glu Ser Lys Ser Thr Gly 
                      580                 585                 590         
          Gly Ser Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro 
                  595                 600                 605             
          Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Ile Asn 
              610                 615                 620                 
          Ala Ser Trp Ile His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu 
          625                 630                 635                 640 
          Trp Val Gly Ala Ile Tyr Pro Tyr Ser Gly Tyr Thr Asn Tyr Ala Asp 
                          645                 650                 655     
          Ser Val Lys Gly Arg Phe Thr Ile Ser Ala Asp Thr Ser Lys Asn Thr 
                      660                 665                 670         
          Ala Tyr Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr 
                  675                 680                 685             
          Tyr Cys Ala Arg Trp Gly His Ser Thr Ser Pro Trp Ala Met Asp Tyr 
              690                 695                 700                 
          Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser 
          705                 710                 715 
          <![CDATA[<210> 17]]>
          <![CDATA[<211> 214]]>
          <![CDATA[<212> PRT]]>
          <![CDATA[<213> 智人]]>
          <![CDATA[<400> 17]]>
          Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly 
          1               5                   10                  15      
          Asp Arg Val Thr Ile Thr Cys Arg Thr Ser Glu Asn Val Tyr Ser Asn 
                      20                  25                  30          
          Leu Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile 
                  35                  40                  45              
          Tyr Ala Ala Ser Asn Leu Gln Ser Gly Val Pro Ser Arg Phe Ser Gly 
              50                  55                  60                  
          Ser Gly Ser Gly Thr Asp Tyr Thr Phe Thr Ile Ser Ser Leu Gln Pro 
          65                  70                  75                  80  
          Glu Asp Ile Ala Thr Tyr Tyr Cys Gln His Phe Trp Gly Ser Pro Phe 
                          85                  90                  95      
          Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys Arg Thr Val Ala Ala 
                      100                 105                 110         
          Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly 
                  115                 120                 125             
          Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala 
              130                 135                 140                 
          Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln 
          145                 150                 155                 160 
          Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser 
                          165                 170                 175     
          Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr 
                      180                 185                 190         
          Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser 
                  195                 200                 205             
          Phe Asn Arg Gly Glu Cys 
              210                 
          <![CDATA[<210> 18]]>
          <![CDATA[<211> 710]]>
          <![CDATA[<212> PRT]]>
          <![CDATA[<213> 智人]]>
          <![CDATA[<400> 18]]>
          Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala 
          1               5                   10                  15      
          Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Asn Tyr 
                      20                  25                  30          
          Asp Ile Ile Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met 
                  35                  40                  45              
          Gly Tyr Ile Asn Pro Tyr Asn Asp Gly Thr Lys Tyr Asn Glu Lys Phe 
              50                  55                  60                  
          Lys Gly Arg Val Thr Met Thr Arg Asp Thr Ser Thr Ser Thr Val Tyr 
          65                  70                  75                  80  
          Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys 
                          85                  90                  95      
          Ala Arg Leu Leu Lys Tyr Arg Arg Phe Arg Tyr Tyr Ala Ile Asp Tyr 
                      100                 105                 110         
          Trp Gly Gln Gly Thr Thr Val Thr Val Ser Ser Ala Ser Thr Lys Gly 
                  115                 120                 125             
          Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly 
              130                 135                 140                 
          Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val 
          145                 150                 155                 160 
          Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe 
                          165                 170                 175     
          Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val 
                      180                 185                 190         
          Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val 
                  195                 200                 205             
          Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys Arg Val Glu Pro Lys 
              210                 215                 220                 
          Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Ala 
          225                 230                 235                 240 
          Ala Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr 
                          245                 250                 255     
          Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val 
                      260                 265                 270         
          Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val 
                  275                 280                 285             
          Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser 
              290                 295                 300                 
          Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu 
          305                 310                 315                 320 
          Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala 
                          325                 330                 335     
          Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro 
                      340                 345                 350         
          Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln 
                  355                 360                 365             
          Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala 
              370                 375                 380                 
          Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr 
          385                 390                 395                 400 
          Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu 
                          405                 410                 415     
          Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser 
                      420                 425                 430         
          Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser 
                  435                 440                 445             
          Leu Ser Pro Gly Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Asp Ile 
              450                 455                 460                 
          Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly Asp Arg 
          465                 470                 475                 480 
          Val Thr Ile Thr Cys Arg Ala Ser Gln Val Ile Arg Arg Ser Leu Ala 
                          485                 490                 495     
          Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile Tyr Ala 
                      500                 505                 510         
          Ala Ser Asn Leu Ala Ser Gly Val Pro Ser Arg Phe Ser Gly Ser Gly 
                  515                 520                 525             
          Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro Glu Asp 
              530                 535                 540                 
          Phe Ala Thr Tyr Tyr Cys Gln Gln Ser Asn Thr Ser Pro Leu Thr Phe 
          545                 550                 555                 560 
          Gly Gln Gly Thr Lys Val Glu Ile Lys Gly Gly Ser Glu Gly Lys Ser 
                          565                 570                 575     
          Ser Gly Ser Gly Ser Glu Ser Lys Ser Thr Gly Gly Ser Glu Val Gln 
                      580                 585                 590         
          Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly Ser Leu Arg 
                  595                 600                 605             
          Leu Ser Cys Ala Ala Ser Gly Phe Thr Ile Asn Ala Ser Trp Ile His 
              610                 615                 620                 
          Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val Gly Ala Ile 
          625                 630                 635                 640 
          Tyr Pro Tyr Ser Gly Tyr Thr Asn Tyr Ala Asp Ser Val Lys Gly Arg 
                          645                 650                 655     
          Phe Thr Ile Ser Ala Asp Thr Ser Lys Asn Thr Ala Tyr Leu Gln Met 
                      660                 665                 670         
          Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Ala Arg Trp 
                  675                 680                 685             
          Gly His Ser Thr Ser Pro Trp Ala Met Asp Tyr Trp Gly Gln Gly Thr 
              690                 695                 700                 
          Leu Val Thr Val Ser Ser 
          705                 710 
          <![CDATA[<210> 19]]>
          <![CDATA[<211> 214]]>
          <![CDATA[<212> PRT]]>
          <![CDATA[<213> 智人]]>
          <![CDATA[<400> 19]]>
          Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly 
          1               5                   10                  15      
          Asp Arg Val Thr Ile Thr Cys Arg Thr Ser Glu Asn Val Tyr Ser Asn 
                      20                  25                  30          
          Leu Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile 
                  35                  40                  45              
          Tyr Ala Ala Ser Asn Leu Gln Ser Gly Val Pro Ser Arg Phe Ser Gly 
              50                  55                  60                  
          Ser Gly Ser Gly Thr Asp Tyr Thr Phe Thr Ile Ser Ser Leu Gln Pro 
          65                  70                  75                  80  
          Glu Asp Ile Ala Thr Tyr Tyr Cys Gln His Phe Trp Gly Ser Pro Phe 
                          85                  90                  95      
          Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys Arg Thr Val Ala Ala 
                      100                 105                 110         
          Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly 
                  115                 120                 125             
          Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala 
              130                 135                 140                 
          Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln 
          145                 150                 155                 160 
          Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser 
                          165                 170                 175     
          Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr 
                      180                 185                 190         
          Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser 
                  195                 200                 205             
          Phe Asn Arg Gly Glu Cys 
              210                 
          <![CDATA[<210> 20]]>
          <![CDATA[<211> 706]]>
          <![CDATA[<212> PRT]]>
          <![CDATA[<213> 智人]]>
          <![CDATA[<400> 20]]>
          Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala 
          1               5                   10                  15      
          Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Asn Tyr 
                      20                  25                  30          
          Asp Ile Ile Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met 
                  35                  40                  45              
          Gly Tyr Ile Asn Pro Tyr Asn Asp Gly Thr Lys Tyr Asn Glu Lys Phe 
              50                  55                  60                  
          Lys Gly Arg Val Thr Met Thr Arg Asp Thr Ser Thr Ser Thr Val Tyr 
          65                  70                  75                  80  
          Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys 
                          85                  90                  95      
          Ala Arg Leu Leu Lys Tyr Arg Arg Phe Arg Tyr Tyr Ala Ile Asp Tyr 
                      100                 105                 110         
          Trp Gly Gln Gly Thr Thr Val Thr Val Ser Ser Ala Ser Thr Lys Gly 
                  115                 120                 125             
          Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly 
              130                 135                 140                 
          Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val 
          145                 150                 155                 160 
          Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe 
                          165                 170                 175     
          Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val 
                      180                 185                 190         
          Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val 
                  195                 200                 205             
          Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys Arg Val Glu Pro Lys 
              210                 215                 220                 
          Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Ala 
          225                 230                 235                 240 
          Ala Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr 
                          245                 250                 255     
          Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val 
                      260                 265                 270         
          Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val 
                  275                 280                 285             
          Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser 
              290                 295                 300                 
          Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu 
          305                 310                 315                 320 
          Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala 
                          325                 330                 335     
          Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro 
                      340                 345                 350         
          Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln 
                  355                 360                 365             
          Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala 
              370                 375                 380                 
          Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr 
          385                 390                 395                 400 
          Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu 
                          405                 410                 415     
          Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser 
                      420                 425                 430         
          Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser 
                  435                 440                 445             
          Leu Ser Pro Gly Gly Gly Ser Gly Gly Ser Asp Ile Gln Met Thr Gln 
              450                 455                 460                 
          Ser Pro Ser Ser Leu Ser Ala Ser Val Gly Asp Arg Val Thr Ile Thr 
          465                 470                 475                 480 
          Cys Arg Ala Ser Gln Val Ile Arg Arg Ser Leu Ala Trp Tyr Gln Gln 
                          485                 490                 495     
          Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile Tyr Ala Ala Ser Asn Leu 
                      500                 505                 510         
          Ala Ser Gly Val Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp 
                  515                 520                 525             
          Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro Glu Asp Phe Ala Thr Tyr 
              530                 535                 540                 
          Tyr Cys Gln Gln Ser Asn Thr Ser Pro Leu Thr Phe Gly Gln Gly Thr 
          545                 550                 555                 560 
          Lys Val Glu Ile Lys Gly Gly Ser Glu Gly Lys Ser Ser Gly Ser Gly 
                          565                 570                 575     
          Ser Glu Ser Lys Ser Thr Gly Gly Ser Glu Val Gln Leu Val Glu Ser 
                      580                 585                 590         
          Gly Gly Gly Leu Val Gln Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala 
                  595                 600                 605             
          Ala Ser Gly Phe Thr Ile Asn Ala Ser Trp Ile His Trp Val Arg Gln 
              610                 615                 620                 
          Ala Pro Gly Lys Gly Leu Glu Trp Val Gly Ala Ile Tyr Pro Tyr Ser 
          625                 630                 635                 640 
          Gly Tyr Thr Asn Tyr Ala Asp Ser Val Lys Gly Arg Phe Thr Ile Ser 
                          645                 650                 655     
          Ala Asp Thr Ser Lys Asn Thr Ala Tyr Leu Gln Met Asn Ser Leu Arg 
                      660                 665                 670         
          Ala Glu Asp Thr Ala Val Tyr Tyr Cys Ala Arg Trp Gly His Ser Thr 
                  675                 680                 685             
          Ser Pro Trp Ala Met Asp Tyr Trp Gly Gln Gly Thr Leu Val Thr Val 
              690                 695                 700                 
          Ser Ser 
          705     
          <![CDATA[<210> 21]]>
          <![CDATA[<211> 214]]>
          <![CDATA[<212> PRT]]>
          <![CDATA[<213> 智人]]>
          <![CDATA[<400> 21]]>
          Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly 
          1               5                   10                  15      
          Asp Arg Val Thr Ile Thr Cys Arg Thr Ser Glu Asn Val Tyr Ser Asn 
                      20                  25                  30          
          Leu Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile 
                  35                  40                  45              
          Tyr Ala Ala Ser Asn Leu Gln Ser Gly Val Pro Ser Arg Phe Ser Gly 
              50                  55                  60                  
          Ser Gly Ser Gly Thr Asp Tyr Thr Phe Thr Ile Ser Ser Leu Gln Pro 
          65                  70                  75                  80  
          Glu Asp Ile Ala Thr Tyr Tyr Cys Gln His Phe Trp Gly Ser Pro Phe 
                          85                  90                  95      
          Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys Arg Thr Val Ala Ala 
                      100                 105                 110         
          Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly 
                  115                 120                 125             
          Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala 
              130                 135                 140                 
          Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln 
          145                 150                 155                 160 
          Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser 
                          165                 170                 175     
          Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr 
                      180                 185                 190         
          Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser 
                  195                 200                 205             
          Phe Asn Arg Gly Glu Cys 
              210                 
          <![CDATA[<210> 22]]>
          <![CDATA[<211> 712]]>
          <![CDATA[<212> PRT]]>
          <![CDATA[<213> 智人]]>
          <![CDATA[<400> 22]]>
          Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala 
          1               5                   10                  15      
          Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Asn Tyr 
                      20                  25                  30          
          Asp Ile Ile Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met 
                  35                  40                  45              
          Gly Tyr Ile Asn Pro Tyr Asn Asp Gly Thr Lys Tyr Asn Glu Lys Phe 
              50                  55                  60                  
          Lys Gly Arg Val Thr Met Thr Arg Asp Thr Ser Thr Ser Thr Val Tyr 
          65                  70                  75                  80  
          Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys 
                          85                  90                  95      
          Ala Arg Leu Leu Lys Tyr Arg Arg Phe Arg Tyr Tyr Ala Ile Asp Tyr 
                      100                 105                 110         
          Trp Gly Gln Gly Thr Thr Val Thr Val Ser Ser Ala Ser Thr Lys Gly 
                  115                 120                 125             
          Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly 
              130                 135                 140                 
          Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val 
          145                 150                 155                 160 
          Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe 
                          165                 170                 175     
          Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val 
                      180                 185                 190         
          Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val 
                  195                 200                 205             
          Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys Arg Val Glu Pro Lys 
              210                 215                 220                 
          Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Ala 
          225                 230                 235                 240 
          Ala Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr 
                          245                 250                 255     
          Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val 
                      260                 265                 270         
          Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val 
                  275                 280                 285             
          Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser 
              290                 295                 300                 
          Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu 
          305                 310                 315                 320 
          Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala 
                          325                 330                 335     
          Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro 
                      340                 345                 350         
          Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln 
                  355                 360                 365             
          Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala 
              370                 375                 380                 
          Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr 
          385                 390                 395                 400 
          Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu 
                          405                 410                 415     
          Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser 
                      420                 425                 430         
          Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser 
                  435                 440                 445             
          Leu Ser Pro Gly Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Glu Val 
              450                 455                 460                 
          Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly Ser Leu 
          465                 470                 475                 480 
          Arg Leu Ser Cys Ala Ala Ser Gly Tyr Asp Phe Thr His Tyr Gly Met 
                          485                 490                 495     
          Asn Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val Gly Trp 
                      500                 505                 510         
          Ile Asn Thr Tyr Thr Gly Glu Pro Thr Tyr Ala Ala Asp Phe Lys Arg 
                  515                 520                 525             
          Arg Phe Thr Phe Ser Leu Asp Thr Ser Lys Ser Thr Ala Tyr Leu Gln 
              530                 535                 540                 
          Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Ala Lys 
          545                 550                 555                 560 
          Tyr Pro Tyr Tyr Tyr Gly Thr Ser His Trp Tyr Phe Asp Val Trp Gly 
                          565                 570                 575     
          Gln Gly Thr Leu Val Thr Val Ser Ser Gly Gly Ser Glu Gly Lys Ser 
                      580                 585                 590         
          Ser Gly Ser Gly Ser Glu Ser Lys Ser Thr Gly Gly Ser Asp Ile Gln 
                  595                 600                 605             
          Leu Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly Asp Arg Val 
              610                 615                 620                 
          Thr Ile Thr Cys Ser Ala Ser Gln Asp Ile Ser Asn Tyr Leu Asn Trp 
          625                 630                 635                 640 
          Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Val Leu Ile Tyr Phe Thr 
                          645                 650                 655     
          Ser Ser Leu His Ser Gly Val Pro Ser Arg Phe Ser Gly Ser Gly Ser 
                      660                 665                 670         
          Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro Glu Asp Phe 
                  675                 680                 685             
          Ala Thr Tyr Tyr Cys Gln Gln Tyr Ser Thr Val Pro Trp Thr Phe Gly 
              690                 695                 700                 
          Gln Gly Thr Lys Val Glu Ile Lys 
          705                 710         
          <![CDATA[<210> 23]]>
          <![CDATA[<211> 214]]>
          <![CDATA[<212> PRT]]>
          <![CDATA[<213> 智人]]>
          <![CDATA[<400> 23]]>
          Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly 
          1               5                   10                  15      
          Asp Arg Val Thr Ile Thr Cys Arg Thr Ser Glu Asn Val Tyr Ser Asn 
                      20                  25                  30          
          Leu Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile 
                  35                  40                  45              
          Tyr Ala Ala Ser Asn Leu Gln Ser Gly Val Pro Ser Arg Phe Ser Gly 
              50                  55                  60                  
          Ser Gly Ser Gly Thr Asp Tyr Thr Phe Thr Ile Ser Ser Leu Gln Pro 
          65                  70                  75                  80  
          Glu Asp Ile Ala Thr Tyr Tyr Cys Gln His Phe Trp Gly Ser Pro Phe 
                          85                  90                  95      
          Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys Arg Thr Val Ala Ala 
                      100                 105                 110         
          Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly 
                  115                 120                 125             
          Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala 
              130                 135                 140                 
          Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln 
          145                 150                 155                 160 
          Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser 
                          165                 170                 175     
          Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr 
                      180                 185                 190         
          Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser 
                  195                 200                 205             
          Phe Asn Arg Gly Glu Cys 
              210                 
          <![CDATA[<210> 24]]>
          <![CDATA[<211> 722]]>
          <![CDATA[<212> PRT]]>
          <![CDATA[<213> 智人]]>
          <![CDATA[<400> 24]]>
          Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala 
          1               5                   10                  15      
          Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Asn Tyr 
                      20                  25                  30          
          Asp Ile Ile Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met 
                  35                  40                  45              
          Gly Tyr Ile Asn Pro Tyr Asn Asp Gly Thr Lys Tyr Asn Glu Lys Phe 
              50                  55                  60                  
          Lys Gly Arg Val Thr Met Thr Arg Asp Thr Ser Thr Ser Thr Val Tyr 
          65                  70                  75                  80  
          Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys 
                          85                  90                  95      
          Ala Arg Leu Leu Lys Tyr Arg Arg Phe Arg Tyr Tyr Ala Ile Asp Tyr 
                      100                 105                 110         
          Trp Gly Gln Gly Thr Thr Val Thr Val Ser Ser Ala Ser Thr Lys Gly 
                  115                 120                 125             
          Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly 
              130                 135                 140                 
          Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val 
          145                 150                 155                 160 
          Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe 
                          165                 170                 175     
          Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val 
                      180                 185                 190         
          Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val 
                  195                 200                 205             
          Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys Arg Val Glu Pro Lys 
              210                 215                 220                 
          Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Ala 
          225                 230                 235                 240 
          Ala Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr 
                          245                 250                 255     
          Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val 
                      260                 265                 270         
          Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val 
                  275                 280                 285             
          Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser 
              290                 295                 300                 
          Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu 
          305                 310                 315                 320 
          Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala 
                          325                 330                 335     
          Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro 
                      340                 345                 350         
          Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln 
                  355                 360                 365             
          Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala 
              370                 375                 380                 
          Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr 
          385                 390                 395                 400 
          Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu 
                          405                 410                 415     
          Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser 
                      420                 425                 430         
          Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser 
                  435                 440                 445             
          Leu Ser Pro Gly Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly 
              450                 455                 460                 
          Gly Gly Ser Gly Gly Gly Gly Ser Glu Val Gln Leu Val Glu Ser Gly 
          465                 470                 475                 480 
          Gly Gly Leu Val Gln Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala 
                          485                 490                 495     
          Ser Gly Tyr Asp Phe Thr His Tyr Gly Met Asn Trp Val Arg Gln Ala 
                      500                 505                 510         
          Pro Gly Lys Gly Leu Glu Trp Val Gly Trp Ile Asn Thr Tyr Thr Gly 
                  515                 520                 525             
          Glu Pro Thr Tyr Ala Ala Asp Phe Lys Arg Arg Phe Thr Phe Ser Leu 
              530                 535                 540                 
          Asp Thr Ser Lys Ser Thr Ala Tyr Leu Gln Met Asn Ser Leu Arg Ala 
          545                 550                 555                 560 
          Glu Asp Thr Ala Val Tyr Tyr Cys Ala Lys Tyr Pro Tyr Tyr Tyr Gly 
                          565                 570                 575     
          Thr Ser His Trp Tyr Phe Asp Val Trp Gly Gln Gly Thr Leu Val Thr 
                      580                 585                 590         
          Val Ser Ser Gly Gly Ser Glu Gly Lys Ser Ser Gly Ser Gly Ser Glu 
                  595                 600                 605             
          Ser Lys Ser Thr Gly Gly Ser Asp Ile Gln Leu Thr Gln Ser Pro Ser 
              610                 615                 620                 
          Ser Leu Ser Ala Ser Val Gly Asp Arg Val Thr Ile Thr Cys Ser Ala 
          625                 630                 635                 640 
          Ser Gln Asp Ile Ser Asn Tyr Leu Asn Trp Tyr Gln Gln Lys Pro Gly 
                          645                 650                 655     
          Lys Ala Pro Lys Val Leu Ile Tyr Phe Thr Ser Ser Leu His Ser Gly 
                      660                 665                 670         
          Val Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu 
                  675                 680                 685             
          Thr Ile Ser Ser Leu Gln Pro Glu Asp Phe Ala Thr Tyr Tyr Cys Gln 
              690                 695                 700                 
          Gln Tyr Ser Thr Val Pro Trp Thr Phe Gly Gln Gly Thr Lys Val Glu 
          705                 710                 715                 720 
          Ile Lys 
          <![CDATA[<210> 25]]>
          <![CDATA[<211> 214]]>
          <![CDATA[<212> PRT]]>
          <![CDATA[<213> 智人]]>
          <![CDATA[<400> 25]]>
          Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly 
          1               5                   10                  15      
          Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Val Ile Arg Arg Ser 
                      20                  25                  30          
          Leu Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile 
                  35                  40                  45              
          Tyr Ala Ala Ser Asn Leu Ala 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 Ser Asn Thr Ser Pro Leu 
                          85                  90                  95      
          Thr Phe Gly Gln 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 Cys 
              210                 
          <![CDATA[<210> 26]]>
          <![CDATA[<211> 720]]>
          <![CDATA[<212> PRT]]>
          <![CDATA[<213> 智人]]>
          <![CDATA[<400> 26]]>
          Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 
          1               5                   10                  15      
          Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Ile Asn Ala Ser 
                      20                  25                  30          
          Trp Ile His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 
                  35                  40                  45              
          Gly Ala Ile Tyr Pro Tyr Ser Gly Tyr Thr Asn Tyr Ala Asp Ser Val 
              50                  55                  60                  
          Lys Gly Arg Phe Thr Ile Ser Ala Asp Thr Ser Lys Asn Thr Ala Tyr 
          65                  70                  75                  80  
          Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 
                          85                  90                  95      
          Ala Arg Trp Gly His Ser Thr Ser Pro Trp Ala Met Asp Tyr Trp Gly 
                      100                 105                 110         
          Gln Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser 
                  115                 120                 125             
          Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala 
              130                 135                 140                 
          Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val 
          145                 150                 155                 160 
          Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala 
                          165                 170                 175     
          Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val 
                      180                 185                 190         
          Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His 
                  195                 200                 205             
          Lys Pro Ser Asn Thr Lys Val Asp Lys Arg Val Glu Pro Lys Ser Cys 
              210                 215                 220                 
          Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Ala Ala Gly 
          225                 230                 235                 240 
          Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met 
                          245                 250                 255     
          Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His 
                      260                 265                 270         
          Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val 
                  275                 280                 285             
          His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr 
              290                 295                 300                 
          Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly 
          305                 310                 315                 320 
          Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile 
                          325                 330                 335     
          Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val 
                      340                 345                 350         
          Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser 
                  355                 360                 365             
          Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu 
              370                 375                 380                 
          Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro 
          385                 390                 395                 400 
          Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val 
                          405                 410                 415     
          Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met 
                      420                 425                 430         
          His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser 
                  435                 440                 445             
          Pro Gly Gly Gly Ser Glu Gly Lys Ser Ser Gly Ser Gly Ser Glu Ser 
              450                 455                 460                 
          Lys Ser Thr Gly Gly Ser Gln Val Gln Leu Val Gln Ser Gly Ala Glu 
          465                 470                 475                 480 
          Val Lys Lys Pro Gly Ala Ser Val Lys Val Ser Cys Lys Ala Ser Gly 
                          485                 490                 495     
          Tyr Thr Phe Thr Asn Tyr Asp Ile Ile Trp Val Arg Gln Ala Pro Gly 
                      500                 505                 510         
          Gln Gly Leu Glu Trp Met Gly Tyr Ile Asn Pro Tyr Asn Asp Gly Thr 
                  515                 520                 525             
          Lys Tyr Asn Glu Lys Phe Lys Gly Arg Val Thr Met Thr Arg Asp Thr 
              530                 535                 540                 
          Ser Thr Ser Thr Val Tyr Met Glu Leu Ser Ser Leu Arg Ser Glu Asp 
          545                 550                 555                 560 
          Thr Ala Val Tyr Tyr Cys Ala Arg Leu Leu Lys Tyr Arg Arg Phe Arg 
                          565                 570                 575     
          Tyr Tyr Ala Ile Asp Tyr Trp Gly Gln Gly Thr Thr Val Thr Val Ser 
                      580                 585                 590         
          Ser Gly Gly Ser Glu Gly Lys Ser Ser Gly Ser Gly Ser Glu Ser Lys 
                  595                 600                 605             
          Ser Thr Gly Gly Ser Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu 
              610                 615                 620                 
          Ser Ala Ser Val Gly Asp Arg Val Thr Ile Thr Cys Arg Thr Ser Glu 
          625                 630                 635                 640 
          Asn Val Tyr Ser Asn Leu Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala 
                          645                 650                 655     
          Pro Lys Leu Leu Ile Tyr Ala Ala Ser Asn Leu Gln Ser Gly Val Pro 
                      660                 665                 670         
          Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Tyr Thr Phe Thr Ile 
                  675                 680                 685             
          Ser Ser Leu Gln Pro Glu Asp Ile Ala Thr Tyr Tyr Cys Gln His Phe 
              690                 695                 700                 
          Trp Gly Ser Pro Phe Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys 
          705                 710                 715                 720 
          <![CDATA[<210> 27]]>
          <![CDATA[<211> 214]]>
          <![CDATA[<212> PRT]]>
          <![CDATA[<213> 智人]]>
          <![CDATA[<400> 27]]>
          Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly 
          1               5                   10                  15      
          Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Val Ile Arg Arg Ser 
                      20                  25                  30          
          Leu Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile 
                  35                  40                  45              
          Tyr Ala Ala Ser Asn Leu Ala 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 Ser Asn Thr Ser Pro Leu 
                          85                  90                  95      
          Thr Phe Gly Gln 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 Cys 
              210                 
          <![CDATA[<210> 28]]>
          <![CDATA[<211> 720]]>
          <![CDATA[<212> PRT]]>
          <![CDATA[<213> 智人]]>
          <![CDATA[<400> 28]]>
          Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 
          1               5                   10                  15      
          Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Ile Asn Ala Ser 
                      20                  25                  30          
          Trp Ile His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 
                  35                  40                  45              
          Gly Ala Ile Tyr Pro Tyr Ser Gly Tyr Thr Asn Tyr Ala Asp Ser Val 
              50                  55                  60                  
          Lys Gly Arg Phe Thr Ile Ser Ala Asp Thr Ser Lys Asn Thr Ala Tyr 
          65                  70                  75                  80  
          Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 
                          85                  90                  95      
          Ala Arg Trp Gly His Ser Thr Ser Pro Trp Ala Met Asp Tyr Trp Gly 
                      100                 105                 110         
          Gln Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser 
                  115                 120                 125             
          Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala 
              130                 135                 140                 
          Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val 
          145                 150                 155                 160 
          Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala 
                          165                 170                 175     
          Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val 
                      180                 185                 190         
          Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His 
                  195                 200                 205             
          Lys Pro Ser Asn Thr Lys Val Asp Lys Arg Val Glu Pro Lys Ser Cys 
              210                 215                 220                 
          Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Ala Ala Gly 
          225                 230                 235                 240 
          Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met 
                          245                 250                 255     
          Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His 
                      260                 265                 270         
          Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val 
                  275                 280                 285             
          His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr 
              290                 295                 300                 
          Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly 
          305                 310                 315                 320 
          Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile 
                          325                 330                 335     
          Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val 
                      340                 345                 350         
          Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser 
                  355                 360                 365             
          Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu 
              370                 375                 380                 
          Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro 
          385                 390                 395                 400 
          Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val 
                          405                 410                 415     
          Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met 
                      420                 425                 430         
          His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser 
                  435                 440                 445             
          Pro Gly Gly Gly Ser Glu Gly Lys Ser Ser Gly Ser Gly Ser Glu Ser 
              450                 455                 460                 
          Lys Ser Thr Gly Gly Ser Asp Ile Gln Met Thr Gln Ser Pro Ser Ser 
          465                 470                 475                 480 
          Leu Ser Ala Ser Val Gly Asp Arg Val Thr Ile Thr Cys Arg Thr Ser 
                          485                 490                 495     
          Glu Asn Val Tyr Ser Asn Leu Ala Trp Tyr Gln Gln Lys Pro Gly Lys 
                      500                 505                 510         
          Ala Pro Lys Leu Leu Ile Tyr Ala Ala Ser Asn Leu Gln Ser Gly Val 
                  515                 520                 525             
          Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Tyr Thr Phe Thr 
              530                 535                 540                 
          Ile Ser Ser Leu Gln Pro Glu Asp Ile Ala Thr Tyr Tyr Cys Gln His 
          545                 550                 555                 560 
          Phe Trp Gly Ser Pro Phe Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile 
                          565                 570                 575     
          Lys Gly Gly Ser Glu Gly Lys Ser Ser Gly Ser Gly Ser Glu Ser Lys 
                      580                 585                 590         
          Ser Thr Gly Gly Ser Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val 
                  595                 600                 605             
          Lys Lys Pro Gly Ala Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr 
              610                 615                 620                 
          Thr Phe Thr Asn Tyr Asp Ile Ile Trp Val Arg Gln Ala Pro Gly Gln 
          625                 630                 635                 640 
          Gly Leu Glu Trp Met Gly Tyr Ile Asn Pro Tyr Asn Asp Gly Thr Lys 
                          645                 650                 655     
          Tyr Asn Glu Lys Phe Lys Gly Arg Val Thr Met Thr Arg Asp Thr Ser 
                      660                 665                 670         
          Thr Ser Thr Val Tyr Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr 
                  675                 680                 685             
          Ala Val Tyr Tyr Cys Ala Arg Leu Leu Lys Tyr Arg Arg Phe Arg Tyr 
              690                 695                 700                 
          Tyr Ala Ile Asp Tyr Trp Gly Gln Gly Thr Thr Val Thr Val Ser Ser 
          705                 710                 715                 720 
          <![CDATA[<210> 29]]>
          <![CDATA[<211> 214]]>
          <![CDATA[<212> PRT]]>
          <![CDATA[<213> 智人]]>
          <![CDATA[<400> 29]]>
          Asp Ile Gln Leu Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly 
          1               5                   10                  15      
          Asp Arg Val Thr Ile Thr Cys Ser Ala Ser Gln Asp Ile Ser Asn Tyr 
                      20                  25                  30          
          Leu Asn Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Val Leu Ile 
                  35                  40                  45              
          Tyr Phe Thr Ser Ser Leu His 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 Tyr Ser Thr Val Pro Trp 
                          85                  90                  95      
          Thr Phe Gly Gln 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 Cys 
              210                 
          <![CDATA[<210> 30]]>
          <![CDATA[<211> 722]]>
          <![CDATA[<212> PRT]]>
          <![CDATA[<213> 智人]]>
          <![CDATA[<400> 30]]>
          Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 
          1               5                   10                  15      
          Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Tyr Asp Phe Thr His Tyr 
                      20                  25                  30          
          Gly Met Asn Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 
                  35                  40                  45              
          Gly Trp Ile Asn Thr Tyr Thr Gly Glu Pro Thr Tyr Ala Ala Asp Phe 
              50                  55                  60                  
          Lys Arg Arg Phe Thr Phe Ser Leu Asp Thr Ser Lys Ser Thr Ala Tyr 
          65                  70                  75                  80  
          Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 
                          85                  90                  95      
          Ala Lys Tyr Pro Tyr Tyr Tyr Gly Thr Ser His Trp Tyr Phe Asp Val 
                      100                 105                 110         
          Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly 
                  115                 120                 125             
          Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly 
              130                 135                 140                 
          Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val 
          145                 150                 155                 160 
          Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe 
                          165                 170                 175     
          Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val 
                      180                 185                 190         
          Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val 
                  195                 200                 205             
          Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys Arg Val Glu Pro Lys 
              210                 215                 220                 
          Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Ala 
          225                 230                 235                 240 
          Ala Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr 
                          245                 250                 255     
          Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val 
                      260                 265                 270         
          Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val 
                  275                 280                 285             
          Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser 
              290                 295                 300                 
          Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu 
          305                 310                 315                 320 
          Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala 
                          325                 330                 335     
          Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro 
                      340                 345                 350         
          Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln 
                  355                 360                 365             
          Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala 
              370                 375                 380                 
          Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr 
          385                 390                 395                 400 
          Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu 
                          405                 410                 415     
          Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser 
                      420                 425                 430         
          Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser 
                  435                 440                 445             
          Leu Ser Pro Gly Gly Gly Ser Glu Gly Lys Ser Ser Gly Ser Gly Ser 
              450                 455                 460                 
          Glu Ser Lys Ser Thr Gly Gly Ser Gln Val Gln Leu Val Gln Ser Gly 
          465                 470                 475                 480 
          Ala Glu Val Lys Lys Pro Gly Ala Ser Val Lys Val Ser Cys Lys Ala 
                          485                 490                 495     
          Ser Gly Tyr Thr Phe Thr Asn Tyr Asp Ile Ile Trp Val Arg Gln Ala 
                      500                 505                 510         
          Pro Gly Gln Gly Leu Glu Trp Met Gly Tyr Ile Asn Pro Tyr Asn Asp 
                  515                 520                 525             
          Gly Thr Lys Tyr Asn Glu Lys Phe Lys Gly Arg Val Thr Met Thr Arg 
              530                 535                 540                 
          Asp Thr Ser Thr Ser Thr Val Tyr Met Glu Leu Ser Ser Leu Arg Ser 
          545                 550                 555                 560 
          Glu Asp Thr Ala Val Tyr Tyr Cys Ala Arg Leu Leu Lys Tyr Arg Arg 
                          565                 570                 575     
          Phe Arg Tyr Tyr Ala Ile Asp Tyr Trp Gly Gln Gly Thr Thr Val Thr 
                      580                 585                 590         
          Val Ser Ser Gly Gly Ser Glu Gly Lys Ser Ser Gly Ser Gly Ser Glu 
                  595                 600                 605             
          Ser Lys Ser Thr Gly Gly Ser Asp Ile Gln Met Thr Gln Ser Pro Ser 
              610                 615                 620                 
          Ser Leu Ser Ala Ser Val Gly Asp Arg Val Thr Ile Thr Cys Arg Thr 
          625                 630                 635                 640 
          Ser Glu Asn Val Tyr Ser Asn Leu Ala Trp Tyr Gln Gln Lys Pro Gly 
                          645                 650                 655     
          Lys Ala Pro Lys Leu Leu Ile Tyr Ala Ala Ser Asn Leu Gln Ser Gly 
                      660                 665                 670         
          Val Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Tyr Thr Phe 
                  675                 680                 685             
          Thr Ile Ser Ser Leu Gln Pro Glu Asp Ile Ala Thr Tyr Tyr Cys Gln 
              690                 695                 700                 
          His Phe Trp Gly Ser Pro Phe Thr Phe Gly Gln Gly Thr Lys Leu Glu 
          705                 710                 715                 720 
          Ile Lys 
          <![CDATA[<210> 31]]>
          <![CDATA[<211> 214]]>
          <![CDATA[<212> PRT]]>
          <![CDATA[<213> 智人]]>
          <![CDATA[<400> 31]]>
          Asp Ile Gln Leu Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly 
          1               5                   10                  15      
          Asp Arg Val Thr Ile Thr Cys Ser Ala Ser Gln Asp Ile Ser Asn Tyr 
                      20                  25                  30          
          Leu Asn Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Val Leu Ile 
                  35                  40                  45              
          Tyr Phe Thr Ser Ser Leu His 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 Tyr Ser Thr Val Pro Trp 
                          85                  90                  95      
          Thr Phe Gly Gln 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 Cys 
              210                 
          <![CDATA[<210> 32]]>
          <![CDATA[<211> 722]]>
          <![CDATA[<212> PRT]]>
          <![CDATA[<213> 智人]]>
          <![CDATA[<400> 32]]>
          Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 
          1               5                   10                  15      
          Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Tyr Asp Phe Thr His Tyr 
                      20                  25                  30          
          Gly Met Asn Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 
                  35                  40                  45              
          Gly Trp Ile Asn Thr Tyr Thr Gly Glu Pro Thr Tyr Ala Ala Asp Phe 
              50                  55                  60                  
          Lys Arg Arg Phe Thr Phe Ser Leu Asp Thr Ser Lys Ser Thr Ala Tyr 
          65                  70                  75                  80  
          Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 
                          85                  90                  95      
          Ala Lys Tyr Pro Tyr Tyr Tyr Gly Thr Ser His Trp Tyr Phe Asp Val 
                      100                 105                 110         
          Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly 
                  115                 120                 125             
          Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly 
              130                 135                 140                 
          Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val 
          145                 150                 155                 160 
          Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe 
                          165                 170                 175     
          Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val 
                      180                 185                 190         
          Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val 
                  195                 200                 205             
          Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys Arg Val Glu Pro Lys 
              210                 215                 220                 
          Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Ala 
          225                 230                 235                 240 
          Ala Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr 
                          245                 250                 255     
          Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val 
                      260                 265                 270         
          Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val 
                  275                 280                 285             
          Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser 
              290                 295                 300                 
          Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu 
          305                 310                 315                 320 
          Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala 
                          325                 330                 335     
          Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro 
                      340                 345                 350         
          Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln 
                  355                 360                 365             
          Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala 
              370                 375                 380                 
          Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr 
          385                 390                 395                 400 
          Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu 
                          405                 410                 415     
          Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser 
                      420                 425                 430         
          Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser 
                  435                 440                 445             
          Leu Ser Pro Gly Gly Gly Ser Glu Gly Lys Ser Ser Gly Ser Gly Ser 
              450                 455                 460                 
          Glu Ser Lys Ser Thr Gly Gly Ser Asp Ile Gln Met Thr Gln Ser Pro 
          465                 470                 475                 480 
          Ser Ser Leu Ser Ala Ser Val Gly Asp Arg Val Thr Ile Thr Cys Arg 
                          485                 490                 495     
          Thr Ser Glu Asn Val Tyr Ser Asn Leu Ala Trp Tyr Gln Gln Lys Pro 
                      500                 505                 510         
          Gly Lys Ala Pro Lys Leu Leu Ile Tyr Ala Ala Ser Asn Leu Gln Ser 
                  515                 520                 525             
          Gly Val Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Tyr Thr 
              530                 535                 540                 
          Phe Thr Ile Ser Ser Leu Gln Pro Glu Asp Ile Ala Thr Tyr Tyr Cys 
          545                 550                 555                 560 
          Gln His Phe Trp Gly Ser Pro Phe Thr Phe Gly Gln Gly Thr Lys Leu 
                          565                 570                 575     
          Glu Ile Lys Gly Gly Ser Glu Gly Lys Ser Ser Gly Ser Gly Ser Glu 
                      580                 585                 590         
          Ser Lys Ser Thr Gly Gly Ser Gln Val Gln Leu Val Gln Ser Gly Ala 
                  595                 600                 605             
          Glu Val Lys Lys Pro Gly Ala Ser Val Lys Val Ser Cys Lys Ala Ser 
              610                 615                 620                 
          Gly Tyr Thr Phe Thr Asn Tyr Asp Ile Ile Trp Val Arg Gln Ala Pro 
          625                 630                 635                 640 
          Gly Gln Gly Leu Glu Trp Met Gly Tyr Ile Asn Pro Tyr Asn Asp Gly 
                          645                 650                 655     
          Thr Lys Tyr Asn Glu Lys Phe Lys Gly Arg Val Thr Met Thr Arg Asp 
                      660                 665                 670         
          Thr Ser Thr Ser Thr Val Tyr Met Glu Leu Ser Ser Leu Arg Ser Glu 
                  675                 680                 685             
          Asp Thr Ala Val Tyr Tyr Cys Ala Arg Leu Leu Lys Tyr Arg Arg Phe 
              690                 695                 700                 
          Arg Tyr Tyr Ala Ile Asp Tyr Trp Gly Gln Gly Thr Thr Val Thr Val 
          705                 710                 715                 720 
          Ser Ser 
          <![CDATA[<210> 33]]>
          <![CDATA[<211> 214]]>
          <![CDATA[<212> PRT]]>
          <![CDATA[<213> 智人]]>
          <![CDATA[<400> 33]]>
          Asp Ile Gln Leu Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly 
          1               5                   10                  15      
          Asp Arg Val Thr Ile Thr Cys Ser Ala Ser Gln Asp Ile Ser Asn Tyr 
                      20                  25                  30          
          Leu Asn Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Val Leu Ile 
                  35                  40                  45              
          Tyr Phe Thr Ser Ser Leu His 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 Tyr Ser Thr Val Pro Trp 
                          85                  90                  95      
          Thr Phe Gly Gln 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 Cys 
              210                 
          <![CDATA[<210> 34]]>
          <![CDATA[<211> 712]]>
          <![CDATA[<212> PRT]]>
          <![CDATA[<213> 智人]]>
          <![CDATA[<400> 34]]>
          Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 
          1               5                   10                  15      
          Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Tyr Asp Phe Thr His Tyr 
                      20                  25                  30          
          Gly Met Asn Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 
                  35                  40                  45              
          Gly Trp Ile Asn Thr Tyr Thr Gly Glu Pro Thr Tyr Ala Ala Asp Phe 
              50                  55                  60                  
          Lys Arg Arg Phe Thr Phe Ser Leu Asp Thr Ser Lys Ser Thr Ala Tyr 
          65                  70                  75                  80  
          Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 
                          85                  90                  95      
          Ala Lys Tyr Pro Tyr Tyr Tyr Gly Thr Ser His Trp Tyr Phe Asp Val 
                      100                 105                 110         
          Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly 
                  115                 120                 125             
          Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly 
              130                 135                 140                 
          Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val 
          145                 150                 155                 160 
          Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe 
                          165                 170                 175     
          Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val 
                      180                 185                 190         
          Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val 
                  195                 200                 205             
          Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys Arg Val Glu Pro Lys 
              210                 215                 220                 
          Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Ala 
          225                 230                 235                 240 
          Ala Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr 
                          245                 250                 255     
          Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val 
                      260                 265                 270         
          Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val 
                  275                 280                 285             
          Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser 
              290                 295                 300                 
          Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu 
          305                 310                 315                 320 
          Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala 
                          325                 330                 335     
          Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro 
                      340                 345                 350         
          Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln 
                  355                 360                 365             
          Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala 
              370                 375                 380                 
          Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr 
          385                 390                 395                 400 
          Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu 
                          405                 410                 415     
          Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser 
                      420                 425                 430         
          Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser 
                  435                 440                 445             
          Leu Ser Pro Gly Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gln Val 
              450                 455                 460                 
          Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala Ser Val 
          465                 470                 475                 480 
          Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Asn Tyr Asp Ile 
                          485                 490                 495     
          Ile Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met Gly Tyr 
                      500                 505                 510         
          Ile Asn Pro Tyr Asn Asp Gly Thr Lys Tyr Asn Glu Lys Phe Lys Gly 
                  515                 520                 525             
          Arg Val Thr Met Thr Arg Asp Thr Ser Thr Ser Thr Val Tyr Met Glu 
              530                 535                 540                 
          Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys Ala Arg 
          545                 550                 555                 560 
          Leu Leu Lys Tyr Arg Arg Phe Arg Tyr Tyr Ala Ile Asp Tyr Trp Gly 
                          565                 570                 575     
          Gln Gly Thr Thr Val Thr Val Ser Ser Gly Gly Ser Glu Gly Lys Ser 
                      580                 585                 590         
          Ser Gly Ser Gly Ser Glu Ser Lys Ser Thr Gly Gly Ser Asp Ile Gln 
                  595                 600                 605             
          Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly Asp Arg Val 
              610                 615                 620                 
          Thr Ile Thr Cys Arg Thr Ser Glu Asn Val Tyr Ser Asn Leu Ala Trp 
          625                 630                 635                 640 
          Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile Tyr Ala Ala 
                          645                 650                 655     
          Ser Asn Leu Gln Ser Gly Val Pro Ser Arg Phe Ser Gly Ser Gly Ser 
                      660                 665                 670         
          Gly Thr Asp Tyr Thr Phe Thr Ile Ser Ser Leu Gln Pro Glu Asp Ile 
                  675                 680                 685             
          Ala Thr Tyr Tyr Cys Gln His Phe Trp Gly Ser Pro Phe Thr Phe Gly 
              690                 695                 700                 
          Gln Gly Thr Lys Leu Glu Ile Lys 
          705                 710         
          <![CDATA[<210> 35]]>
          <![CDATA[<211> 214]]>
          <![CDATA[<212> PRT]]>
          <![CDATA[<213> 智人]]>
          <![CDATA[<400> 35]]>
          Asp Ile Gln Leu Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly 
          1               5                   10                  15      
          Asp Arg Val Thr Ile Thr Cys Ser Ala Ser Gln Asp Ile Ser Asn Tyr 
                      20                  25                  30          
          Leu Asn Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Val Leu Ile 
                  35                  40                  45              
          Tyr Phe Thr Ser Ser Leu His 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 Tyr Ser Thr Val Pro Trp 
                          85                  90                  95      
          Thr Phe Gly Gln 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 Cys 
              210                 
          <![CDATA[<210> 36]]>
          <![CDATA[<211> 722]]>
          <![CDATA[<212> PRT]]>
          <![CDATA[<213> 智人]]>
          <![CDATA[<400> 36]]>
          Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 
          1               5                   10                  15      
          Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Tyr Asp Phe Thr His Tyr 
                      20                  25                  30          
          Gly Met Asn Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 
                  35                  40                  45              
          Gly Trp Ile Asn Thr Tyr Thr Gly Glu Pro Thr Tyr Ala Ala Asp Phe 
              50                  55                  60                  
          Lys Arg Arg Phe Thr Phe Ser Leu Asp Thr Ser Lys Ser Thr Ala Tyr 
          65                  70                  75                  80  
          Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 
                          85                  90                  95      
          Ala Lys Tyr Pro Tyr Tyr Tyr Gly Thr Ser His Trp Tyr Phe Asp Val 
                      100                 105                 110         
          Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly 
                  115                 120                 125             
          Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly 
              130                 135                 140                 
          Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val 
          145                 150                 155                 160 
          Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe 
                          165                 170                 175     
          Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val 
                      180                 185                 190         
          Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val 
                  195                 200                 205             
          Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys Arg Val Glu Pro Lys 
              210                 215                 220                 
          Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Ala 
          225                 230                 235                 240 
          Ala Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr 
                          245                 250                 255     
          Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val 
                      260                 265                 270         
          Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val 
                  275                 280                 285             
          Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser 
              290                 295                 300                 
          Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu 
          305                 310                 315                 320 
          Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala 
                          325                 330                 335     
          Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro 
                      340                 345                 350         
          Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln 
                  355                 360                 365             
          Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala 
              370                 375                 380                 
          Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr 
          385                 390                 395                 400 
          Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu 
                          405                 410                 415     
          Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser 
                      420                 425                 430         
          Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser 
                  435                 440                 445             
          Leu Ser Pro Gly Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly 
              450                 455                 460                 
          Gly Gly Ser Gly Gly Gly Gly Ser Gln Val Gln Leu Val Gln Ser Gly 
          465                 470                 475                 480 
          Ala Glu Val Lys Lys Pro Gly Ala Ser Val Lys Val Ser Cys Lys Ala 
                          485                 490                 495     
          Ser Gly Tyr Thr Phe Thr Asn Tyr Asp Ile Ile Trp Val Arg Gln Ala 
                      500                 505                 510         
          Pro Gly Gln Gly Leu Glu Trp Met Gly Tyr Ile Asn Pro Tyr Asn Asp 
                  515                 520                 525             
          Gly Thr Lys Tyr Asn Glu Lys Phe Lys Gly Arg Val Thr Met Thr Arg 
              530                 535                 540                 
          Asp Thr Ser Thr Ser Thr Val Tyr Met Glu Leu Ser Ser Leu Arg Ser 
          545                 550                 555                 560 
          Glu Asp Thr Ala Val Tyr Tyr Cys Ala Arg Leu Leu Lys Tyr Arg Arg 
                          565                 570                 575     
          Phe Arg Tyr Tyr Ala Ile Asp Tyr Trp Gly Gln Gly Thr Thr Val Thr 
                      580                 585                 590         
          Val Ser Ser Gly Gly Ser Glu Gly Lys Ser Ser Gly Ser Gly Ser Glu 
                  595                 600                 605             
          Ser Lys Ser Thr Gly Gly Ser Asp Ile Gln Met Thr Gln Ser Pro Ser 
              610                 615                 620                 
          Ser Leu Ser Ala Ser Val Gly Asp Arg Val Thr Ile Thr Cys Arg Thr 
          625                 630                 635                 640 
          Ser Glu Asn Val Tyr Ser Asn Leu Ala Trp Tyr Gln Gln Lys Pro Gly 
                          645                 650                 655     
          Lys Ala Pro Lys Leu Leu Ile Tyr Ala Ala Ser Asn Leu Gln Ser Gly 
                      660                 665                 670         
          Val Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Tyr Thr Phe 
                  675                 680                 685             
          Thr Ile Ser Ser Leu Gln Pro Glu Asp Ile Ala Thr Tyr Tyr Cys Gln 
              690                 695                 700                 
          His Phe Trp Gly Ser Pro Phe Thr Phe Gly Gln Gly Thr Lys Leu Glu 
          705                 710                 715                 720 
          Ile Lys 
          <![CDATA[<210> 37]]>
          <![CDATA[<211> 214]]>
          <![CDATA[<212> PRT]]>
          <![CDATA[<213> 智人]]>
          <![CDATA[<400> 37]]>
          Asp Ile Gln Leu Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly 
          1               5                   10                  15      
          Asp Arg Val Thr Ile Thr Cys Ser Ala Ser Gln Asp Ile Ser Asn Tyr 
                      20                  25                  30          
          Leu Asn Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Val Leu Ile 
                  35                  40                  45              
          Tyr Phe Thr Ser Ser Leu His 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 Tyr Ser Thr Val Pro Trp 
                          85                  90                  95      
          Thr Phe Gly Gln 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 Cys 
              210                 
          <![CDATA[<210> 38]]>
          <![CDATA[<211> 712]]>
          <![CDATA[<212> PRT]]>
          <![CDATA[<213> 智人]]>
          <![CDATA[<400> 38]]>
          Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 
          1               5                   10                  15      
          Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Tyr Asp Phe Thr His Tyr 
                      20                  25                  30          
          Gly Met Asn Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 
                  35                  40                  45              
          Gly Trp Ile Asn Thr Tyr Thr Gly Glu Pro Thr Tyr Ala Ala Asp Phe 
              50                  55                  60                  
          Lys Arg Arg Phe Thr Phe Ser Leu Asp Thr Ser Lys Ser Thr Ala Tyr 
          65                  70                  75                  80  
          Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 
                          85                  90                  95      
          Ala Lys Tyr Pro Tyr Tyr Tyr Gly Thr Ser His Trp Tyr Phe Asp Val 
                      100                 105                 110         
          Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly 
                  115                 120                 125             
          Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly 
              130                 135                 140                 
          Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val 
          145                 150                 155                 160 
          Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe 
                          165                 170                 175     
          Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val 
                      180                 185                 190         
          Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val 
                  195                 200                 205             
          Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys Arg Val Glu Pro Lys 
              210                 215                 220                 
          Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Ala 
          225                 230                 235                 240 
          Ala Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr 
                          245                 250                 255     
          Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val 
                      260                 265                 270         
          Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val 
                  275                 280                 285             
          Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser 
              290                 295                 300                 
          Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu 
          305                 310                 315                 320 
          Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala 
                          325                 330                 335     
          Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro 
                      340                 345                 350         
          Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln 
                  355                 360                 365             
          Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala 
              370                 375                 380                 
          Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr 
          385                 390                 395                 400 
          Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu 
                          405                 410                 415     
          Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser 
                      420                 425                 430         
          Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser 
                  435                 440                 445             
          Leu Ser Pro Gly Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Asp Ile 
              450                 455                 460                 
          Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly Asp Arg 
          465                 470                 475                 480 
          Val Thr Ile Thr Cys Arg Thr Ser Glu Asn Val Tyr Ser Asn Leu Ala 
                          485                 490                 495     
          Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile Tyr Ala 
                      500                 505                 510         
          Ala Ser Asn Leu Gln Ser Gly Val Pro Ser Arg Phe Ser Gly Ser Gly 
                  515                 520                 525             
          Ser Gly Thr Asp Tyr Thr Phe Thr Ile Ser Ser Leu Gln Pro Glu Asp 
              530                 535                 540                 
          Ile Ala Thr Tyr Tyr Cys Gln His Phe Trp Gly Ser Pro Phe Thr Phe 
          545                 550                 555                 560 
          Gly Gln Gly Thr Lys Leu Glu Ile Lys Gly Gly Ser Glu Gly Lys Ser 
                          565                 570                 575     
          Ser Gly Ser Gly Ser Glu Ser Lys Ser Thr Gly Gly Ser Gln Val Gln 
                      580                 585                 590         
          Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala Ser Val Lys 
                  595                 600                 605             
          Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Asn Tyr Asp Ile Ile 
              610                 615                 620                 
          Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met Gly Tyr Ile 
          625                 630                 635                 640 
          Asn Pro Tyr Asn Asp Gly Thr Lys Tyr Asn Glu Lys Phe Lys Gly Arg 
                          645                 650                 655     
          Val Thr Met Thr Arg Asp Thr Ser Thr Ser Thr Val Tyr Met Glu Leu 
                      660                 665                 670         
          Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys Ala Arg Leu 
                  675                 680                 685             
          Leu Lys Tyr Arg Arg Phe Arg Tyr Tyr Ala Ile Asp Tyr Trp Gly Gln 
              690                 695                 700                 
          Gly Thr Thr Val Thr Val Ser Ser 
          705                 710         
          <![CDATA[<210> 39]]>
          <![CDATA[<211> 214]]>
          <![CDATA[<212> PRT]]>
          <![CDATA[<213> 智人]]>
          <![CDATA[<400> 39]]>
          Asp Ile Gln Leu Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly 
          1               5                   10                  15      
          Asp Arg Val Thr Ile Thr Cys Ser Ala Ser Gln Asp Ile Ser Asn Tyr 
                      20                  25                  30          
          Leu Asn Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Val Leu Ile 
                  35                  40                  45              
          Tyr Phe Thr Ser Ser Leu His 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 Tyr Ser Thr Val Pro Trp 
                          85                  90                  95      
          Thr Phe Gly Gln 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 Cys 
              210                 
          <![CDATA[<210> 40]]>
          <![CDATA[<211> 722]]>
          <![CDATA[<212> PRT]]>
          <![CDATA[<213> 智人]]>
          <![CDATA[<400> 40]]>
          Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 
          1               5                   10                  15      
          Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Tyr Asp Phe Thr His Tyr 
                      20                  25                  30          
          Gly Met Asn Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 
                  35                  40                  45              
          Gly Trp Ile Asn Thr Tyr Thr Gly Glu Pro Thr Tyr Ala Ala Asp Phe 
              50                  55                  60                  
          Lys Arg Arg Phe Thr Phe Ser Leu Asp Thr Ser Lys Ser Thr Ala Tyr 
          65                  70                  75                  80  
          Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 
                          85                  90                  95      
          Ala Lys Tyr Pro Tyr Tyr Tyr Gly Thr Ser His Trp Tyr Phe Asp Val 
                      100                 105                 110         
          Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly 
                  115                 120                 125             
          Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly 
              130                 135                 140                 
          Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val 
          145                 150                 155                 160 
          Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe 
                          165                 170                 175     
          Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val 
                      180                 185                 190         
          Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val 
                  195                 200                 205             
          Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys Arg Val Glu Pro Lys 
              210                 215                 220                 
          Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Ala 
          225                 230                 235                 240 
          Ala Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr 
                          245                 250                 255     
          Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val 
                      260                 265                 270         
          Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val 
                  275                 280                 285             
          Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser 
              290                 295                 300                 
          Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu 
          305                 310                 315                 320 
          Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala 
                          325                 330                 335     
          Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro 
                      340                 345                 350         
          Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln 
                  355                 360                 365             
          Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala 
              370                 375                 380                 
          Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr 
          385                 390                 395                 400 
          Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu 
                          405                 410                 415     
          Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser 
                      420                 425                 430         
          Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser 
                  435                 440                 445             
          Leu Ser Pro Gly Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly 
              450                 455                 460                 
          Gly Gly Ser Gly Gly Gly Gly Ser Asp Ile Gln Met Thr Gln Ser Pro 
          465                 470                 475                 480 
          Ser Ser Leu Ser Ala Ser Val Gly Asp Arg Val Thr Ile Thr Cys Arg 
                          485                 490                 495     
          Thr Ser Glu Asn Val Tyr Ser Asn Leu Ala Trp Tyr Gln Gln Lys Pro 
                      500                 505                 510         
          Gly Lys Ala Pro Lys Leu Leu Ile Tyr Ala Ala Ser Asn Leu Gln Ser 
                  515                 520                 525             
          Gly Val Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Tyr Thr 
              530                 535                 540                 
          Phe Thr Ile Ser Ser Leu Gln Pro Glu Asp Ile Ala Thr Tyr Tyr Cys 
          545                 550                 555                 560 
          Gln His Phe Trp Gly Ser Pro Phe Thr Phe Gly Gln Gly Thr Lys Leu 
                          565                 570                 575     
          Glu Ile Lys Gly Gly Ser Glu Gly Lys Ser Ser Gly Ser Gly Ser Glu 
                      580                 585                 590         
          Ser Lys Ser Thr Gly Gly Ser Gln Val Gln Leu Val Gln Ser Gly Ala 
                  595                 600                 605             
          Glu Val Lys Lys Pro Gly Ala Ser Val Lys Val Ser Cys Lys Ala Ser 
              610                 615                 620                 
          Gly Tyr Thr Phe Thr Asn Tyr Asp Ile Ile Trp Val Arg Gln Ala Pro 
          625                 630                 635                 640 
          Gly Gln Gly Leu Glu Trp Met Gly Tyr Ile Asn Pro Tyr Asn Asp Gly 
                          645                 650                 655     
          Thr Lys Tyr Asn Glu Lys Phe Lys Gly Arg Val Thr Met Thr Arg Asp 
                      660                 665                 670         
          Thr Ser Thr Ser Thr Val Tyr Met Glu Leu Ser Ser Leu Arg Ser Glu 
                  675                 680                 685             
          Asp Thr Ala Val Tyr Tyr Cys Ala Arg Leu Leu Lys Tyr Arg Arg Phe 
              690                 695                 700                 
          Arg Tyr Tyr Ala Ile Asp Tyr Trp Gly Gln Gly Thr Thr Val Thr Val 
          705                 710                 715                 720 
          Ser Ser 
          <![CDATA[<210> 41]]>
          <![CDATA[<211> 214]]>
          <![CDATA[<212> PRT]]>
          <![CDATA[<213> 智人]]>
          <![CDATA[<400> 41]]>
          Asp Ile Gln Leu Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly 
          1               5                   10                  15      
          Asp Arg Val Thr Ile Thr Cys Ser Ala Ser Gln Asp Ile Ser Asn Tyr 
                      20                  25                  30          
          Leu Asn Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Val Leu Ile 
                  35                  40                  45              
          Tyr Phe Thr Ser Ser Leu His 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 Tyr Ser Thr Val Pro Trp 
                          85                  90                  95      
          Thr Phe Gly Gln 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 Cys 
              210                 
          <![CDATA[<210> 42]]>
          <![CDATA[<211> 712]]>
          <![CDATA[<212> PRT]]>
          <![CDATA[<213> 智人]]>
          <![CDATA[<400> 42]]>
          Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 
          1               5                   10                  15      
          Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Tyr Asp Phe Thr His Tyr 
                      20                  25                  30          
          Gly Met Asn Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 
                  35                  40                  45              
          Gly Trp Ile Asn Thr Tyr Thr Gly Glu Pro Thr Tyr Ala Ala Asp Phe 
              50                  55                  60                  
          Lys Arg Arg Phe Thr Phe Ser Leu Asp Thr Ser Lys Ser Thr Ala Tyr 
          65                  70                  75                  80  
          Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 
                          85                  90                  95      
          Ala Lys Tyr Pro Tyr Tyr Tyr Gly Thr Ser His Trp Tyr Phe Asp Val 
                      100                 105                 110         
          Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly 
                  115                 120                 125             
          Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly 
              130                 135                 140                 
          Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val 
          145                 150                 155                 160 
          Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe 
                          165                 170                 175     
          Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val 
                      180                 185                 190         
          Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val 
                  195                 200                 205             
          Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys Arg Val Glu Pro Lys 
              210                 215                 220                 
          Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Ala 
          225                 230                 235                 240 
          Ala Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr 
                          245                 250                 255     
          Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val 
                      260                 265                 270         
          Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val 
                  275                 280                 285             
          Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser 
              290                 295                 300                 
          Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu 
          305                 310                 315                 320 
          Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala 
                          325                 330                 335     
          Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro 
                      340                 345                 350         
          Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln 
                  355                 360                 365             
          Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala 
              370                 375                 380                 
          Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr 
          385                 390                 395                 400 
          Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu 
                          405                 410                 415     
          Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser 
                      420                 425                 430         
          Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser 
                  435                 440                 445             
          Leu Ser Pro Gly Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gln Val 
              450                 455                 460                 
          Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala Ser Val 
          465                 470                 475                 480 
          Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Asn Tyr Asp Ile 
                          485                 490                 495     
          Ile Trp Val Arg Gln Ala Pro Gly Gln Cys Leu Glu Trp Met Gly Tyr 
                      500                 505                 510         
          Ile Asn Pro Tyr Asn Asp Gly Thr Lys Tyr Asn Glu Lys Phe Lys Gly 
                  515                 520                 525             
          Arg Val Thr Met Thr Arg Asp Thr Ser Thr Ser Thr Val Tyr Met Glu 
              530                 535                 540                 
          Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys Ala Arg 
          545                 550                 555                 560 
          Leu Leu Lys Tyr Arg Arg Phe Arg Tyr Tyr Ala Ile Asp Tyr Trp Gly 
                          565                 570                 575     
          Gln Gly Thr Thr Val Thr Val Ser Ser Gly Gly Ser Glu Gly Lys Ser 
                      580                 585                 590         
          Ser Gly Ser Gly Ser Glu Ser Lys Ser Thr Gly Gly Ser Asp Ile Gln 
                  595                 600                 605             
          Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly Asp Arg Val 
              610                 615                 620                 
          Thr Ile Thr Cys Arg Thr Ser Glu Asn Val Tyr Ser Asn Leu Ala Trp 
          625                 630                 635                 640 
          Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile Tyr Ala Ala 
                          645                 650                 655     
          Ser Asn Leu Gln Ser Gly Val Pro Ser Arg Phe Ser Gly Ser Gly Ser 
                      660                 665                 670         
          Gly Thr Asp Tyr Thr Phe Thr Ile Ser Ser Leu Gln Pro Glu Asp Ile 
                  675                 680                 685             
          Ala Thr Tyr Tyr Cys Gln His Phe Trp Gly Ser Pro Phe Thr Phe Gly 
              690                 695                 700                 
          Cys Gly Thr Lys Leu Glu Ile Lys 
          705                 710         
          <![CDATA[<210> 43]]>
          <![CDATA[<211> 214]]>
          <![CDATA[<212> PRT]]>
          <![CDATA[<213> 智人]]>
          <![CDATA[<400> 43]]>
          Asp Ile Gln Leu Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly 
          1               5                   10                  15      
          Asp Arg Val Thr Ile Thr Cys Ser Ala Ser Gln Asp Ile Ser Asn Tyr 
                      20                  25                  30          
          Leu Asn Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Val Leu Ile 
                  35                  40                  45              
          Tyr Phe Thr Ser Ser Leu His 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 Tyr Ser Thr Val Pro Trp 
                          85                  90                  95      
          Thr Phe Gly Gln 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 Cys 
              210                 
          <![CDATA[<210> 44]]>
          <![CDATA[<211> 722]]>
          <![CDATA[<212> PRT]]>
          <![CDATA[<213> 智人]]>
          <![CDATA[<400> 44]]>
          Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 
          1               5                   10                  15      
          Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Tyr Asp Phe Thr His Tyr 
                      20                  25                  30          
          Gly Met Asn Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 
                  35                  40                  45              
          Gly Trp Ile Asn Thr Tyr Thr Gly Glu Pro Thr Tyr Ala Ala Asp Phe 
              50                  55                  60                  
          Lys Arg Arg Phe Thr Phe Ser Leu Asp Thr Ser Lys Ser Thr Ala Tyr 
          65                  70                  75                  80  
          Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 
                          85                  90                  95      
          Ala Lys Tyr Pro Tyr Tyr Tyr Gly Thr Ser His Trp Tyr Phe Asp Val 
                      100                 105                 110         
          Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly 
                  115                 120                 125             
          Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly 
              130                 135                 140                 
          Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val 
          145                 150                 155                 160 
          Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe 
                          165                 170                 175     
          Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val 
                      180                 185                 190         
          Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val 
                  195                 200                 205             
          Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys Arg Val Glu Pro Lys 
              210                 215                 220                 
          Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Ala 
          225                 230                 235                 240 
          Ala Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr 
                          245                 250                 255     
          Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val 
                      260                 265                 270         
          Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val 
                  275                 280                 285             
          Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser 
              290                 295                 300                 
          Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu 
          305                 310                 315                 320 
          Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala 
                          325                 330                 335     
          Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro 
                      340                 345                 350         
          Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln 
                  355                 360                 365             
          Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala 
              370                 375                 380                 
          Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr 
          385                 390                 395                 400 
          Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu 
                          405                 410                 415     
          Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser 
                      420                 425                 430         
          Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser 
                  435                 440                 445             
          Leu Ser Pro Gly Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly 
              450                 455                 460                 
          Gly Gly Ser Gly Gly Gly Gly Ser Gln Val Gln Leu Val Gln Ser Gly 
          465                 470                 475                 480 
          Ala Glu Val Lys Lys Pro Gly Ala Ser Val Lys Val Ser Cys Lys Ala 
                          485                 490                 495     
          Ser Gly Tyr Thr Phe Thr Asn Tyr Asp Ile Ile Trp Val Arg Gln Ala 
                      500                 505                 510         
          Pro Gly Gln Cys Leu Glu Trp Met Gly Tyr Ile Asn Pro Tyr Asn Asp 
                  515                 520                 525             
          Gly Thr Lys Tyr Asn Glu Lys Phe Lys Gly Arg Val Thr Met Thr Arg 
              530                 535                 540                 
          Asp Thr Ser Thr Ser Thr Val Tyr Met Glu Leu Ser Ser Leu Arg Ser 
          545                 550                 555                 560 
          Glu Asp Thr Ala Val Tyr Tyr Cys Ala Arg Leu Leu Lys Tyr Arg Arg 
                          565                 570                 575     
          Phe Arg Tyr Tyr Ala Ile Asp Tyr Trp Gly Gln Gly Thr Thr Val Thr 
                      580                 585                 590         
          Val Ser Ser Gly Gly Ser Glu Gly Lys Ser Ser Gly Ser Gly Ser Glu 
                  595                 600                 605             
          Ser Lys Ser Thr Gly Gly Ser Asp Ile Gln Met Thr Gln Ser Pro Ser 
              610                 615                 620                 
          Ser Leu Ser Ala Ser Val Gly Asp Arg Val Thr Ile Thr Cys Arg Thr 
          625                 630                 635                 640 
          Ser Glu Asn Val Tyr Ser Asn Leu Ala Trp Tyr Gln Gln Lys Pro Gly 
                          645                 650                 655     
          Lys Ala Pro Lys Leu Leu Ile Tyr Ala Ala Ser Asn Leu Gln Ser Gly 
                      660                 665                 670         
          Val Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Tyr Thr Phe 
                  675                 680                 685             
          Thr Ile Ser Ser Leu Gln Pro Glu Asp Ile Ala Thr Tyr Tyr Cys Gln 
              690                 695                 700                 
          His Phe Trp Gly Ser Pro Phe Thr Phe Gly Cys Gly Thr Lys Leu Glu 
          705                 710                 715                 720 
          Ile Lys 
          <![CDATA[<210> 45]]>
          <![CDATA[<211> 214]]>
          <![CDATA[<212> PRT]]>
          <![CDATA[<213> 智人]]>
          <![CDATA[<400> 45]]>
          Asp Ile Gln Leu Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly 
          1               5                   10                  15      
          Asp Arg Val Thr Ile Thr Cys Ser Ala Ser Gln Asp Ile Ser Asn Tyr 
                      20                  25                  30          
          Leu Asn Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Val Leu Ile 
                  35                  40                  45              
          Tyr Phe Thr Ser Ser Leu His 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 Tyr Ser Thr Val Pro Trp 
                          85                  90                  95      
          Thr Phe Gly Gln 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 Cys 
              210                 
          <![CDATA[<210> 46]]>
          <![CDATA[<211> 712]]>
          <![CDATA[<212> PRT]]>
          <![CDATA[<213> 智人]]>
          <![CDATA[<400> 46]]>
          Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 
          1               5                   10                  15      
          Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Tyr Asp Phe Thr His Tyr 
                      20                  25                  30          
          Gly Met Asn Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 
                  35                  40                  45              
          Gly Trp Ile Asn Thr Tyr Thr Gly Glu Pro Thr Tyr Ala Ala Asp Phe 
              50                  55                  60                  
          Lys Arg Arg Phe Thr Phe Ser Leu Asp Thr Ser Lys Ser Thr Ala Tyr 
          65                  70                  75                  80  
          Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 
                          85                  90                  95      
          Ala Lys Tyr Pro Tyr Tyr Tyr Gly Thr Ser His Trp Tyr Phe Asp Val 
                      100                 105                 110         
          Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly 
                  115                 120                 125             
          Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly 
              130                 135                 140                 
          Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val 
          145                 150                 155                 160 
          Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe 
                          165                 170                 175     
          Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val 
                      180                 185                 190         
          Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val 
                  195                 200                 205             
          Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys Arg Val Glu Pro Lys 
              210                 215                 220                 
          Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Ala 
          225                 230                 235                 240 
          Ala Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr 
                          245                 250                 255     
          Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val 
                      260                 265                 270         
          Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val 
                  275                 280                 285             
          Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser 
              290                 295                 300                 
          Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu 
          305                 310                 315                 320 
          Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala 
                          325                 330                 335     
          Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro 
                      340                 345                 350         
          Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln 
                  355                 360                 365             
          Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala 
              370                 375                 380                 
          Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr 
          385                 390                 395                 400 
          Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu 
                          405                 410                 415     
          Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser 
                      420                 425                 430         
          Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser 
                  435                 440                 445             
          Leu Ser Pro Gly Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Asp Ile 
              450                 455                 460                 
          Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly Asp Arg 
          465                 470                 475                 480 
          Val Thr Ile Thr Cys Arg Thr Ser Glu Asn Val Tyr Ser Asn Leu Ala 
                          485                 490                 495     
          Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile Tyr Ala 
                      500                 505                 510         
          Ala Ser Asn Leu Gln Ser Gly Val Pro Ser Arg Phe Ser Gly Ser Gly 
                  515                 520                 525             
          Ser Gly Thr Asp Tyr Thr Phe Thr Ile Ser Ser Leu Gln Pro Glu Asp 
              530                 535                 540                 
          Ile Ala Thr Tyr Tyr Cys Gln His Phe Trp Gly Ser Pro Phe Thr Phe 
          545                 550                 555                 560 
          Gly Cys Gly Thr Lys Leu Glu Ile Lys Gly Gly Ser Glu Gly Lys Ser 
                          565                 570                 575     
          Ser Gly Ser Gly Ser Glu Ser Lys Ser Thr Gly Gly Ser Gln Val Gln 
                      580                 585                 590         
          Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala Ser Val Lys 
                  595                 600                 605             
          Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Asn Tyr Asp Ile Ile 
              610                 615                 620                 
          Trp Val Arg Gln Ala Pro Gly Gln Cys Leu Glu Trp Met Gly Tyr Ile 
          625                 630                 635                 640 
          Asn Pro Tyr Asn Asp Gly Thr Lys Tyr Asn Glu Lys Phe Lys Gly Arg 
                          645                 650                 655     
          Val Thr Met Thr Arg Asp Thr Ser Thr Ser Thr Val Tyr Met Glu Leu 
                      660                 665                 670         
          Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys Ala Arg Leu 
                  675                 680                 685             
          Leu Lys Tyr Arg Arg Phe Arg Tyr Tyr Ala Ile Asp Tyr Trp Gly Gln 
              690                 695                 700                 
          Gly Thr Thr Val Thr Val Ser Ser 
          705                 710         
          <![CDATA[<210> 47]]>
          <![CDATA[<211> 214]]>
          <![CDATA[<212> PRT]]>
          <![CDATA[<213> 智人]]>
          <![CDATA[<400> 47]]>
          Asp Ile Gln Leu Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly 
          1               5                   10                  15      
          Asp Arg Val Thr Ile Thr Cys Ser Ala Ser Gln Asp Ile Ser Asn Tyr 
                      20                  25                  30          
          Leu Asn Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Val Leu Ile 
                  35                  40                  45              
          Tyr Phe Thr Ser Ser Leu His 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 Tyr Ser Thr Val Pro Trp 
                          85                  90                  95      
          Thr Phe Gly Gln 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 Cys 
              210                 
          <![CDATA[<210> 48]]>
          <![CDATA[<211> 722]]>
          <![CDATA[<212> PRT]]>
          <![CDATA[<213> 智人]]>
          <![CDATA[<400> 48]]>
          Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 
          1               5                   10                  15      
          Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Tyr Asp Phe Thr His Tyr 
                      20                  25                  30          
          Gly Met Asn Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 
                  35                  40                  45              
          Gly Trp Ile Asn Thr Tyr Thr Gly Glu Pro Thr Tyr Ala Ala Asp Phe 
              50                  55                  60                  
          Lys Arg Arg Phe Thr Phe Ser Leu Asp Thr Ser Lys Ser Thr Ala Tyr 
          65                  70                  75                  80  
          Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 
                          85                  90                  95      
          Ala Lys Tyr Pro Tyr Tyr Tyr Gly Thr Ser His Trp Tyr Phe Asp Val 
                      100                 105                 110         
          Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly 
                  115                 120                 125             
          Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly 
              130                 135                 140                 
          Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val 
          145                 150                 155                 160 
          Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe 
                          165                 170                 175     
          Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val 
                      180                 185                 190         
          Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val 
                  195                 200                 205             
          Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys Arg Val Glu Pro Lys 
              210                 215                 220                 
          Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Ala 
          225                 230                 235                 240 
          Ala Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr 
                          245                 250                 255     
          Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val 
                      260                 265                 270         
          Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val 
                  275                 280                 285             
          Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser 
              290                 295                 300                 
          Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu 
          305                 310                 315                 320 
          Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala 
                          325                 330                 335     
          Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro 
                      340                 345                 350         
          Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln 
                  355                 360                 365             
          Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala 
              370                 375                 380                 
          Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr 
          385                 390                 395                 400 
          Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu 
                          405                 410                 415     
          Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser 
                      420                 425                 430         
          Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser 
                  435                 440                 445             
          Leu Ser Pro Gly Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly 
              450                 455                 460                 
          Gly Gly Ser Gly Gly Gly Gly Ser Asp Ile Gln Met Thr Gln Ser Pro 
          465                 470                 475                 480 
          Ser Ser Leu Ser Ala Ser Val Gly Asp Arg Val Thr Ile Thr Cys Arg 
                          485                 490                 495     
          Thr Ser Glu Asn Val Tyr Ser Asn Leu Ala Trp Tyr Gln Gln Lys Pro 
                      500                 505                 510         
          Gly Lys Ala Pro Lys Leu Leu Ile Tyr Ala Ala Ser Asn Leu Gln Ser 
                  515                 520                 525             
          Gly Val Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Tyr Thr 
              530                 535                 540                 
          Phe Thr Ile Ser Ser Leu Gln Pro Glu Asp Ile Ala Thr Tyr Tyr Cys 
          545                 550                 555                 560 
          Gln His Phe Trp Gly Ser Pro Phe Thr Phe Gly Cys Gly Thr Lys Leu 
                          565                 570                 575     
          Glu Ile Lys Gly Gly Ser Glu Gly Lys Ser Ser Gly Ser Gly Ser Glu 
                      580                 585                 590         
          Ser Lys Ser Thr Gly Gly Ser Gln Val Gln Leu Val Gln Ser Gly Ala 
                  595                 600                 605             
          Glu Val Lys Lys Pro Gly Ala Ser Val Lys Val Ser Cys Lys Ala Ser 
              610                 615                 620                 
          Gly Tyr Thr Phe Thr Asn Tyr Asp Ile Ile Trp Val Arg Gln Ala Pro 
          625                 630                 635                 640 
          Gly Gln Cys Leu Glu Trp Met Gly Tyr Ile Asn Pro Tyr Asn Asp Gly 
                          645                 650                 655     
          Thr Lys Tyr Asn Glu Lys Phe Lys Gly Arg Val Thr Met Thr Arg Asp 
                      660                 665                 670         
          Thr Ser Thr Ser Thr Val Tyr Met Glu Leu Ser Ser Leu Arg Ser Glu 
                  675                 680                 685             
          Asp Thr Ala Val Tyr Tyr Cys Ala Arg Leu Leu Lys Tyr Arg Arg Phe 
              690                 695                 700                 
          Arg Tyr Tyr Ala Ile Asp Tyr Trp Gly Gln Gly Thr Thr Val Thr Val 
          705                 710                 715                 720 
          Ser Ser 
          <![CDATA[<210> 49]]>
          <![CDATA[<211> 214]]>
          <![CDATA[<212> PRT]]>
          <![CDATA[<213> 智人]]>
          <![CDATA[<400> 49]]>
          Asp Ile Gln Leu Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly 
          1               5                   10                  15      
          Asp Arg Val Thr Ile Thr Cys Ser Ala Ser Gln Asp Ile Ser Asn Tyr 
                      20                  25                  30          
          Leu Asn Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Val Leu Ile 
                  35                  40                  45              
          Tyr Phe Thr Ser Ser Leu His 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 Tyr Ser Thr Val Pro Trp 
                          85                  90                  95      
          Thr Phe Gly Gln 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 Cys 
              210                 
          <![CDATA[<210> 50]]>
          <![CDATA[<211> 712]]>
          <![CDATA[<212> PRT]]>
          <![CDATA[<213> 智人]]>
          <![CDATA[<400> 50]]>
          Gln Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 
          1               5                   10                  15      
          Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Tyr Asp Phe Thr His Tyr 
                      20                  25                  30          
          Gly Met Asn Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 
                  35                  40                  45              
          Gly Trp Ile Asn Thr Tyr Thr Gly Glu Pro Thr Tyr Ala Ala Asp Phe 
              50                  55                  60                  
          Lys Arg Arg Phe Thr Phe Ser Leu Asp Thr Ser Lys Ser Thr Ala Tyr 
          65                  70                  75                  80  
          Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 
                          85                  90                  95      
          Ala Lys Tyr Pro Tyr Tyr Tyr Gly Thr Ser His Trp Tyr Phe Asp Val 
                      100                 105                 110         
          Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly 
                  115                 120                 125             
          Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly 
              130                 135                 140                 
          Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val 
          145                 150                 155                 160 
          Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe 
                          165                 170                 175     
          Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val 
                      180                 185                 190         
          Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val 
                  195                 200                 205             
          Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys Arg Val Glu Pro Lys 
              210                 215                 220                 
          Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Ala 
          225                 230                 235                 240 
          Ala Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr 
                          245                 250                 255     
          Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val 
                      260                 265                 270         
          Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val 
                  275                 280                 285             
          Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser 
              290                 295                 300                 
          Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu 
          305                 310                 315                 320 
          Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala 
                          325                 330                 335     
          Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro 
                      340                 345                 350         
          Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln 
                  355                 360                 365             
          Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala 
              370                 375                 380                 
          Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr 
          385                 390                 395                 400 
          Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu 
                          405                 410                 415     
          Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser 
                      420                 425                 430         
          Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser 
                  435                 440                 445             
          Leu Ser Pro Gly Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gln Val 
              450                 455                 460                 
          Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala Ser Val 
          465                 470                 475                 480 
          Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Asn Tyr Asp Ile 
                          485                 490                 495     
          Ile Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met Gly Tyr 
                      500                 505                 510         
          Ile Asn Pro Tyr Asn Asp Gly Thr Lys Tyr Asn Glu Lys Phe Lys Gly 
                  515                 520                 525             
          Arg Val Thr Met Thr Arg Asp Thr Ser Thr Ser Thr Val Tyr Met Glu 
              530                 535                 540                 
          Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys Ala Arg 
          545                 550                 555                 560 
          Leu Leu Lys Tyr Arg Arg Phe Arg Tyr Tyr Ala Ile Asp Tyr Trp Gly 
                          565                 570                 575     
          Gln Gly Thr Thr Val Thr Val Ser Ser Gly Gly Ser Glu Gly Lys Ser 
                      580                 585                 590         
          Ser Gly Ser Gly Ser Glu Ser Lys Ser Thr Gly Gly Ser Asp Ile Gln 
                  595                 600                 605             
          Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly Asp Arg Val 
              610                 615                 620                 
          Thr Ile Thr Cys Arg Thr Ser Glu Asn Val Tyr Ser Asn Leu Ala Trp 
          625                 630                 635                 640 
          Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile Tyr Ala Ala 
                          645                 650                 655     
          Ser Asn Leu Gln Ser Gly Val Pro Ser Arg Phe Ser Gly Ser Gly Ser 
                      660                 665                 670         
          Gly Thr Asp Tyr Thr Phe Thr Ile Ser Ser Leu Gln Pro Glu Asp Ile 
                  675                 680                 685             
          Ala Thr Tyr Tyr Cys Gln His Phe Trp Gly Ser Pro Phe Thr Phe Gly 
              690                 695                 700                 
          Gln Gly Thr Lys Leu Glu Ile Lys 
          705                 710         
          <![CDATA[<210> 51]]>
          <![CDATA[<211> 214]]>
          <![CDATA[<212> PRT]]>
          <![CDATA[<213> 智人]]>
          <![CDATA[<400> 51]]>
          Asp Ile Gln Leu Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly 
          1               5                   10                  15      
          Asp Arg Val Thr Ile Thr Cys Ser Ala Ser Gln Asp Ile Ser Asn Tyr 
                      20                  25                  30          
          Leu Asn Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Val Leu Ile 
                  35                  40                  45              
          Tyr Phe Thr Ser Ser Leu His 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 Tyr Ser Thr Val Pro Trp 
                          85                  90                  95      
          Thr Phe Gly Gln 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 Cys 
              210                 
          <![CDATA[<210> 52]]>
          <![CDATA[<211> 712]]>
          <![CDATA[<212> PRT]]>
          <![CDATA[<213> 智人]]>
          <![CDATA[<400> 52]]>
          Glu Val Gln Leu Val Gln Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 
          1               5                   10                  15      
          Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Tyr Asp Phe Thr His Tyr 
                      20                  25                  30          
          Gly Met Asn Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 
                  35                  40                  45              
          Gly Trp Ile Asn Thr Tyr Thr Gly Glu Pro Thr Tyr Ala Ala Asp Phe 
              50                  55                  60                  
          Lys Arg Arg Phe Thr Phe Ser Leu Asp Thr Ser Lys Ser Thr Ala Tyr 
          65                  70                  75                  80  
          Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 
                          85                  90                  95      
          Ala Lys Tyr Pro Tyr Tyr Tyr Gly Thr Ser His Trp Tyr Phe Asp Val 
                      100                 105                 110         
          Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly 
                  115                 120                 125             
          Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly 
              130                 135                 140                 
          Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val 
          145                 150                 155                 160 
          Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe 
                          165                 170                 175     
          Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val 
                      180                 185                 190         
          Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val 
                  195                 200                 205             
          Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys Arg Val Glu Pro Lys 
              210                 215                 220                 
          Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Ala 
          225                 230                 235                 240 
          Ala Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr 
                          245                 250                 255     
          Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val 
                      260                 265                 270         
          Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val 
                  275                 280                 285             
          Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser 
              290                 295                 300                 
          Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu 
          305                 310                 315                 320 
          Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala 
                          325                 330                 335     
          Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro 
                      340                 345                 350         
          Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln 
                  355                 360                 365             
          Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala 
              370                 375                 380                 
          Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr 
          385                 390                 395                 400 
          Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu 
                          405                 410                 415     
          Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser 
                      420                 425                 430         
          Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser 
                  435                 440                 445             
          Leu Ser Pro Gly Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gln Val 
              450                 455                 460                 
          Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala Ser Val 
          465                 470                 475                 480 
          Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Asn Tyr Asp Ile 
                          485                 490                 495     
          Ile Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met Gly Tyr 
                      500                 505                 510         
          Ile Asn Pro Tyr Asn Asp Gly Thr Lys Tyr Asn Glu Lys Phe Lys Gly 
                  515                 520                 525             
          Arg Val Thr Met Thr Arg Asp Thr Ser Thr Ser Thr Val Tyr Met Glu 
              530                 535                 540                 
          Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys Ala Arg 
          545                 550                 555                 560 
          Leu Leu Lys Tyr Arg Arg Phe Arg Tyr Tyr Ala Ile Asp Tyr Trp Gly 
                          565                 570                 575     
          Gln Gly Thr Thr Val Thr Val Ser Ser Gly Gly Ser Glu Gly Lys Ser 
                      580                 585                 590         
          Ser Gly Ser Gly Ser Glu Ser Lys Ser Thr Gly Gly Ser Asp Ile Gln 
                  595                 600                 605             
          Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly Asp Arg Val 
              610                 615                 620                 
          Thr Ile Thr Cys Arg Thr Ser Glu Asn Val Tyr Ser Asn Leu Ala Trp 
          625                 630                 635                 640 
          Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile Tyr Ala Ala 
                          645                 650                 655     
          Ser Asn Leu Gln Ser Gly Val Pro Ser Arg Phe Ser Gly Ser Gly Ser 
                      660                 665                 670         
          Gly Thr Asp Tyr Thr Phe Thr Ile Ser Ser Leu Gln Pro Glu Asp Ile 
                  675                 680                 685             
          Ala Thr Tyr Tyr Cys Gln His Phe Trp Gly Ser Pro Phe Thr Phe Gly 
              690                 695                 700                 
          Gln Gly Thr Lys Leu Glu Ile Lys 
          705                 710         
          <![CDATA[<210> 53]]>
          <![CDATA[<211> 214]]>
          <![CDATA[<212> PRT]]>
          <![CDATA[<213> 智人]]>
          <![CDATA[<400> 53]]>
          Asp Ile Gln Leu Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly 
          1               5                   10                  15      
          Asp Arg Val Thr Ile Thr Cys Ser Ala Ser Gln Asp Ile Ser Asn Tyr 
                      20                  25                  30          
          Leu Asn Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Val Leu Ile 
                  35                  40                  45              
          Tyr Phe Thr Ser Ser Leu His Ser Gly Val Pro Ser Arg Phe Ser Gly 
              50                  55                  60                  
          Ser Gly Ser Gly Thr Gly Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro 
          65                  70                  75                  80  
          Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Tyr Ser Thr Val Pro Trp 
                          85                  90                  95      
          Thr Phe Gly Gln 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 Cys 
              210                 
          <![CDATA[<210> 54]]>
          <![CDATA[<211> 712]]>
          <![CDATA[<212> PRT]]>
          <![CDATA[<213> 智人]]>
          <![CDATA[<400> 54]]>
          Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 
          1               5                   10                  15      
          Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Tyr Asp Phe Thr His Tyr 
                      20                  25                  30          
          Gly Met Asn Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 
                  35                  40                  45              
          Gly Trp Ile Asn Thr Tyr Thr Gly Glu Pro Thr Tyr Ala Ala Asp Phe 
              50                  55                  60                  
          Lys Arg Arg Phe Thr Phe Ser Leu Asp Thr Ser Lys Ser Thr Ala Tyr 
          65                  70                  75                  80  
          Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 
                          85                  90                  95      
          Ala Lys Tyr Pro Tyr Tyr Tyr Gly Thr Ser His Trp Tyr Phe Asp Val 
                      100                 105                 110         
          Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly 
                  115                 120                 125             
          Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly 
              130                 135                 140                 
          Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val 
          145                 150                 155                 160 
          Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe 
                          165                 170                 175     
          Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val 
                      180                 185                 190         
          Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val 
                  195                 200                 205             
          Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys Arg Val Glu Pro Lys 
              210                 215                 220                 
          Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Ala 
          225                 230                 235                 240 
          Ala Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr 
                          245                 250                 255     
          Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val 
                      260                 265                 270         
          Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val 
                  275                 280                 285             
          Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser 
              290                 295                 300                 
          Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu 
          305                 310                 315                 320 
          Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala 
                          325                 330                 335     
          Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro 
                      340                 345                 350         
          Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln 
                  355                 360                 365             
          Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala 
              370                 375                 380                 
          Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr 
          385                 390                 395                 400 
          Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu 
                          405                 410                 415     
          Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser 
                      420                 425                 430         
          Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser 
                  435                 440                 445             
          Leu Ser Pro Gly Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gln Val 
              450                 455                 460                 
          Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala Ser Val 
          465                 470                 475                 480 
          Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Asn Tyr Asp Ile 
                          485                 490                 495     
          Ile Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met Gly Tyr 
                      500                 505                 510         
          Ile Asn Pro Tyr Asn Asp Gly Thr Lys Tyr Asn Glu Lys Phe Lys Gly 
                  515                 520                 525             
          Arg Val Thr Met Thr Arg Asp Thr Ser Thr Ser Thr Val Tyr Met Glu 
              530                 535                 540                 
          Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys Ala Arg 
          545                 550                 555                 560 
          Leu Leu Lys Tyr Arg Arg Phe Arg Tyr Tyr Ala Ile Asp Tyr Trp Gly 
                          565                 570                 575     
          Gln Gly Thr Thr Val Thr Val Ser Ser Gly Gly Ser Glu Gly Lys Ser 
                      580                 585                 590         
          Ser Gly Ser Gly Ser Glu Ser Lys Ser Thr Gly Gly Ser Asp Ile Gln 
                  595                 600                 605             
          Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly Asp Arg Val 
              610                 615                 620                 
          Thr Ile Thr Cys Arg Thr Ser Glu Asn Val Tyr Ser Asn Leu Ala Trp 
          625                 630                 635                 640 
          Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile Tyr Ala Ala 
                          645                 650                 655     
          Ser Asn Leu Gln Ser Gly Val Pro Ser Arg Phe Ser Gly Ser Gly Ser 
                      660                 665                 670         
          Gly Thr Asp Tyr Thr Phe Thr Ile Ser Ser Leu Gln Pro Glu Asp Ile 
                  675                 680                 685             
          Ala Thr Tyr Tyr Cys Gln His Phe Trp Gly Ser Pro Phe Thr Phe Gly 
              690                 695                 700                 
          Gln Gly Thr Lys Leu Glu Ile Lys 
          705                 710         
          <![CDATA[<210> 55]]>
          <![CDATA[<211> 214]]>
          <![CDATA[<212> PRT]]>
          <![CDATA[<213> 智人]]>
          <![CDATA[<400> 55]]>
          Asp Ile Gln Leu Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly 
          1               5                   10                  15      
          Asp Arg Val Thr Ile Thr Cys Ser Ala Ser Gln Asp Ile Ser Asn Tyr 
                      20                  25                  30          
          Leu Asn Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Val Leu Ile 
                  35                  40                  45              
          Tyr Phe Thr Ser Ser Leu His Ser Gly Val Pro Ser Arg Phe Ser Gly 
              50                  55                  60                  
          Ser Gly Ser Gly Thr Gly Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro 
          65                  70                  75                  80  
          Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Tyr Ser Thr Val Pro Trp 
                          85                  90                  95      
          Thr Phe Gly Gln 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 Cys 
              210                 
          <![CDATA[<210> 56]]>
          <![CDATA[<211> 712]]>
          <![CDATA[<212> PRT]]>
          <![CDATA[<213> 智人]]>
          <![CDATA[<400> 56]]>
          Gln Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 
          1               5                   10                  15      
          Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Tyr Asp Phe Thr His Tyr 
                      20                  25                  30          
          Gly Met Asn Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 
                  35                  40                  45              
          Gly Trp Ile Asn Thr Tyr Thr Gly Glu Pro Thr Tyr Ala Ala Asp Phe 
              50                  55                  60                  
          Lys Arg Arg Phe Thr Phe Ser Leu Asp Thr Ser Lys Ser Thr Ala Tyr 
          65                  70                  75                  80  
          Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 
                          85                  90                  95      
          Ala Lys Tyr Pro Tyr Tyr Tyr Gly Thr Ser His Trp Tyr Phe Asp Val 
                      100                 105                 110         
          Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly 
                  115                 120                 125             
          Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly 
              130                 135                 140                 
          Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val 
          145                 150                 155                 160 
          Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe 
                          165                 170                 175     
          Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val 
                      180                 185                 190         
          Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val 
                  195                 200                 205             
          Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys Arg Val Glu Pro Lys 
              210                 215                 220                 
          Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Ala 
          225                 230                 235                 240 
          Ala Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr 
                          245                 250                 255     
          Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val 
                      260                 265                 270         
          Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val 
                  275                 280                 285             
          Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser 
              290                 295                 300                 
          Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu 
          305                 310                 315                 320 
          Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala 
                          325                 330                 335     
          Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro 
                      340                 345                 350         
          Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln 
                  355                 360                 365             
          Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala 
              370                 375                 380                 
          Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr 
          385                 390                 395                 400 
          Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu 
                          405                 410                 415     
          Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser 
                      420                 425                 430         
          Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser 
                  435                 440                 445             
          Leu Ser Pro Gly Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gln Val 
              450                 455                 460                 
          Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala Ser Val 
          465                 470                 475                 480 
          Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Asn Tyr Asp Ile 
                          485                 490                 495     
          Ile Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met Gly Tyr 
                      500                 505                 510         
          Ile Asn Pro Tyr Asn Asp Gly Thr Lys Tyr Asn Glu Lys Phe Lys Gly 
                  515                 520                 525             
          Arg Val Thr Met Thr Arg Asp Thr Ser Thr Ser Thr Val Tyr Met Glu 
              530                 535                 540                 
          Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys Ala Arg 
          545                 550                 555                 560 
          Leu Leu Lys Tyr Arg Arg Phe Arg Tyr Tyr Ala Ile Asp Tyr Trp Gly 
                          565                 570                 575     
          Gln Gly Thr Thr Val Thr Val Ser Ser Gly Gly Ser Glu Gly Lys Ser 
                      580                 585                 590         
          Ser Gly Ser Gly Ser Glu Ser Lys Ser Thr Gly Gly Ser Asp Ile Gln 
                  595                 600                 605             
          Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly Asp Arg Val 
              610                 615                 620                 
          Thr Ile Thr Cys Arg Thr Ser Glu Asn Val Tyr Ser Asn Leu Ala Trp 
          625                 630                 635                 640 
          Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile Tyr Ala Ala 
                          645                 650                 655     
          Ser Asn Leu Gln Ser Gly Val Pro Ser Arg Phe Ser Gly Ser Gly Ser 
                      660                 665                 670         
          Gly Thr Asp Tyr Thr Phe Thr Ile Ser Ser Leu Gln Pro Glu Asp Ile 
                  675                 680                 685             
          Ala Thr Tyr Tyr Cys Gln His Phe Trp Gly Ser Pro Phe Thr Phe Gly 
              690                 695                 700                 
          Gln Gly Thr Lys Leu Glu Ile Lys 
          705                 710         
          <![CDATA[<210> 57]]>
          <![CDATA[<211> 214]]>
          <![CDATA[<212> PRT]]>
          <![CDATA[<213> 智人]]>
          <![CDATA[<400> 57]]>
          Asp Ile Gln Leu Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly 
          1               5                   10                  15      
          Asp Arg Val Thr Ile Thr Cys Ser Ala Ser Gln Asp Ile Ser Asn Tyr 
                      20                  25                  30          
          Leu Asn Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Val Leu Ile 
                  35                  40                  45              
          Tyr Phe Thr Ser Ser Leu His Ser Gly Val Pro Ser Arg Phe Ser Gly 
              50                  55                  60                  
          Ser Gly Ser Gly Thr Gly Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro 
          65                  70                  75                  80  
          Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Tyr Ser Thr Val Pro Trp 
                          85                  90                  95      
          Thr Phe Gly Gln 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 Cys 
              210                 
          <![CDATA[<210> 58]]>
          <![CDATA[<211> 712]]>
          <![CDATA[<212> PRT]]>
          <![CDATA[<213> 智人]]>
          <![CDATA[<400> 58]]>
          Glu Val Gln Leu Val Gln Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 
          1               5                   10                  15      
          Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Tyr Asp Phe Thr His Tyr 
                      20                  25                  30          
          Gly Met Asn Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 
                  35                  40                  45              
          Gly Trp Ile Asn Thr Tyr Thr Gly Glu Pro Thr Tyr Ala Ala Asp Phe 
              50                  55                  60                  
          Lys Arg Arg Phe Thr Phe Ser Leu Asp Thr Ser Lys Ser Thr Ala Tyr 
          65                  70                  75                  80  
          Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 
                          85                  90                  95      
          Ala Lys Tyr Pro Tyr Tyr Tyr Gly Thr Ser His Trp Tyr Phe Asp Val 
                      100                 105                 110         
          Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly 
                  115                 120                 125             
          Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly 
              130                 135                 140                 
          Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val 
          145                 150                 155                 160 
          Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe 
                          165                 170                 175     
          Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val 
                      180                 185                 190         
          Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val 
                  195                 200                 205             
          Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys Arg Val Glu Pro Lys 
              210                 215                 220                 
          Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Ala 
          225                 230                 235                 240 
          Ala Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr 
                          245                 250                 255     
          Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val 
                      260                 265                 270         
          Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val 
                  275                 280                 285             
          Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser 
              290                 295                 300                 
          Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu 
          305                 310                 315                 320 
          Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala 
                          325                 330                 335     
          Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro 
                      340                 345                 350         
          Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln 
                  355                 360                 365             
          Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala 
              370                 375                 380                 
          Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr 
          385                 390                 395                 400 
          Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu 
                          405                 410                 415     
          Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser 
                      420                 425                 430         
          Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser 
                  435                 440                 445             
          Leu Ser Pro Gly Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gln Val 
              450                 455                 460                 
          Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala Ser Val 
          465                 470                 475                 480 
          Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Asn Tyr Asp Ile 
                          485                 490                 495     
          Ile Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met Gly Tyr 
                      500                 505                 510         
          Ile Asn Pro Tyr Asn Asp Gly Thr Lys Tyr Asn Glu Lys Phe Lys Gly 
                  515                 520                 525             
          Arg Val Thr Met Thr Arg Asp Thr Ser Thr Ser Thr Val Tyr Met Glu 
              530                 535                 540                 
          Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys Ala Arg 
          545                 550                 555                 560 
          Leu Leu Lys Tyr Arg Arg Phe Arg Tyr Tyr Ala Ile Asp Tyr Trp Gly 
                          565                 570                 575     
          Gln Gly Thr Thr Val Thr Val Ser Ser Gly Gly Ser Glu Gly Lys Ser 
                      580                 585                 590         
          Ser Gly Ser Gly Ser Glu Ser Lys Ser Thr Gly Gly Ser Asp Ile Gln 
                  595                 600                 605             
          Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly Asp Arg Val 
              610                 615                 620                 
          Thr Ile Thr Cys Arg Thr Ser Glu Asn Val Tyr Ser Asn Leu Ala Trp 
          625                 630                 635                 640 
          Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile Tyr Ala Ala 
                          645                 650                 655     
          Ser Asn Leu Gln Ser Gly Val Pro Ser Arg Phe Ser Gly Ser Gly Ser 
                      660                 665                 670         
          Gly Thr Asp Tyr Thr Phe Thr Ile Ser Ser Leu Gln Pro Glu Asp Ile 
                  675                 680                 685             
          Ala Thr Tyr Tyr Cys Gln His Phe Trp Gly Ser Pro Phe Thr Phe Gly 
              690                 695                 700                 
          Gln Gly Thr Lys Leu Glu Ile Lys 
          705                 710         
          <![CDATA[<210> 59]]>
          <![CDATA[<211> 214]]>
          <![CDATA[<212> PRT]]>
          <![CDATA[<213> 智人]]>
          <![CDATA[<400> 59]]>
          Asp Ile Gln Leu Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly 
          1               5                   10                  15      
          Asp Arg Val Thr Ile Thr Cys Ser Ala Ser Gln Asp Ile Ser Asn Tyr 
                      20                  25                  30          
          Leu Asn Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Val Leu Ile 
                  35                  40                  45              
          Tyr Phe Thr Ser Ser Leu His Ser Gly Val Pro Ser Arg Phe Ser Gly 
              50                  55                  60                  
          Ser Gly Ser Gly Thr Gly Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro 
          65                  70                  75                  80  
          Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Tyr Ser Thr Val Pro Trp 
                          85                  90                  95      
          Thr Phe Gly Gln 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 Cys 
              210                 
          <![CDATA[<210> 60]]>
          <![CDATA[<211> 712]]>
          <![CDATA[<212> PRT]]>
          <![CDATA[<213> 智人]]>
          <![CDATA[<400> 60]]>
          Gln Val Gln Leu Val Gln Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 
          1               5                   10                  15      
          Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Tyr Asp Phe Thr His Tyr 
                      20                  25                  30          
          Gly Met Asn Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 
                  35                  40                  45              
          Gly Trp Ile Asn Thr Tyr Thr Gly Glu Pro Thr Tyr Ala Ala Asp Phe 
              50                  55                  60                  
          Lys Arg Arg Phe Thr Phe Ser Leu Asp Thr Ser Lys Ser Thr Ala Tyr 
          65                  70                  75                  80  
          Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 
                          85                  90                  95      
          Ala Lys Tyr Pro Tyr Tyr Tyr Gly Thr Ser His Trp Tyr Phe Asp Val 
                      100                 105                 110         
          Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly 
                  115                 120                 125             
          Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly 
              130                 135                 140                 
          Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val 
          145                 150                 155                 160 
          Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe 
                          165                 170                 175     
          Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val 
                      180                 185                 190         
          Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val 
                  195                 200                 205             
          Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys Arg Val Glu Pro Lys 
              210                 215                 220                 
          Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Ala 
          225                 230                 235                 240 
          Ala Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr 
                          245                 250                 255     
          Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val 
                      260                 265                 270         
          Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val 
                  275                 280                 285             
          Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser 
              290                 295                 300                 
          Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu 
          305                 310                 315                 320 
          Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala 
                          325                 330                 335     
          Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro 
                      340                 345                 350         
          Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln 
                  355                 360                 365             
          Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala 
              370                 375                 380                 
          Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr 
          385                 390                 395                 400 
          Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu 
                          405                 410                 415     
          Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser 
                      420                 425                 430         
          Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser 
                  435                 440                 445             
          Leu Ser Pro Gly Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gln Val 
              450                 455                 460                 
          Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala Ser Val 
          465                 470                 475                 480 
          Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Asn Tyr Asp Ile 
                          485                 490                 495     
          Ile Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met Gly Tyr 
                      500                 505                 510         
          Ile Asn Pro Tyr Asn Asp Gly Thr Lys Tyr Asn Glu Lys Phe Lys Gly 
                  515                 520                 525             
          Arg Val Thr Met Thr Arg Asp Thr Ser Thr Ser Thr Val Tyr Met Glu 
              530                 535                 540                 
          Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys Ala Arg 
          545                 550                 555                 560 
          Leu Leu Lys Tyr Arg Arg Phe Arg Tyr Tyr Ala Ile Asp Tyr Trp Gly 
                          565                 570                 575     
          Gln Gly Thr Thr Val Thr Val Ser Ser Gly Gly Ser Glu Gly Lys Ser 
                      580                 585                 590         
          Ser Gly Ser Gly Ser Glu Ser Lys Ser Thr Gly Gly Ser Asp Ile Gln 
                  595                 600                 605             
          Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly Asp Arg Val 
              610                 615                 620                 
          Thr Ile Thr Cys Arg Thr Ser Glu Asn Val Tyr Ser Asn Leu Ala Trp 
          625                 630                 635                 640 
          Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile Tyr Ala Ala 
                          645                 650                 655     
          Ser Asn Leu Gln Ser Gly Val Pro Ser Arg Phe Ser Gly Ser Gly Ser 
                      660                 665                 670         
          Gly Thr Asp Tyr Thr Phe Thr Ile Ser Ser Leu Gln Pro Glu Asp Ile 
                  675                 680                 685             
          Ala Thr Tyr Tyr Cys Gln His Phe Trp Gly Ser Pro Phe Thr Phe Gly 
              690                 695                 700                 
          Gln Gly Thr Lys Leu Glu Ile Lys 
          705                 710         
          <![CDATA[<210> 61]]>
          <![CDATA[<211> 214]]>
          <![CDATA[<212> PRT]]>
          <![CDATA[<213> 智人]]>
          <![CDATA[<400> 61]]>
          Asp Ile Gln Leu Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly 
          1               5                   10                  15      
          Asp Arg Val Thr Ile Thr Cys Ser Ala Ser Gln Asp Ile Ser Asn Tyr 
                      20                  25                  30          
          Leu Asn Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Val Leu Ile 
                  35                  40                  45              
          Tyr Phe Thr Ser Ser Leu His 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 Tyr Ser Thr Val Pro Trp 
                          85                  90                  95      
          Thr Phe Gly Gln 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 Cys 
              210                 
          <![CDATA[<210> 62]]>
          <![CDATA[<211> 722]]>
          <![CDATA[<212> PRT]]>
          <![CDATA[<213> 智人]]>
          <![CDATA[<400> 62]]>
          Gln Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 
          1               5                   10                  15      
          Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Tyr Asp Phe Thr His Tyr 
                      20                  25                  30          
          Gly Met Asn Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 
                  35                  40                  45              
          Gly Trp Ile Asn Thr Tyr Thr Gly Glu Pro Thr Tyr Ala Ala Asp Phe 
              50                  55                  60                  
          Lys Arg Arg Phe Thr Phe Ser Leu Asp Thr Ser Lys Ser Thr Ala Tyr 
          65                  70                  75                  80  
          Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 
                          85                  90                  95      
          Ala Lys Tyr Pro Tyr Tyr Tyr Gly Thr Ser His Trp Tyr Phe Asp Val 
                      100                 105                 110         
          Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly 
                  115                 120                 125             
          Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly 
              130                 135                 140                 
          Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val 
          145                 150                 155                 160 
          Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe 
                          165                 170                 175     
          Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val 
                      180                 185                 190         
          Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val 
                  195                 200                 205             
          Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys Arg Val Glu Pro Lys 
              210                 215                 220                 
          Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Ala 
          225                 230                 235                 240 
          Ala Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr 
                          245                 250                 255     
          Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val 
                      260                 265                 270         
          Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val 
                  275                 280                 285             
          Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser 
              290                 295                 300                 
          Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu 
          305                 310                 315                 320 
          Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala 
                          325                 330                 335     
          Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro 
                      340                 345                 350         
          Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln 
                  355                 360                 365             
          Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala 
              370                 375                 380                 
          Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr 
          385                 390                 395                 400 
          Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu 
                          405                 410                 415     
          Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser 
                      420                 425                 430         
          Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser 
                  435                 440                 445             
          Leu Ser Pro Gly Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly 
              450                 455                 460                 
          Gly Gly Ser Gly Gly Gly Gly Ser Gln Val Gln Leu Val Gln Ser Gly 
          465                 470                 475                 480 
          Ala Glu Val Lys Lys Pro Gly Ala Ser Val Lys Val Ser Cys Lys Ala 
                          485                 490                 495     
          Ser Gly Tyr Thr Phe Thr Asn Tyr Asp Ile Ile Trp Val Arg Gln Ala 
                      500                 505                 510         
          Pro Gly Gln Gly Leu Glu Trp Met Gly Tyr Ile Asn Pro Tyr Asn Asp 
                  515                 520                 525             
          Gly Thr Lys Tyr Asn Glu Lys Phe Lys Gly Arg Val Thr Met Thr Arg 
              530                 535                 540                 
          Asp Thr Ser Thr Ser Thr Val Tyr Met Glu Leu Ser Ser Leu Arg Ser 
          545                 550                 555                 560 
          Glu Asp Thr Ala Val Tyr Tyr Cys Ala Arg Leu Leu Lys Tyr Arg Arg 
                          565                 570                 575     
          Phe Arg Tyr Tyr Ala Ile Asp Tyr Trp Gly Gln Gly Thr Thr Val Thr 
                      580                 585                 590         
          Val Ser Ser Gly Gly Ser Glu Gly Lys Ser Ser Gly Ser Gly Ser Glu 
                  595                 600                 605             
          Ser Lys Ser Thr Gly Gly Ser Asp Ile Gln Met Thr Gln Ser Pro Ser 
              610                 615                 620                 
          Ser Leu Ser Ala Ser Val Gly Asp Arg Val Thr Ile Thr Cys Arg Thr 
          625                 630                 635                 640 
          Ser Glu Asn Val Tyr Ser Asn Leu Ala Trp Tyr Gln Gln Lys Pro Gly 
                          645                 650                 655     
          Lys Ala Pro Lys Leu Leu Ile Tyr Ala Ala Ser Asn Leu Gln Ser Gly 
                      660                 665                 670         
          Val Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Tyr Thr Phe 
                  675                 680                 685             
          Thr Ile Ser Ser Leu Gln Pro Glu Asp Ile Ala Thr Tyr Tyr Cys Gln 
              690                 695                 700                 
          His Phe Trp Gly Ser Pro Phe Thr Phe Gly Gln Gly Thr Lys Leu Glu 
          705                 710                 715                 720 
          Ile Lys 
          <![CDATA[<210> 63]]>
          <![CDATA[<211> 214]]>
          <![CDATA[<212> PRT]]>
          <![CDATA[<213> 智人]]>
          <![CDATA[<400> 63]]>
          Asp Ile Gln Leu Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly 
          1               5                   10                  15      
          Asp Arg Val Thr Ile Thr Cys Ser Ala Ser Gln Asp Ile Ser Asn Tyr 
                      20                  25                  30          
          Leu Asn Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Val Leu Ile 
                  35                  40                  45              
          Tyr Phe Thr Ser Ser Leu His 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 Tyr Ser Thr Val Pro Trp 
                          85                  90                  95      
          Thr Phe Gly Gln 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 Cys 
              210                 
          <![CDATA[<210> 64]]>
          <![CDATA[<211> 722]]>
          <![CDATA[<212> PRT]]>
          <![CDATA[<213> 智人]]>
          <![CDATA[<400> 64]]>
          Glu Val Gln Leu Val Gln Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 
          1               5                   10                  15      
          Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Tyr Asp Phe Thr His Tyr 
                      20                  25                  30          
          Gly Met Asn Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 
                  35                  40                  45              
          Gly Trp Ile Asn Thr Tyr Thr Gly Glu Pro Thr Tyr Ala Ala Asp Phe 
              50                  55                  60                  
          Lys Arg Arg Phe Thr Phe Ser Leu Asp Thr Ser Lys Ser Thr Ala Tyr 
          65                  70                  75                  80  
          Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 
                          85                  90                  95      
          Ala Lys Tyr Pro Tyr Tyr Tyr Gly Thr Ser His Trp Tyr Phe Asp Val 
                      100                 105                 110         
          Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly 
                  115                 120                 125             
          Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly 
              130                 135                 140                 
          Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val 
          145                 150                 155                 160 
          Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe 
                          165                 170                 175     
          Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val 
                      180                 185                 190         
          Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val 
                  195                 200                 205             
          Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys Arg Val Glu Pro Lys 
              210                 215                 220                 
          Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Ala 
          225                 230                 235                 240 
          Ala Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr 
                          245                 250                 255     
          Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val 
                      260                 265                 270         
          Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val 
                  275                 280                 285             
          Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser 
              290                 295                 300                 
          Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu 
          305                 310                 315                 320 
          Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala 
                          325                 330                 335     
          Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro 
                      340                 345                 350         
          Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln 
                  355                 360                 365             
          Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala 
              370                 375                 380                 
          Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr 
          385                 390                 395                 400 
          Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu 
                          405                 410                 415     
          Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser 
                      420                 425                 430         
          Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser 
                  435                 440                 445             
          Leu Ser Pro Gly Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly 
              450                 455                 460                 
          Gly Gly Ser Gly Gly Gly Gly Ser Gln Val Gln Leu Val Gln Ser Gly 
          465                 470                 475                 480 
          Ala Glu Val Lys Lys Pro Gly Ala Ser Val Lys Val Ser Cys Lys Ala 
                          485                 490                 495     
          Ser Gly Tyr Thr Phe Thr Asn Tyr Asp Ile Ile Trp Val Arg Gln Ala 
                      500                 505                 510         
          Pro Gly Gln Gly Leu Glu Trp Met Gly Tyr Ile Asn Pro Tyr Asn Asp 
                  515                 520                 525             
          Gly Thr Lys Tyr Asn Glu Lys Phe Lys Gly Arg Val Thr Met Thr Arg 
              530                 535                 540                 
          Asp Thr Ser Thr Ser Thr Val Tyr Met Glu Leu Ser Ser Leu Arg Ser 
          545                 550                 555                 560 
          Glu Asp Thr Ala Val Tyr Tyr Cys Ala Arg Leu Leu Lys Tyr Arg Arg 
                          565                 570                 575     
          Phe Arg Tyr Tyr Ala Ile Asp Tyr Trp Gly Gln Gly Thr Thr Val Thr 
                      580                 585                 590         
          Val Ser Ser Gly Gly Ser Glu Gly Lys Ser Ser Gly Ser Gly Ser Glu 
                  595                 600                 605             
          Ser Lys Ser Thr Gly Gly Ser Asp Ile Gln Met Thr Gln Ser Pro Ser 
              610                 615                 620                 
          Ser Leu Ser Ala Ser Val Gly Asp Arg Val Thr Ile Thr Cys Arg Thr 
          625                 630                 635                 640 
          Ser Glu Asn Val Tyr Ser Asn Leu Ala Trp Tyr Gln Gln Lys Pro Gly 
                          645                 650                 655     
          Lys Ala Pro Lys Leu Leu Ile Tyr Ala Ala Ser Asn Leu Gln Ser Gly 
                      660                 665                 670         
          Val Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Tyr Thr Phe 
                  675                 680                 685             
          Thr Ile Ser Ser Leu Gln Pro Glu Asp Ile Ala Thr Tyr Tyr Cys Gln 
              690                 695                 700                 
          His Phe Trp Gly Ser Pro Phe Thr Phe Gly Gln Gly Thr Lys Leu Glu 
          705                 710                 715                 720 
          Ile Lys 
          <![CDATA[<210> 65]]>
          <![CDATA[<211> 214]]>
          <![CDATA[<212> PRT]]>
          <![CDATA[<213> 智人]]>
          <![CDATA[<400> 65]]>
          Asp Ile Gln Leu Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly 
          1               5                   10                  15      
          Asp Arg Val Thr Ile Thr Cys Ser Ala Ser Gln Asp Ile Ser Asn Tyr 
                      20                  25                  30          
          Leu Asn Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Val Leu Ile 
                  35                  40                  45              
          Tyr Phe Thr Ser Ser Leu His Ser Gly Val Pro Ser Arg Phe Ser Gly 
              50                  55                  60                  
          Ser Gly Ser Gly Thr Gly Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro 
          65                  70                  75                  80  
          Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Tyr Ser Thr Val Pro Trp 
                          85                  90                  95      
          Thr Phe Gly Gln 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 Cys 
              210                 
          <![CDATA[<210> 66]]>
          <![CDATA[<211> 722]]>
          <![CDATA[<212> PRT]]>
          <![CDATA[<213> 智人]]>
          <![CDATA[<400> 66]]>
          Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 
          1               5                   10                  15      
          Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Tyr Asp Phe Thr His Tyr 
                      20                  25                  30          
          Gly Met Asn Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 
                  35                  40                  45              
          Gly Trp Ile Asn Thr Tyr Thr Gly Glu Pro Thr Tyr Ala Ala Asp Phe 
              50                  55                  60                  
          Lys Arg Arg Phe Thr Phe Ser Leu Asp Thr Ser Lys Ser Thr Ala Tyr 
          65                  70                  75                  80  
          Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 
                          85                  90                  95      
          Ala Lys Tyr Pro Tyr Tyr Tyr Gly Thr Ser His Trp Tyr Phe Asp Val 
                      100                 105                 110         
          Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly 
                  115                 120                 125             
          Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly 
              130                 135                 140                 
          Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val 
          145                 150                 155                 160 
          Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe 
                          165                 170                 175     
          Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val 
                      180                 185                 190         
          Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val 
                  195                 200                 205             
          Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys Arg Val Glu Pro Lys 
              210                 215                 220                 
          Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Ala 
          225                 230                 235                 240 
          Ala Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr 
                          245                 250                 255     
          Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val 
                      260                 265                 270         
          Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val 
                  275                 280                 285             
          Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser 
              290                 295                 300                 
          Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu 
          305                 310                 315                 320 
          Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala 
                          325                 330                 335     
          Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro 
                      340                 345                 350         
          Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln 
                  355                 360                 365             
          Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala 
              370                 375                 380                 
          Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr 
          385                 390                 395                 400 
          Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu 
                          405                 410                 415     
          Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser 
                      420                 425                 430         
          Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser 
                  435                 440                 445             
          Leu Ser Pro Gly Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly 
              450                 455                 460                 
          Gly Gly Ser Gly Gly Gly Gly Ser Gln Val Gln Leu Val Gln Ser Gly 
          465                 470                 475                 480 
          Ala Glu Val Lys Lys Pro Gly Ala Ser Val Lys Val Ser Cys Lys Ala 
                          485                 490                 495     
          Ser Gly Tyr Thr Phe Thr Asn Tyr Asp Ile Ile Trp Val Arg Gln Ala 
                      500                 505                 510         
          Pro Gly Gln Gly Leu Glu Trp Met Gly Tyr Ile Asn Pro Tyr Asn Asp 
                  515                 520                 525             
          Gly Thr Lys Tyr Asn Glu Lys Phe Lys Gly Arg Val Thr Met Thr Arg 
              530                 535                 540                 
          Asp Thr Ser Thr Ser Thr Val Tyr Met Glu Leu Ser Ser Leu Arg Ser 
          545                 550                 555                 560 
          Glu Asp Thr Ala Val Tyr Tyr Cys Ala Arg Leu Leu Lys Tyr Arg Arg 
                          565                 570                 575     
          Phe Arg Tyr Tyr Ala Ile Asp Tyr Trp Gly Gln Gly Thr Thr Val Thr 
                      580                 585                 590         
          Val Ser Ser Gly Gly Ser Glu Gly Lys Ser Ser Gly Ser Gly Ser Glu 
                  595                 600                 605             
          Ser Lys Ser Thr Gly Gly Ser Asp Ile Gln Met Thr Gln Ser Pro Ser 
              610                 615                 620                 
          Ser Leu Ser Ala Ser Val Gly Asp Arg Val Thr Ile Thr Cys Arg Thr 
          625                 630                 635                 640 
          Ser Glu Asn Val Tyr Ser Asn Leu Ala Trp Tyr Gln Gln Lys Pro Gly 
                          645                 650                 655     
          Lys Ala Pro Lys Leu Leu Ile Tyr Ala Ala Ser Asn Leu Gln Ser Gly 
                      660                 665                 670         
          Val Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Tyr Thr Phe 
                  675                 680                 685             
          Thr Ile Ser Ser Leu Gln Pro Glu Asp Ile Ala Thr Tyr Tyr Cys Gln 
              690                 695                 700                 
          His Phe Trp Gly Ser Pro Phe Thr Phe Gly Gln Gly Thr Lys Leu Glu 
          705                 710                 715                 720 
          Ile Lys 
          <![CDATA[<210> 67]]>
          <![CDATA[<211> 214]]>
          <![CDATA[<212> PRT]]>
          <![CDATA[<213> 智人]]>
          <![CDATA[<400> 67]]>
          Asp Ile Gln Leu Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly 
          1               5                   10                  15      
          Asp Arg Val Thr Ile Thr Cys Ser Ala Ser Gln Asp Ile Ser Asn Tyr 
                      20                  25                  30          
          Leu Asn Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Val Leu Ile 
                  35                  40                  45              
          Tyr Phe Thr Ser Ser Leu His Ser Gly Val Pro Ser Arg Phe Ser Gly 
              50                  55                  60                  
          Ser Gly Ser Gly Thr Gly Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro 
          65                  70                  75                  80  
          Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Tyr Ser Thr Val Pro Trp 
                          85                  90                  95      
          Thr Phe Gly Gln 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 Cys 
              210                 
          <![CDATA[<210> 68]]>
          <![CDATA[<211> 722]]>
          <![CDATA[<212> PRT]]>
          <![CDATA[<213> 智人]]>
          <![CDATA[<400> 68]]>
          Gln Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 
          1               5                   10                  15      
          Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Tyr Asp Phe Thr His Tyr 
                      20                  25                  30          
          Gly Met Asn Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 
                  35                  40                  45              
          Gly Trp Ile Asn Thr Tyr Thr Gly Glu Pro Thr Tyr Ala Ala Asp Phe 
              50                  55                  60                  
          Lys Arg Arg Phe Thr Phe Ser Leu Asp Thr Ser Lys Ser Thr Ala Tyr 
          65                  70                  75                  80  
          Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 
                          85                  90                  95      
          Ala Lys Tyr Pro Tyr Tyr Tyr Gly Thr Ser His Trp Tyr Phe Asp Val 
                      100                 105                 110         
          Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly 
                  115                 120                 125             
          Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly 
              130                 135                 140                 
          Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val 
          145                 150                 155                 160 
          Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe 
                          165                 170                 175     
          Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val 
                      180                 185                 190         
          Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val 
                  195                 200                 205             
          Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys Arg Val Glu Pro Lys 
              210                 215                 220                 
          Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Ala 
          225                 230                 235                 240 
          Ala Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr 
                          245                 250                 255     
          Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val 
                      260                 265                 270         
          Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val 
                  275                 280                 285             
          Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser 
              290                 295                 300                 
          Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu 
          305                 310                 315                 320 
          Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala 
                          325                 330                 335     
          Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro 
                      340                 345                 350         
          Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln 
                  355                 360                 365             
          Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala 
              370                 375                 380                 
          Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr 
          385                 390                 395                 400 
          Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu 
                          405                 410                 415     
          Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser 
                      420                 425                 430         
          Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser 
                  435                 440                 445             
          Leu Ser Pro Gly Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly 
              450                 455                 460                 
          Gly Gly Ser Gly Gly Gly Gly Ser Gln Val Gln Leu Val Gln Ser Gly 
          465                 470                 475                 480 
          Ala Glu Val Lys Lys Pro Gly Ala Ser Val Lys Val Ser Cys Lys Ala 
                          485                 490                 495     
          Ser Gly Tyr Thr Phe Thr Asn Tyr Asp Ile Ile Trp Val Arg Gln Ala 
                      500                 505                 510         
          Pro Gly Gln Gly Leu Glu Trp Met Gly Tyr Ile Asn Pro Tyr Asn Asp 
                  515                 520                 525             
          Gly Thr Lys Tyr Asn Glu Lys Phe Lys Gly Arg Val Thr Met Thr Arg 
              530                 535                 540                 
          Asp Thr Ser Thr Ser Thr Val Tyr Met Glu Leu Ser Ser Leu Arg Ser 
          545                 550                 555                 560 
          Glu Asp Thr Ala Val Tyr Tyr Cys Ala Arg Leu Leu Lys Tyr Arg Arg 
                          565                 570                 575     
          Phe Arg Tyr Tyr Ala Ile Asp Tyr Trp Gly Gln Gly Thr Thr Val Thr 
                      580                 585                 590         
          Val Ser Ser Gly Gly Ser Glu Gly Lys Ser Ser Gly Ser Gly Ser Glu 
                  595                 600                 605             
          Ser Lys Ser Thr Gly Gly Ser Asp Ile Gln Met Thr Gln Ser Pro Ser 
              610                 615                 620                 
          Ser Leu Ser Ala Ser Val Gly Asp Arg Val Thr Ile Thr Cys Arg Thr 
          625                 630                 635                 640 
          Ser Glu Asn Val Tyr Ser Asn Leu Ala Trp Tyr Gln Gln Lys Pro Gly 
                          645                 650                 655     
          Lys Ala Pro Lys Leu Leu Ile Tyr Ala Ala Ser Asn Leu Gln Ser Gly 
                      660                 665                 670         
          Val Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Tyr Thr Phe 
                  675                 680                 685             
          Thr Ile Ser Ser Leu Gln Pro Glu Asp Ile Ala Thr Tyr Tyr Cys Gln 
              690                 695                 700                 
          His Phe Trp Gly Ser Pro Phe Thr Phe Gly Gln Gly Thr Lys Leu Glu 
          705                 710                 715                 720 
          Ile Lys 
          <![CDATA[<210> 69]]>
          <![CDATA[<211> 214]]>
          <![CDATA[<212> PRT]]>
          <![CDATA[<213> 智人]]>
          <![CDATA[<400> 69]]>
          Asp Ile Gln Leu Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly 
          1               5                   10                  15      
          Asp Arg Val Thr Ile Thr Cys Ser Ala Ser Gln Asp Ile Ser Asn Tyr 
                      20                  25                  30          
          Leu Asn Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Val Leu Ile 
                  35                  40                  45              
          Tyr Phe Thr Ser Ser Leu His Ser Gly Val Pro Ser Arg Phe Ser Gly 
              50                  55                  60                  
          Ser Gly Ser Gly Thr Gly Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro 
          65                  70                  75                  80  
          Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Tyr Ser Thr Val Pro Trp 
                          85                  90                  95      
          Thr Phe Gly Gln 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 Cys 
              210                 
          <![CDATA[<210> 70]]>
          <![CDATA[<211> 722]]>
          <![CDATA[<212> PRT]]>
          <![CDATA[<213> 智人]]>
          <![CDATA[<400> 70]]>
          Glu Val Gln Leu Val Gln Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 
          1               5                   10                  15      
          Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Tyr Asp Phe Thr His Tyr 
                      20                  25                  30          
          Gly Met Asn Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 
                  35                  40                  45              
          Gly Trp Ile Asn Thr Tyr Thr Gly Glu Pro Thr Tyr Ala Ala Asp Phe 
              50                  55                  60                  
          Lys Arg Arg Phe Thr Phe Ser Leu Asp Thr Ser Lys Ser Thr Ala Tyr 
          65                  70                  75                  80  
          Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 
                          85                  90                  95      
          Ala Lys Tyr Pro Tyr Tyr Tyr Gly Thr Ser His Trp Tyr Phe Asp Val 
                      100                 105                 110         
          Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly 
                  115                 120                 125             
          Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly 
              130                 135                 140                 
          Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val 
          145                 150                 155                 160 
          Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe 
                          165                 170                 175     
          Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val 
                      180                 185                 190         
          Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val 
                  195                 200                 205             
          Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys Arg Val Glu Pro Lys 
              210                 215                 220                 
          Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Ala 
          225                 230                 235                 240 
          Ala Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr 
                          245                 250                 255     
          Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val 
                      260                 265                 270         
          Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val 
                  275                 280                 285             
          Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser 
              290                 295                 300                 
          Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu 
          305                 310                 315                 320 
          Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala 
                          325                 330                 335     
          Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro 
                      340                 345                 350         
          Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln 
                  355                 360                 365             
          Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala 
              370                 375                 380                 
          Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr 
          385                 390                 395                 400 
          Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu 
                          405                 410                 415     
          Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser 
                      420                 425                 430         
          Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser 
                  435                 440                 445             
          Leu Ser Pro Gly Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly 
              450                 455                 460                 
          Gly Gly Ser Gly Gly Gly Gly Ser Gln Val Gln Leu Val Gln Ser Gly 
          465                 470                 475                 480 
          Ala Glu Val Lys Lys Pro Gly Ala Ser Val Lys Val Ser Cys Lys Ala 
                          485                 490                 495     
          Ser Gly Tyr Thr Phe Thr Asn Tyr Asp Ile Ile Trp Val Arg Gln Ala 
                      500                 505                 510         
          Pro Gly Gln Gly Leu Glu Trp Met Gly Tyr Ile Asn Pro Tyr Asn Asp 
                  515                 520                 525             
          Gly Thr Lys Tyr Asn Glu Lys Phe Lys Gly Arg Val Thr Met Thr Arg 
              530                 535                 540                 
          Asp Thr Ser Thr Ser Thr Val Tyr Met Glu Leu Ser Ser Leu Arg Ser 
          545                 550                 555                 560 
          Glu Asp Thr Ala Val Tyr Tyr Cys Ala Arg Leu Leu Lys Tyr Arg Arg 
                          565                 570                 575     
          Phe Arg Tyr Tyr Ala Ile Asp Tyr Trp Gly Gln Gly Thr Thr Val Thr 
                      580                 585                 590         
          Val Ser Ser Gly Gly Ser Glu Gly Lys Ser Ser Gly Ser Gly Ser Glu 
                  595                 600                 605             
          Ser Lys Ser Thr Gly Gly Ser Asp Ile Gln Met Thr Gln Ser Pro Ser 
              610                 615                 620                 
          Ser Leu Ser Ala Ser Val Gly Asp Arg Val Thr Ile Thr Cys Arg Thr 
          625                 630                 635                 640 
          Ser Glu Asn Val Tyr Ser Asn Leu Ala Trp Tyr Gln Gln Lys Pro Gly 
                          645                 650                 655     
          Lys Ala Pro Lys Leu Leu Ile Tyr Ala Ala Ser Asn Leu Gln Ser Gly 
                      660                 665                 670         
          Val Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Tyr Thr Phe 
                  675                 680                 685             
          Thr Ile Ser Ser Leu Gln Pro Glu Asp Ile Ala Thr Tyr Tyr Cys Gln 
              690                 695                 700                 
          His Phe Trp Gly Ser Pro Phe Thr Phe Gly Gln Gly Thr Lys Leu Glu 
          705                 710                 715                 720 
          Ile Lys 
          <![CDATA[<210> 71]]>
          <![CDATA[<211> 214]]>
          <![CDATA[<212> PRT]]>
          <![CDATA[<213> 智人]]>
          <![CDATA[<400> 71]]>
          Asp Ile Gln Leu Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly 
          1               5                   10                  15      
          Asp Arg Val Thr Ile Thr Cys Ser Ala Ser Gln Asp Ile Ser Asn Tyr 
                      20                  25                  30          
          Leu Asn Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Val Leu Ile 
                  35                  40                  45              
          Tyr Phe Thr Ser Ser Leu His Ser Gly Val Pro Ser Arg Phe Ser Gly 
              50                  55                  60                  
          Ser Gly Ser Gly Thr Gly Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro 
          65                  70                  75                  80  
          Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Tyr Ser Thr Val Pro Trp 
                          85                  90                  95      
          Thr Phe Gly Gln 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 Cys 
              210                 
          <![CDATA[<210> 72]]>
          <![CDATA[<211> 722]]>
          <![CDATA[<212> PRT]]>
          <![CDATA[<213> 智人]]>
          <![CDATA[<400> 72]]>
          Gln Val Gln Leu Val Gln Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 
          1               5                   10                  15      
          Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Tyr Asp Phe Thr His Tyr 
                      20                  25                  30          
          Gly Met Asn Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 
                  35                  40                  45              
          Gly Trp Ile Asn Thr Tyr Thr Gly Glu Pro Thr Tyr Ala Ala Asp Phe 
              50                  55                  60                  
          Lys Arg Arg Phe Thr Phe Ser Leu Asp Thr Ser Lys Ser Thr Ala Tyr 
          65                  70                  75                  80  
          Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 
                          85                  90                  95      
          Ala Lys Tyr Pro Tyr Tyr Tyr Gly Thr Ser His Trp Tyr Phe Asp Val 
                      100                 105                 110         
          Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly 
                  115                 120                 125             
          Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly 
              130                 135                 140                 
          Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val 
          145                 150                 155                 160 
          Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe 
                          165                 170                 175     
          Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val 
                      180                 185                 190         
          Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val 
                  195                 200                 205             
          Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys Arg Val Glu Pro Lys 
              210                 215                 220                 
          Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Ala 
          225                 230                 235                 240 
          Ala Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr 
                          245                 250                 255     
          Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val 
                      260                 265                 270         
          Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val 
                  275                 280                 285             
          Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser 
              290                 295                 300                 
          Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu 
          305                 310                 315                 320 
          Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala 
                          325                 330                 335     
          Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro 
                      340                 345                 350         
          Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln 
                  355                 360                 365             
          Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala 
              370                 375                 380                 
          Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr 
          385                 390                 395                 400 
          Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu 
                          405                 410                 415     
          Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser 
                      420                 425                 430         
          Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser 
                  435                 440                 445             
          Leu Ser Pro Gly Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly 
              450                 455                 460                 
          Gly Gly Ser Gly Gly Gly Gly Ser Gln Val Gln Leu Val Gln Ser Gly 
          465                 470                 475                 480 
          Ala Glu Val Lys Lys Pro Gly Ala Ser Val Lys Val Ser Cys Lys Ala 
                          485                 490                 495     
          Ser Gly Tyr Thr Phe Thr Asn Tyr Asp Ile Ile Trp Val Arg Gln Ala 
                      500                 505                 510         
          Pro Gly Gln Gly Leu Glu Trp Met Gly Tyr Ile Asn Pro Tyr Asn Asp 
                  515                 520                 525             
          Gly Thr Lys Tyr Asn Glu Lys Phe Lys Gly Arg Val Thr Met Thr Arg 
              530                 535                 540                 
          Asp Thr Ser Thr Ser Thr Val Tyr Met Glu Leu Ser Ser Leu Arg Ser 
          545                 550                 555                 560 
          Glu Asp Thr Ala Val Tyr Tyr Cys Ala Arg Leu Leu Lys Tyr Arg Arg 
                          565                 570                 575     
          Phe Arg Tyr Tyr Ala Ile Asp Tyr Trp Gly Gln Gly Thr Thr Val Thr 
                      580                 585                 590         
          Val Ser Ser Gly Gly Ser Glu Gly Lys Ser Ser Gly Ser Gly Ser Glu 
                  595                 600                 605             
          Ser Lys Ser Thr Gly Gly Ser Asp Ile Gln Met Thr Gln Ser Pro Ser 
              610                 615                 620                 
          Ser Leu Ser Ala Ser Val Gly Asp Arg Val Thr Ile Thr Cys Arg Thr 
          625                 630                 635                 640 
          Ser Glu Asn Val Tyr Ser Asn Leu Ala Trp Tyr Gln Gln Lys Pro Gly 
                          645                 650                 655     
          Lys Ala Pro Lys Leu Leu Ile Tyr Ala Ala Ser Asn Leu Gln Ser Gly 
                      660                 665                 670         
          Val Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Tyr Thr Phe 
                  675                 680                 685             
          Thr Ile Ser Ser Leu Gln Pro Glu Asp Ile Ala Thr Tyr Tyr Cys Gln 
              690                 695                 700                 
          His Phe Trp Gly Ser Pro Phe Thr Phe Gly Gln Gly Thr Lys Leu Glu 
          705                 710                 715                 720 
          Ile Lys 
          <![CDATA[<210> 73]]>
          <![CDATA[<211> 214]]>
          <![CDATA[<212> PRT]]>
          <![CDATA[<213> 智人]]>
          <![CDATA[<400> 73]]>
          Asp Ile Gln Leu Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly 
          1               5                   10                  15      
          Asp Arg Val Thr Ile Thr Cys Ser Ala Ser Gln Asp Ile Ser Asn Tyr 
                      20                  25                  30          
          Leu Asn Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Val Leu Ile 
                  35                  40                  45              
          Tyr Phe Thr Ser Ser Leu His 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 Tyr Ser Thr Val Pro Trp 
                          85                  90                  95      
          Thr Phe Gly Gln 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 Cys 
              210                 
          <![CDATA[<210> 74]]>
          <![CDATA[<211> 712]]>
          <![CDATA[<212> PRT]]>
          <![CDATA[<213> 智人]]>
          <![CDATA[<400> 74]]>
          Gln Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 
          1               5                   10                  15      
          Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Tyr Asp Phe Thr His Tyr 
                      20                  25                  30          
          Gly Met Asn Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 
                  35                  40                  45              
          Gly Trp Ile Asn Thr Tyr Thr Gly Glu Pro Thr Tyr Ala Ala Asp Phe 
              50                  55                  60                  
          Lys Arg Arg Phe Thr Phe Ser Leu Asp Thr Ser Lys Ser Thr Ala Tyr 
          65                  70                  75                  80  
          Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 
                          85                  90                  95      
          Ala Lys Tyr Pro Tyr Tyr Tyr Gly Thr Ser His Trp Tyr Phe Asp Val 
                      100                 105                 110         
          Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly 
                  115                 120                 125             
          Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly 
              130                 135                 140                 
          Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val 
          145                 150                 155                 160 
          Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe 
                          165                 170                 175     
          Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val 
                      180                 185                 190         
          Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val 
                  195                 200                 205             
          Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys Arg Val Glu Pro Lys 
              210                 215                 220                 
          Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Ala 
          225                 230                 235                 240 
          Ala Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr 
                          245                 250                 255     
          Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val 
                      260                 265                 270         
          Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val 
                  275                 280                 285             
          Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser 
              290                 295                 300                 
          Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu 
          305                 310                 315                 320 
          Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala 
                          325                 330                 335     
          Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro 
                      340                 345                 350         
          Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln 
                  355                 360                 365             
          Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala 
              370                 375                 380                 
          Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr 
          385                 390                 395                 400 
          Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu 
                          405                 410                 415     
          Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser 
                      420                 425                 430         
          Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser 
                  435                 440                 445             
          Leu Ser Pro Gly Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Asp Ile 
              450                 455                 460                 
          Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly Asp Arg 
          465                 470                 475                 480 
          Val Thr Ile Thr Cys Arg Thr Ser Glu Asn Val Tyr Ser Asn Leu Ala 
                          485                 490                 495     
          Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile Tyr Ala 
                      500                 505                 510         
          Ala Ser Asn Leu Gln Ser Gly Val Pro Ser Arg Phe Ser Gly Ser Gly 
                  515                 520                 525             
          Ser Gly Thr Asp Tyr Thr Phe Thr Ile Ser Ser Leu Gln Pro Glu Asp 
              530                 535                 540                 
          Ile Ala Thr Tyr Tyr Cys Gln His Phe Trp Gly Ser Pro Phe Thr Phe 
          545                 550                 555                 560 
          Gly Gln Gly Thr Lys Leu Glu Ile Lys Gly Gly Ser Glu Gly Lys Ser 
                          565                 570                 575     
          Ser Gly Ser Gly Ser Glu Ser Lys Ser Thr Gly Gly Ser Gln Val Gln 
                      580                 585                 590         
          Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala Ser Val Lys 
                  595                 600                 605             
          Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Asn Tyr Asp Ile Ile 
              610                 615                 620                 
          Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met Gly Tyr Ile 
          625                 630                 635                 640 
          Asn Pro Tyr Asn Asp Gly Thr Lys Tyr Asn Glu Lys Phe Lys Gly Arg 
                          645                 650                 655     
          Val Thr Met Thr Arg Asp Thr Ser Thr Ser Thr Val Tyr Met Glu Leu 
                      660                 665                 670         
          Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys Ala Arg Leu 
                  675                 680                 685             
          Leu Lys Tyr Arg Arg Phe Arg Tyr Tyr Ala Ile Asp Tyr Trp Gly Gln 
              690                 695                 700                 
          Gly Thr Thr Val Thr Val Ser Ser 
          705                 710         
          <![CDATA[<210> 75]]>
          <![CDATA[<211> 214]]>
          <![CDATA[<212> PRT]]>
          <![CDATA[<213> 智人]]>
          <![CDATA[<400> 75]]>
          Asp Ile Gln Leu Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly 
          1               5                   10                  15      
          Asp Arg Val Thr Ile Thr Cys Ser Ala Ser Gln Asp Ile Ser Asn Tyr 
                      20                  25                  30          
          Leu Asn Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Val Leu Ile 
                  35                  40                  45              
          Tyr Phe Thr Ser Ser Leu His 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 Tyr Ser Thr Val Pro Trp 
                          85                  90                  95      
          Thr Phe Gly Gln 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 Cys 
              210                 
          <![CDATA[<210> 76]]>
          <![CDATA[<211> 712]]>
          <![CDATA[<212> PRT]]>
          <![CDATA[<213> 智人]]>
          <![CDATA[<400> 76]]>
          Glu Val Gln Leu Val Gln Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 
          1               5                   10                  15      
          Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Tyr Asp Phe Thr His Tyr 
                      20                  25                  30          
          Gly Met Asn Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 
                  35                  40                  45              
          Gly Trp Ile Asn Thr Tyr Thr Gly Glu Pro Thr Tyr Ala Ala Asp Phe 
              50                  55                  60                  
          Lys Arg Arg Phe Thr Phe Ser Leu Asp Thr Ser Lys Ser Thr Ala Tyr 
          65                  70                  75                  80  
          Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 
                          85                  90                  95      
          Ala Lys Tyr Pro Tyr Tyr Tyr Gly Thr Ser His Trp Tyr Phe Asp Val 
                      100                 105                 110         
          Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly 
                  115                 120                 125             
          Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly 
              130                 135                 140                 
          Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val 
          145                 150                 155                 160 
          Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe 
                          165                 170                 175     
          Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val 
                      180                 185                 190         
          Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val 
                  195                 200                 205             
          Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys Arg Val Glu Pro Lys 
              210                 215                 220                 
          Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Ala 
          225                 230                 235                 240 
          Ala Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr 
                          245                 250                 255     
          Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val 
                      260                 265                 270         
          Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val 
                  275                 280                 285             
          Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser 
              290                 295                 300                 
          Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu 
          305                 310                 315                 320 
          Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala 
                          325                 330                 335     
          Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro 
                      340                 345                 350         
          Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln 
                  355                 360                 365             
          Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala 
              370                 375                 380                 
          Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr 
          385                 390                 395                 400 
          Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu 
                          405                 410                 415     
          Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser 
                      420                 425                 430         
          Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser 
                  435                 440                 445             
          Leu Ser Pro Gly Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Asp Ile 
              450                 455                 460                 
          Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly Asp Arg 
          465                 470                 475                 480 
          Val Thr Ile Thr Cys Arg Thr Ser Glu Asn Val Tyr Ser Asn Leu Ala 
                          485                 490                 495     
          Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile Tyr Ala 
                      500                 505                 510         
          Ala Ser Asn Leu Gln Ser Gly Val Pro Ser Arg Phe Ser Gly Ser Gly 
                  515                 520                 525             
          Ser Gly Thr Asp Tyr Thr Phe Thr Ile Ser Ser Leu Gln Pro Glu Asp 
              530                 535                 540                 
          Ile Ala Thr Tyr Tyr Cys Gln His Phe Trp Gly Ser Pro Phe Thr Phe 
          545                 550                 555                 560 
          Gly Gln Gly Thr Lys Leu Glu Ile Lys Gly Gly Ser Glu Gly Lys Ser 
                          565                 570                 575     
          Ser Gly Ser Gly Ser Glu Ser Lys Ser Thr Gly Gly Ser Gln Val Gln 
                      580                 585                 590         
          Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala Ser Val Lys 
                  595                 600                 605             
          Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Asn Tyr Asp Ile Ile 
              610                 615                 620                 
          Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met Gly Tyr Ile 
          625                 630                 635                 640 
          Asn Pro Tyr Asn Asp Gly Thr Lys Tyr Asn Glu Lys Phe Lys Gly Arg 
                          645                 650                 655     
          Val Thr Met Thr Arg Asp Thr Ser Thr Ser Thr Val Tyr Met Glu Leu 
                      660                 665                 670         
          Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys Ala Arg Leu 
                  675                 680                 685             
          Leu Lys Tyr Arg Arg Phe Arg Tyr Tyr Ala Ile Asp Tyr Trp Gly Gln 
              690                 695                 700                 
          Gly Thr Thr Val Thr Val Ser Ser 
          705                 710         
          <![CDATA[<210> 77]]>
          <![CDATA[<211> 214]]>
          <![CDATA[<212> PRT]]>
          <![CDATA[<213> 智人]]>
          <![CDATA[<400> 77]]>
          Asp Ile Gln Leu Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly 
          1               5                   10                  15      
          Asp Arg Val Thr Ile Thr Cys Ser Ala Ser Gln Asp Ile Ser Asn Tyr 
                      20                  25                  30          
          Leu Asn Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Val Leu Ile 
                  35                  40                  45              
          Tyr Phe Thr Ser Ser Leu His Ser Gly Val Pro Ser Arg Phe Ser Gly 
              50                  55                  60                  
          Ser Gly Ser Gly Thr Gly Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro 
          65                  70                  75                  80  
          Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Tyr Ser Thr Val Pro Trp 
                          85                  90                  95      
          Thr Phe Gly Gln 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 Cys 
              210                 
          <![CDATA[<210> 78]]>
          <![CDATA[<211> 712]]>
          <![CDATA[<212> PRT]]>
          <![CDATA[<213> 智人]]>
          <![CDATA[<400> 78]]>
          Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 
          1               5                   10                  15      
          Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Tyr Asp Phe Thr His Tyr 
                      20                  25                  30          
          Gly Met Asn Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 
                  35                  40                  45              
          Gly Trp Ile Asn Thr Tyr Thr Gly Glu Pro Thr Tyr Ala Ala Asp Phe 
              50                  55                  60                  
          Lys Arg Arg Phe Thr Phe Ser Leu Asp Thr Ser Lys Ser Thr Ala Tyr 
          65                  70                  75                  80  
          Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 
                          85                  90                  95      
          Ala Lys Tyr Pro Tyr Tyr Tyr Gly Thr Ser His Trp Tyr Phe Asp Val 
                      100                 105                 110         
          Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly 
                  115                 120                 125             
          Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly 
              130                 135                 140                 
          Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val 
          145                 150                 155                 160 
          Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe 
                          165                 170                 175     
          Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val 
                      180                 185                 190         
          Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val 
                  195                 200                 205             
          Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys Arg Val Glu Pro Lys 
              210                 215                 220                 
          Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Ala 
          225                 230                 235                 240 
          Ala Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr 
                          245                 250                 255     
          Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val 
                      260                 265                 270         
          Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val 
                  275                 280                 285             
          Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser 
              290                 295                 300                 
          Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu 
          305                 310                 315                 320 
          Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala 
                          325                 330                 335     
          Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro 
                      340                 345                 350         
          Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln 
                  355                 360                 365             
          Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala 
              370                 375                 380                 
          Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr 
          385                 390                 395                 400 
          Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu 
                          405                 410                 415     
          Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser 
                      420                 425                 430         
          Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser 
                  435                 440                 445             
          Leu Ser Pro Gly Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Asp Ile 
              450                 455                 460                 
          Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly Asp Arg 
          465                 470                 475                 480 
          Val Thr Ile Thr Cys Arg Thr Ser Glu Asn Val Tyr Ser Asn Leu Ala 
                          485                 490                 495     
          Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile Tyr Ala 
                      500                 505                 510         
          Ala Ser Asn Leu Gln Ser Gly Val Pro Ser Arg Phe Ser Gly Ser Gly 
                  515                 520                 525             
          Ser Gly Thr Asp Tyr Thr Phe Thr Ile Ser Ser Leu Gln Pro Glu Asp 
              530                 535                 540                 
          Ile Ala Thr Tyr Tyr Cys Gln His Phe Trp Gly Ser Pro Phe Thr Phe 
          545                 550                 555                 560 
          Gly Gln Gly Thr Lys Leu Glu Ile Lys Gly Gly Ser Glu Gly Lys Ser 
                          565                 570                 575     
          Ser Gly Ser Gly Ser Glu Ser Lys Ser Thr Gly Gly Ser Gln Val Gln 
                      580                 585                 590         
          Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala Ser Val Lys 
                  595                 600                 605             
          Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Asn Tyr Asp Ile Ile 
              610                 615                 620                 
          Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met Gly Tyr Ile 
          625                 630                 635                 640 
          Asn Pro Tyr Asn Asp Gly Thr Lys Tyr Asn Glu Lys Phe Lys Gly Arg 
                          645                 650                 655     
          Val Thr Met Thr Arg Asp Thr Ser Thr Ser Thr Val Tyr Met Glu Leu 
                      660                 665                 670         
          Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys Ala Arg Leu 
                  675                 680                 685             
          Leu Lys Tyr Arg Arg Phe Arg Tyr Tyr Ala Ile Asp Tyr Trp Gly Gln 
              690                 695                 700                 
          Gly Thr Thr Val Thr Val Ser Ser 
          705                 710         
          <![CDATA[<210> 79]]>
          <![CDATA[<211> 214]]>
          <![CDATA[<212> PRT]]>
          <![CDATA[<213> 智人]]>
          <![CDATA[<400> 79]]>
          Asp Ile Gln Leu Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly 
          1               5                   10                  15      
          Asp Arg Val Thr Ile Thr Cys Ser Ala Ser Gln Asp Ile Ser Asn Tyr 
                      20                  25                  30          
          Leu Asn Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Val Leu Ile 
                  35                  40                  45              
          Tyr Phe Thr Ser Ser Leu His Ser Gly Val Pro Ser Arg Phe Ser Gly 
              50                  55                  60                  
          Ser Gly Ser Gly Thr Gly Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro 
          65                  70                  75                  80  
          Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Tyr Ser Thr Val Pro Trp 
                          85                  90                  95      
          Thr Phe Gly Gln 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 Cys 
              210                 
          <![CDATA[<210> 80]]>
          <![CDATA[<211> 712]]>
          <![CDATA[<212> PRT]]>
          <![CDATA[<213> 智人]]>
          <![CDATA[<400> 80]]>
          Gln Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 
          1               5                   10                  15      
          Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Tyr Asp Phe Thr His Tyr 
                      20                  25                  30          
          Gly Met Asn Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 
                  35                  40                  45              
          Gly Trp Ile Asn Thr Tyr Thr Gly Glu Pro Thr Tyr Ala Ala Asp Phe 
              50                  55                  60                  
          Lys Arg Arg Phe Thr Phe Ser Leu Asp Thr Ser Lys Ser Thr Ala Tyr 
          65                  70                  75                  80  
          Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 
                          85                  90                  95      
          Ala Lys Tyr Pro Tyr Tyr Tyr Gly Thr Ser His Trp Tyr Phe Asp Val 
                      100                 105                 110         
          Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly 
                  115                 120                 125             
          Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly 
              130                 135                 140                 
          Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val 
          145                 150                 155                 160 
          Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe 
                          165                 170                 175     
          Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val 
                      180                 185                 190         
          Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val 
                  195                 200                 205             
          Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys Arg Val Glu Pro Lys 
              210                 215                 220                 
          Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Ala 
          225                 230                 235                 240 
          Ala Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr 
                          245                 250                 255     
          Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val 
                      260                 265                 270         
          Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val 
                  275                 280                 285             
          Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser 
              290                 295                 300                 
          Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu 
          305                 310                 315                 320 
          Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala 
                          325                 330                 335     
          Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro 
                      340                 345                 350         
          Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln 
                  355                 360                 365             
          Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala 
              370                 375                 380                 
          Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr 
          385                 390                 395                 400 
          Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu 
                          405                 410                 415     
          Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser 
                      420                 425                 430         
          Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser 
                  435                 440                 445             
          Leu Ser Pro Gly Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Asp Ile 
              450                 455                 460                 
          Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly Asp Arg 
          465                 470                 475                 480 
          Val Thr Ile Thr Cys Arg Thr Ser Glu Asn Val Tyr Ser Asn Leu Ala 
                          485                 490                 495     
          Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile Tyr Ala 
                      500                 505                 510         
          Ala Ser Asn Leu Gln Ser Gly Val Pro Ser Arg Phe Ser Gly Ser Gly 
                  515                 520                 525             
          Ser Gly Thr Asp Tyr Thr Phe Thr Ile Ser Ser Leu Gln Pro Glu Asp 
              530                 535                 540                 
          Ile Ala Thr Tyr Tyr Cys Gln His Phe Trp Gly Ser Pro Phe Thr Phe 
          545                 550                 555                 560 
          Gly Gln Gly Thr Lys Leu Glu Ile Lys Gly Gly Ser Glu Gly Lys Ser 
                          565                 570                 575     
          Ser Gly Ser Gly Ser Glu Ser Lys Ser Thr Gly Gly Ser Gln Val Gln 
                      580                 585                 590         
          Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala Ser Val Lys 
                  595                 600                 605             
          Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Asn Tyr Asp Ile Ile 
              610                 615                 620                 
          Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met Gly Tyr Ile 
          625                 630                 635                 640 
          Asn Pro Tyr Asn Asp Gly Thr Lys Tyr Asn Glu Lys Phe Lys Gly Arg 
                          645                 650                 655     
          Val Thr Met Thr Arg Asp Thr Ser Thr Ser Thr Val Tyr Met Glu Leu 
                      660                 665                 670         
          Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys Ala Arg Leu 
                  675                 680                 685             
          Leu Lys Tyr Arg Arg Phe Arg Tyr Tyr Ala Ile Asp Tyr Trp Gly Gln 
              690                 695                 700                 
          Gly Thr Thr Val Thr Val Ser Ser 
          705                 710         
          <![CDATA[<210> 81]]>
          <![CDATA[<211> 214]]>
          <![CDATA[<212> PRT]]>
          <![CDATA[<213> 智人]]>
          <![CDATA[<400> 81]]>
          Asp Ile Gln Leu Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly 
          1               5                   10                  15      
          Asp Arg Val Thr Ile Thr Cys Ser Ala Ser Gln Asp Ile Ser Asn Tyr 
                      20                  25                  30          
          Leu Asn Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Val Leu Ile 
                  35                  40                  45              
          Tyr Phe Thr Ser Ser Leu His Ser Gly Val Pro Ser Arg Phe Ser Gly 
              50                  55                  60                  
          Ser Gly Ser Gly Thr Gly Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro 
          65                  70                  75                  80  
          Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Tyr Ser Thr Val Pro Trp 
                          85                  90                  95      
          Thr Phe Gly Gln 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 Cys 
              210                 
          <![CDATA[<210> 82]]>
          <![CDATA[<211> 712]]>
          <![CDATA[<212> PRT]]>
          <![CDATA[<213> 智人]]>
          <![CDATA[<400> 82]]>
          Glu Val Gln Leu Val Gln Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 
          1               5                   10                  15      
          Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Tyr Asp Phe Thr His Tyr 
                      20                  25                  30          
          Gly Met Asn Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 
                  35                  40                  45              
          Gly Trp Ile Asn Thr Tyr Thr Gly Glu Pro Thr Tyr Ala Ala Asp Phe 
              50                  55                  60                  
          Lys Arg Arg Phe Thr Phe Ser Leu Asp Thr Ser Lys Ser Thr Ala Tyr 
          65                  70                  75                  80  
          Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 
                          85                  90                  95      
          Ala Lys Tyr Pro Tyr Tyr Tyr Gly Thr Ser His Trp Tyr Phe Asp Val 
                      100                 105                 110         
          Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly 
                  115                 120                 125             
          Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly 
              130                 135                 140                 
          Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val 
          145                 150                 155                 160 
          Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe 
                          165                 170                 175     
          Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val 
                      180                 185                 190         
          Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val 
                  195                 200                 205             
          Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys Arg Val Glu Pro Lys 
              210                 215                 220                 
          Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Ala 
          225                 230                 235                 240 
          Ala Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr 
                          245                 250                 255     
          Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val 
                      260                 265                 270         
          Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val 
                  275                 280                 285             
          Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser 
              290                 295                 300                 
          Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu 
          305                 310                 315                 320 
          Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala 
                          325                 330                 335     
          Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro 
                      340                 345                 350         
          Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln 
                  355                 360                 365             
          Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala 
              370                 375                 380                 
          Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr 
          385                 390                 395                 400 
          Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu 
                          405                 410                 415     
          Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser 
                      420                 425                 430         
          Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser 
                  435                 440                 445             
          Leu Ser Pro Gly Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Asp Ile 
              450                 455                 460                 
          Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly Asp Arg 
          465                 470                 475                 480 
          Val Thr Ile Thr Cys Arg Thr Ser Glu Asn Val Tyr Ser Asn Leu Ala 
                          485                 490                 495     
          Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile Tyr Ala 
                      500                 505                 510         
          Ala Ser Asn Leu Gln Ser Gly Val Pro Ser Arg Phe Ser Gly Ser Gly 
                  515                 520                 525             
          Ser Gly Thr Asp Tyr Thr Phe Thr Ile Ser Ser Leu Gln Pro Glu Asp 
              530                 535                 540                 
          Ile Ala Thr Tyr Tyr Cys Gln His Phe Trp Gly Ser Pro Phe Thr Phe 
          545                 550                 555                 560 
          Gly Gln Gly Thr Lys Leu Glu Ile Lys Gly Gly Ser Glu Gly Lys Ser 
                          565                 570                 575     
          Ser Gly Ser Gly Ser Glu Ser Lys Ser Thr Gly Gly Ser Gln Val Gln 
                      580                 585                 590         
          Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala Ser Val Lys 
                  595                 600                 605             
          Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Asn Tyr Asp Ile Ile 
              610                 615                 620                 
          Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met Gly Tyr Ile 
          625                 630                 635                 640 
          Asn Pro Tyr Asn Asp Gly Thr Lys Tyr Asn Glu Lys Phe Lys Gly Arg 
                          645                 650                 655     
          Val Thr Met Thr Arg Asp Thr Ser Thr Ser Thr Val Tyr Met Glu Leu 
                      660                 665                 670         
          Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys Ala Arg Leu 
                  675                 680                 685             
          Leu Lys Tyr Arg Arg Phe Arg Tyr Tyr Ala Ile Asp Tyr Trp Gly Gln 
              690                 695                 700                 
          Gly Thr Thr Val Thr Val Ser Ser 
          705                 710         
          <![CDATA[<210> 83]]>
          <![CDATA[<211> 214]]>
          <![CDATA[<212> PRT]]>
          <![CDATA[<213> 智人]]>
          <![CDATA[<400> 83]]>
          Asp Ile Gln Leu Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly 
          1               5                   10                  15      
          Asp Arg Val Thr Ile Thr Cys Ser Ala Ser Gln Asp Ile Ser Asn Tyr 
                      20                  25                  30          
          Leu Asn Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Val Leu Ile 
                  35                  40                  45              
          Tyr Phe Thr Ser Ser Leu His Ser Gly Val Pro Ser Arg Phe Ser Gly 
              50                  55                  60                  
          Ser Gly Ser Gly Thr Gly Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro 
          65                  70                  75                  80  
          Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Tyr Ser Thr Val Pro Trp 
                          85                  90                  95      
          Thr Phe Gly Gln 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 Cys 
              210                 
          <![CDATA[<210> 84]]>
          <![CDATA[<211> 712]]>
          <![CDATA[<212> PRT]]>
          <![CDATA[<213> 智人]]>
          <![CDATA[<400> 84]]>
          Gln Val Gln Leu Val Gln Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 
          1               5                   10                  15      
          Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Tyr Asp Phe Thr His Tyr 
                      20                  25                  30          
          Gly Met Asn Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 
                  35                  40                  45              
          Gly Trp Ile Asn Thr Tyr Thr Gly Glu Pro Thr Tyr Ala Ala Asp Phe 
              50                  55                  60                  
          Lys Arg Arg Phe Thr Phe Ser Leu Asp Thr Ser Lys Ser Thr Ala Tyr 
          65                  70                  75                  80  
          Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 
                          85                  90                  95      
          Ala Lys Tyr Pro Tyr Tyr Tyr Gly Thr Ser His Trp Tyr Phe Asp Val 
                      100                 105                 110         
          Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly 
                  115                 120                 125             
          Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly 
              130                 135                 140                 
          Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val 
          145                 150                 155                 160 
          Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe 
                          165                 170                 175     
          Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val 
                      180                 185                 190         
          Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val 
                  195                 200                 205             
          Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys Arg Val Glu Pro Lys 
              210                 215                 220                 
          Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Ala 
          225                 230                 235                 240 
          Ala Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr 
                          245                 250                 255     
          Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val 
                      260                 265                 270         
          Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val 
                  275                 280                 285             
          Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser 
              290                 295                 300                 
          Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu 
          305                 310                 315                 320 
          Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala 
                          325                 330                 335     
          Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro 
                      340                 345                 350         
          Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln 
                  355                 360                 365             
          Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala 
              370                 375                 380                 
          Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr 
          385                 390                 395                 400 
          Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu 
                          405                 410                 415     
          Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser 
                      420                 425                 430         
          Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser 
                  435                 440                 445             
          Leu Ser Pro Gly Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Asp Ile 
              450                 455                 460                 
          Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly Asp Arg 
          465                 470                 475                 480 
          Val Thr Ile Thr Cys Arg Thr Ser Glu Asn Val Tyr Ser Asn Leu Ala 
                          485                 490                 495     
          Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile Tyr Ala 
                      500                 505                 510         
          Ala Ser Asn Leu Gln Ser Gly Val Pro Ser Arg Phe Ser Gly Ser Gly 
                  515                 520                 525             
          Ser Gly Thr Asp Tyr Thr Phe Thr Ile Ser Ser Leu Gln Pro Glu Asp 
              530                 535                 540                 
          Ile Ala Thr Tyr Tyr Cys Gln His Phe Trp Gly Ser Pro Phe Thr Phe 
          545                 550                 555                 560 
          Gly Gln Gly Thr Lys Leu Glu Ile Lys Gly Gly Ser Glu Gly Lys Ser 
                          565                 570                 575     
          Ser Gly Ser Gly Ser Glu Ser Lys Ser Thr Gly Gly Ser Gln Val Gln 
                      580                 585                 590         
          Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala Ser Val Lys 
                  595                 600                 605             
          Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Asn Tyr Asp Ile Ile 
              610                 615                 620                 
          Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met Gly Tyr Ile 
          625                 630                 635                 640 
          Asn Pro Tyr Asn Asp Gly Thr Lys Tyr Asn Glu Lys Phe Lys Gly Arg 
                          645                 650                 655     
          Val Thr Met Thr Arg Asp Thr Ser Thr Ser Thr Val Tyr Met Glu Leu 
                      660                 665                 670         
          Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys Ala Arg Leu 
                  675                 680                 685             
          Leu Lys Tyr Arg Arg Phe Arg Tyr Tyr Ala Ile Asp Tyr Trp Gly Gln 
              690                 695                 700                 
          Gly Thr Thr Val Thr Val Ser Ser 
          705                 710         
          <![CDATA[<210> 85]]>
          <![CDATA[<211> 214]]>
          <![CDATA[<212> PRT]]>
          <![CDATA[<213> 智人]]>
          <![CDATA[<400> 85]]>
          Asp Ile Gln Leu Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly 
          1               5                   10                  15      
          Asp Arg Val Thr Ile Thr Cys Ser Ala Ser Gln Asp Ile Ser Asn Tyr 
                      20                  25                  30          
          Leu Asn Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Val Leu Ile 
                  35                  40                  45              
          Tyr Phe Thr Ser Ser Leu His 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 Tyr Ser Thr Val Pro Trp 
                          85                  90                  95      
          Thr Phe Gly Gln 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 Cys 
              210                 
          <![CDATA[<210> 86]]>
          <![CDATA[<211> 722]]>
          <![CDATA[<212> PRT]]>
          <![CDATA[<213> 智人]]>
          <![CDATA[<400> 86]]>
          Gln Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 
          1               5                   10                  15      
          Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Tyr Asp Phe Thr His Tyr 
                      20                  25                  30          
          Gly Met Asn Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 
                  35                  40                  45              
          Gly Trp Ile Asn Thr Tyr Thr Gly Glu Pro Thr Tyr Ala Ala Asp Phe 
              50                  55                  60                  
          Lys Arg Arg Phe Thr Phe Ser Leu Asp Thr Ser Lys Ser Thr Ala Tyr 
          65                  70                  75                  80  
          Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 
                          85                  90                  95      
          Ala Lys Tyr Pro Tyr Tyr Tyr Gly Thr Ser His Trp Tyr Phe Asp Val 
                      100                 105                 110         
          Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly 
                  115                 120                 125             
          Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly 
              130                 135                 140                 
          Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val 
          145                 150                 155                 160 
          Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe 
                          165                 170                 175     
          Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val 
                      180                 185                 190         
          Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val 
                  195                 200                 205             
          Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys Arg Val Glu Pro Lys 
              210                 215                 220                 
          Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Ala 
          225                 230                 235                 240 
          Ala Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr 
                          245                 250                 255     
          Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val 
                      260                 265                 270         
          Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val 
                  275                 280                 285             
          Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser 
              290                 295                 300                 
          Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu 
          305                 310                 315                 320 
          Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala 
                          325                 330                 335     
          Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro 
                      340                 345                 350         
          Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln 
                  355                 360                 365             
          Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala 
              370                 375                 380                 
          Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr 
          385                 390                 395                 400 
          Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu 
                          405                 410                 415     
          Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser 
                      420                 425                 430         
          Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser 
                  435                 440                 445             
          Leu Ser Pro Gly Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly 
              450                 455                 460                 
          Gly Gly Ser Gly Gly Gly Gly Ser Asp Ile Gln Met Thr Gln Ser Pro 
          465                 470                 475                 480 
          Ser Ser Leu Ser Ala Ser Val Gly Asp Arg Val Thr Ile Thr Cys Arg 
                          485                 490                 495     
          Thr Ser Glu Asn Val Tyr Ser Asn Leu Ala Trp Tyr Gln Gln Lys Pro 
                      500                 505                 510         
          Gly Lys Ala Pro Lys Leu Leu Ile Tyr Ala Ala Ser Asn Leu Gln Ser 
                  515                 520                 525             
          Gly Val Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Tyr Thr 
              530                 535                 540                 
          Phe Thr Ile Ser Ser Leu Gln Pro Glu Asp Ile Ala Thr Tyr Tyr Cys 
          545                 550                 555                 560 
          Gln His Phe Trp Gly Ser Pro Phe Thr Phe Gly Gln Gly Thr Lys Leu 
                          565                 570                 575     
          Glu Ile Lys Gly Gly Ser Glu Gly Lys Ser Ser Gly Ser Gly Ser Glu 
                      580                 585                 590         
          Ser Lys Ser Thr Gly Gly Ser Gln Val Gln Leu Val Gln Ser Gly Ala 
                  595                 600                 605             
          Glu Val Lys Lys Pro Gly Ala Ser Val Lys Val Ser Cys Lys Ala Ser 
              610                 615                 620                 
          Gly Tyr Thr Phe Thr Asn Tyr Asp Ile Ile Trp Val Arg Gln Ala Pro 
          625                 630                 635                 640 
          Gly Gln Gly Leu Glu Trp Met Gly Tyr Ile Asn Pro Tyr Asn Asp Gly 
                          645                 650                 655     
          Thr Lys Tyr Asn Glu Lys Phe Lys Gly Arg Val Thr Met Thr Arg Asp 
                      660                 665                 670         
          Thr Ser Thr Ser Thr Val Tyr Met Glu Leu Ser Ser Leu Arg Ser Glu 
                  675                 680                 685             
          Asp Thr Ala Val Tyr Tyr Cys Ala Arg Leu Leu Lys Tyr Arg Arg Phe 
              690                 695                 700                 
          Arg Tyr Tyr Ala Ile Asp Tyr Trp Gly Gln Gly Thr Thr Val Thr Val 
          705                 710                 715                 720 
          Ser Ser 
          <![CDATA[<210> 87]]>
          <![CDATA[<211> 214]]>
          <![CDATA[<212> PRT]]>
          <![CDATA[<213> 智人]]>
          <![CDATA[<400> 87]]>
          Asp Ile Gln Leu Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly 
          1               5                   10                  15      
          Asp Arg Val Thr Ile Thr Cys Ser Ala Ser Gln Asp Ile Ser Asn Tyr 
                      20                  25                  30          
          Leu Asn Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Val Leu Ile 
                  35                  40                  45              
          Tyr Phe Thr Ser Ser Leu His 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 Tyr Ser Thr Val Pro Trp 
                          85                  90                  95      
          Thr Phe Gly Gln 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 Cys 
              210                 
          <![CDATA[<210> 88]]>
          <![CDATA[<211> 722]]>
          <![CDATA[<212> PRT]]>
          <![CDATA[<213> 智人]]>
          <![CDATA[<400> 88]]>
          Glu Val Gln Leu Val Gln Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 
          1               5                   10                  15      
          Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Tyr Asp Phe Thr His Tyr 
                      20                  25                  30          
          Gly Met Asn Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 
                  35                  40                  45              
          Gly Trp Ile Asn Thr Tyr Thr Gly Glu Pro Thr Tyr Ala Ala Asp Phe 
              50                  55                  60                  
          Lys Arg Arg Phe Thr Phe Ser Leu Asp Thr Ser Lys Ser Thr Ala Tyr 
          65                  70                  75                  80  
          Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 
                          85                  90                  95      
          Ala Lys Tyr Pro Tyr Tyr Tyr Gly Thr Ser His Trp Tyr Phe Asp Val 
                      100                 105                 110         
          Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly 
                  115                 120                 125             
          Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly 
              130                 135                 140                 
          Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val 
          145                 150                 155                 160 
          Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe 
                          165                 170                 175     
          Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val 
                      180                 185                 190         
          Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val 
                  195                 200                 205             
          Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys Arg Val Glu Pro Lys 
              210                 215                 220                 
          Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Ala 
          225                 230                 235                 240 
          Ala Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr 
                          245                 250                 255     
          Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val 
                      260                 265                 270         
          Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val 
                  275                 280                 285             
          Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser 
              290                 295                 300                 
          Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu 
          305                 310                 315                 320 
          Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala 
                          325                 330                 335     
          Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro 
                      340                 345                 350         
          Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln 
                  355                 360                 365             
          Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala 
              370                 375                 380                 
          Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr 
          385                 390                 395                 400 
          Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu 
                          405                 410                 415     
          Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser 
                      420                 425                 430         
          Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser 
                  435                 440                 445             
          Leu Ser Pro Gly Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly 
              450                 455                 460                 
          Gly Gly Ser Gly Gly Gly Gly Ser Asp Ile Gln Met Thr Gln Ser Pro 
          465                 470                 475                 480 
          Ser Ser Leu Ser Ala Ser Val Gly Asp Arg Val Thr Ile Thr Cys Arg 
                          485                 490                 495     
          Thr Ser Glu Asn Val Tyr Ser Asn Leu Ala Trp Tyr Gln Gln Lys Pro 
                      500                 505                 510         
          Gly Lys Ala Pro Lys Leu Leu Ile Tyr Ala Ala Ser Asn Leu Gln Ser 
                  515                 520                 525             
          Gly Val Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Tyr Thr 
              530                 535                 540                 
          Phe Thr Ile Ser Ser Leu Gln Pro Glu Asp Ile Ala Thr Tyr Tyr Cys 
          545                 550                 555                 560 
          Gln His Phe Trp Gly Ser Pro Phe Thr Phe Gly Gln Gly Thr Lys Leu 
                          565                 570                 575     
          Glu Ile Lys Gly Gly Ser Glu Gly Lys Ser Ser Gly Ser Gly Ser Glu 
                      580                 585                 590         
          Ser Lys Ser Thr Gly Gly Ser Gln Val Gln Leu Val Gln Ser Gly Ala 
                  595                 600                 605             
          Glu Val Lys Lys Pro Gly Ala Ser Val Lys Val Ser Cys Lys Ala Ser 
              610                 615                 620                 
          Gly Tyr Thr Phe Thr Asn Tyr Asp Ile Ile Trp Val Arg Gln Ala Pro 
          625                 630                 635                 640 
          Gly Gln Gly Leu Glu Trp Met Gly Tyr Ile Asn Pro Tyr Asn Asp Gly 
                          645                 650                 655     
          Thr Lys Tyr Asn Glu Lys Phe Lys Gly Arg Val Thr Met Thr Arg Asp 
                      660                 665                 670         
          Thr Ser Thr Ser Thr Val Tyr Met Glu Leu Ser Ser Leu Arg Ser Glu 
                  675                 680                 685             
          Asp Thr Ala Val Tyr Tyr Cys Ala Arg Leu Leu Lys Tyr Arg Arg Phe 
              690                 695                 700                 
          Arg Tyr Tyr Ala Ile Asp Tyr Trp Gly Gln Gly Thr Thr Val Thr Val 
          705                 710                 715                 720 
          Ser Ser 
          <![CDATA[<210> 89]]>
          <![CDATA[<211> 214]]>
          <![CDATA[<212> PRT]]>
          <![CDATA[<213> 智人]]>
          <![CDATA[<400> 89]]>
          Asp Ile Gln Leu Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly 
          1               5                   10                  15      
          Asp Arg Val Thr Ile Thr Cys Ser Ala Ser Gln Asp Ile Ser Asn Tyr 
                      20                  25                  30          
          Leu Asn Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Val Leu Ile 
                  35                  40                  45              
          Tyr Phe Thr Ser Ser Leu His Ser Gly Val Pro Ser Arg Phe Ser Gly 
              50                  55                  60                  
          Ser Gly Ser Gly Thr Gly Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro 
          65                  70                  75                  80  
          Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Tyr Ser Thr Val Pro Trp 
                          85                  90                  95      
          Thr Phe Gly Gln 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 Cys 
              210                 
          <![CDATA[<210> 90]]>
          <![CDATA[<211> 722]]>
          <![CDATA[<212> PRT]]>
          <![CDATA[<213> 智人]]>
          <![CDATA[<400> 90]]>
          Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 
          1               5                   10                  15      
          Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Tyr Asp Phe Thr His Tyr 
                      20                  25                  30          
          Gly Met Asn Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 
                  35                  40                  45              
          Gly Trp Ile Asn Thr Tyr Thr Gly Glu Pro Thr Tyr Ala Ala Asp Phe 
              50                  55                  60                  
          Lys Arg Arg Phe Thr Phe Ser Leu Asp Thr Ser Lys Ser Thr Ala Tyr 
          65                  70                  75                  80  
          Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 
                          85                  90                  95      
          Ala Lys Tyr Pro Tyr Tyr Tyr Gly Thr Ser His Trp Tyr Phe Asp Val 
                      100                 105                 110         
          Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly 
                  115                 120                 125             
          Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly 
              130                 135                 140                 
          Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val 
          145                 150                 155                 160 
          Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe 
                          165                 170                 175     
          Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val 
                      180                 185                 190         
          Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val 
                  195                 200                 205             
          Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys Arg Val Glu Pro Lys 
              210                 215                 220                 
          Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Ala 
          225                 230                 235                 240 
          Ala Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr 
                          245                 250                 255     
          Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val 
                      260                 265                 270         
          Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val 
                  275                 280                 285             
          Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser 
              290                 295                 300                 
          Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu 
          305                 310                 315                 320 
          Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala 
                          325                 330                 335     
          Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro 
                      340                 345                 350         
          Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln 
                  355                 360                 365             
          Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala 
              370                 375                 380                 
          Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr 
          385                 390                 395                 400 
          Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu 
                          405                 410                 415     
          Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser 
                      420                 425                 430         
          Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser 
                  435                 440                 445             
          Leu Ser Pro Gly Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly 
              450                 455                 460                 
          Gly Gly Ser Gly Gly Gly Gly Ser Asp Ile Gln Met Thr Gln Ser Pro 
          465                 470                 475                 480 
          Ser Ser Leu Ser Ala Ser Val Gly Asp Arg Val Thr Ile Thr Cys Arg 
                          485                 490                 495     
          Thr Ser Glu Asn Val Tyr Ser Asn Leu Ala Trp Tyr Gln Gln Lys Pro 
                      500                 505                 510         
          Gly Lys Ala Pro Lys Leu Leu Ile Tyr Ala Ala Ser Asn Leu Gln Ser 
                  515                 520                 525             
          Gly Val Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Tyr Thr 
              530                 535                 540                 
          Phe Thr Ile Ser Ser Leu Gln Pro Glu Asp Ile Ala Thr Tyr Tyr Cys 
          545                 550                 555                 560 
          Gln His Phe Trp Gly Ser Pro Phe Thr Phe Gly Gln Gly Thr Lys Leu 
                          565                 570                 575     
          Glu Ile Lys Gly Gly Ser Glu Gly Lys Ser Ser Gly Ser Gly Ser Glu 
                      580                 585                 590         
          Ser Lys Ser Thr Gly Gly Ser Gln Val Gln Leu Val Gln Ser Gly Ala 
                  595                 600                 605             
          Glu Val Lys Lys Pro Gly Ala Ser Val Lys Val Ser Cys Lys Ala Ser 
              610                 615                 620                 
          Gly Tyr Thr Phe Thr Asn Tyr Asp Ile Ile Trp Val Arg Gln Ala Pro 
          625                 630                 635                 640 
          Gly Gln Gly Leu Glu Trp Met Gly Tyr Ile Asn Pro Tyr Asn Asp Gly 
                          645                 650                 655     
          Thr Lys Tyr Asn Glu Lys Phe Lys Gly Arg Val Thr Met Thr Arg Asp 
                      660                 665                 670         
          Thr Ser Thr Ser Thr Val Tyr Met Glu Leu Ser Ser Leu Arg Ser Glu 
                  675                 680                 685             
          Asp Thr Ala Val Tyr Tyr Cys Ala Arg Leu Leu Lys Tyr Arg Arg Phe 
              690                 695                 700                 
          Arg Tyr Tyr Ala Ile Asp Tyr Trp Gly Gln Gly Thr Thr Val Thr Val 
          705                 710                 715                 720 
          Ser Ser 
          <![CDATA[<210> 91]]>
          <![CDATA[<211> 214]]>
          <![CDATA[<212> PRT]]>
          <![CDATA[<213> 智人]]>
          <![CDATA[<400> 91]]>
          Asp Ile Gln Leu Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly 
          1               5                   10                  15      
          Asp Arg Val Thr Ile Thr Cys Ser Ala Ser Gln Asp Ile Ser Asn Tyr 
                      20                  25                  30          
          Leu Asn Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Val Leu Ile 
                  35                  40                  45              
          Tyr Phe Thr Ser Ser Leu His Ser Gly Val Pro Ser Arg Phe Ser Gly 
              50                  55                  60                  
          Ser Gly Ser Gly Thr Gly Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro 
          65                  70                  75                  80  
          Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Tyr Ser Thr Val Pro Trp 
                          85                  90                  95      
          Thr Phe Gly Gln 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 Cys 
              210                 
          <![CDATA[<210> 92]]>
          <![CDATA[<211> 722]]>
          <![CDATA[<212> PRT]]>
          <![CDATA[<213> 智人]]>
          <![CDATA[<400> 92]]>
          Gln Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 
          1               5                   10                  15      
          Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Tyr Asp Phe Thr His Tyr 
                      20                  25                  30          
          Gly Met Asn Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 
                  35                  40                  45              
          Gly Trp Ile Asn Thr Tyr Thr Gly Glu Pro Thr Tyr Ala Ala Asp Phe 
              50                  55                  60                  
          Lys Arg Arg Phe Thr Phe Ser Leu Asp Thr Ser Lys Ser Thr Ala Tyr 
          65                  70                  75                  80  
          Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 
                          85                  90                  95      
          Ala Lys Tyr Pro Tyr Tyr Tyr Gly Thr Ser His Trp Tyr Phe Asp Val 
                      100                 105                 110         
          Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly 
                  115                 120                 125             
          Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly 
              130                 135                 140                 
          Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val 
          145                 150                 155                 160 
          Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe 
                          165                 170                 175     
          Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val 
                      180                 185                 190         
          Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val 
                  195                 200                 205             
          Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys Arg Val Glu Pro Lys 
              210                 215                 220                 
          Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Ala 
          225                 230                 235                 240 
          Ala Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr 
                          245                 250                 255     
          Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val 
                      260                 265                 270         
          Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val 
                  275                 280                 285             
          Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser 
              290                 295                 300                 
          Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu 
          305                 310                 315                 320 
          Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala 
                          325                 330                 335     
          Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro 
                      340                 345                 350         
          Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln 
                  355                 360                 365             
          Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala 
              370                 375                 380                 
          Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr 
          385                 390                 395                 400 
          Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu 
                          405                 410                 415     
          Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser 
                      420                 425                 430         
          Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser 
                  435                 440                 445             
          Leu Ser Pro Gly Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly 
              450                 455                 460                 
          Gly Gly Ser Gly Gly Gly Gly Ser Asp Ile Gln Met Thr Gln Ser Pro 
          465                 470                 475                 480 
          Ser Ser Leu Ser Ala Ser Val Gly Asp Arg Val Thr Ile Thr Cys Arg 
                          485                 490                 495     
          Thr Ser Glu Asn Val Tyr Ser Asn Leu Ala Trp Tyr Gln Gln Lys Pro 
                      500                 505                 510         
          Gly Lys Ala Pro Lys Leu Leu Ile Tyr Ala Ala Ser Asn Leu Gln Ser 
                  515                 520                 525             
          Gly Val Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Tyr Thr 
              530                 535                 540                 
          Phe Thr Ile Ser Ser Leu Gln Pro Glu Asp Ile Ala Thr Tyr Tyr Cys 
          545                 550                 555                 560 
          Gln His Phe Trp Gly Ser Pro Phe Thr Phe Gly Gln Gly Thr Lys Leu 
                          565                 570                 575     
          Glu Ile Lys Gly Gly Ser Glu Gly Lys Ser Ser Gly Ser Gly Ser Glu 
                      580                 585                 590         
          Ser Lys Ser Thr Gly Gly Ser Gln Val Gln Leu Val Gln Ser Gly Ala 
                  595                 600                 605             
          Glu Val Lys Lys Pro Gly Ala Ser Val Lys Val Ser Cys Lys Ala Ser 
              610                 615                 620                 
          Gly Tyr Thr Phe Thr Asn Tyr Asp Ile Ile Trp Val Arg Gln Ala Pro 
          625                 630                 635                 640 
          Gly Gln Gly Leu Glu Trp Met Gly Tyr Ile Asn Pro Tyr Asn Asp Gly 
                          645                 650                 655     
          Thr Lys Tyr Asn Glu Lys Phe Lys Gly Arg Val Thr Met Thr Arg Asp 
                      660                 665                 670         
          Thr Ser Thr Ser Thr Val Tyr Met Glu Leu Ser Ser Leu Arg Ser Glu 
                  675                 680                 685             
          Asp Thr Ala Val Tyr Tyr Cys Ala Arg Leu Leu Lys Tyr Arg Arg Phe 
              690                 695                 700                 
          Arg Tyr Tyr Ala Ile Asp Tyr Trp Gly Gln Gly Thr Thr Val Thr Val 
          705                 710                 715                 720 
          Ser Ser 
          <![CDATA[<210> 93]]>
          <![CDATA[<211> 214]]>
          <![CDATA[<212> PRT]]>
          <![CDATA[<213> 智人]]>
          <![CDATA[<400> 93]]>
          Asp Ile Gln Leu Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly 
          1               5                   10                  15      
          Asp Arg Val Thr Ile Thr Cys Ser Ala Ser Gln Asp Ile Ser Asn Tyr 
                      20                  25                  30          
          Leu Asn Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Val Leu Ile 
                  35                  40                  45              
          Tyr Phe Thr Ser Ser Leu His Ser Gly Val Pro Ser Arg Phe Ser Gly 
              50                  55                  60                  
          Ser Gly Ser Gly Thr Gly Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro 
          65                  70                  75                  80  
          Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Tyr Ser Thr Val Pro Trp 
                          85                  90                  95      
          Thr Phe Gly Gln 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 Cys 
              210                 
          <![CDATA[<210> 94]]>
          <![CDATA[<211> 722]]>
          <![CDATA[<212> PRT]]>
          <![CDATA[<213> 智人]]>
          <![CDATA[<400> 94]]>
          Glu Val Gln Leu Val Gln Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 
          1               5                   10                  15      
          Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Tyr Asp Phe Thr His Tyr 
                      20                  25                  30          
          Gly Met Asn Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 
                  35                  40                  45              
          Gly Trp Ile Asn Thr Tyr Thr Gly Glu Pro Thr Tyr Ala Ala Asp Phe 
              50                  55                  60                  
          Lys Arg Arg Phe Thr Phe Ser Leu Asp Thr Ser Lys Ser Thr Ala Tyr 
          65                  70                  75                  80  
          Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 
                          85                  90                  95      
          Ala Lys Tyr Pro Tyr Tyr Tyr Gly Thr Ser His Trp Tyr Phe Asp Val 
                      100                 105                 110         
          Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly 
                  115                 120                 125             
          Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly 
              130                 135                 140                 
          Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val 
          145                 150                 155                 160 
          Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe 
                          165                 170                 175     
          Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val 
                      180                 185                 190         
          Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val 
                  195                 200                 205             
          Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys Arg Val Glu Pro Lys 
              210                 215                 220                 
          Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Ala 
          225                 230                 235                 240 
          Ala Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr 
                          245                 250                 255     
          Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val 
                      260                 265                 270         
          Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val 
                  275                 280                 285             
          Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser 
              290                 295                 300                 
          Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu 
          305                 310                 315                 320 
          Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala 
                          325                 330                 335     
          Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro 
                      340                 345                 350         
          Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln 
                  355                 360                 365             
          Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala 
              370                 375                 380                 
          Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr 
          385                 390                 395                 400 
          Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu 
                          405                 410                 415     
          Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser 
                      420                 425                 430         
          Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser 
                  435                 440                 445             
          Leu Ser Pro Gly Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly 
              450                 455                 460                 
          Gly Gly Ser Gly Gly Gly Gly Ser Asp Ile Gln Met Thr Gln Ser Pro 
          465                 470                 475                 480 
          Ser Ser Leu Ser Ala Ser Val Gly Asp Arg Val Thr Ile Thr Cys Arg 
                          485                 490                 495     
          Thr Ser Glu Asn Val Tyr Ser Asn Leu Ala Trp Tyr Gln Gln Lys Pro 
                      500                 505                 510         
          Gly Lys Ala Pro Lys Leu Leu Ile Tyr Ala Ala Ser Asn Leu Gln Ser 
                  515                 520                 525             
          Gly Val Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Tyr Thr 
              530                 535                 540                 
          Phe Thr Ile Ser Ser Leu Gln Pro Glu Asp Ile Ala Thr Tyr Tyr Cys 
          545                 550                 555                 560 
          Gln His Phe Trp Gly Ser Pro Phe Thr Phe Gly Gln Gly Thr Lys Leu 
                          565                 570                 575     
          Glu Ile Lys Gly Gly Ser Glu Gly Lys Ser Ser Gly Ser Gly Ser Glu 
                      580                 585                 590         
          Ser Lys Ser Thr Gly Gly Ser Gln Val Gln Leu Val Gln Ser Gly Ala 
                  595                 600                 605             
          Glu Val Lys Lys Pro Gly Ala Ser Val Lys Val Ser Cys Lys Ala Ser 
              610                 615                 620                 
          Gly Tyr Thr Phe Thr Asn Tyr Asp Ile Ile Trp Val Arg Gln Ala Pro 
          625                 630                 635                 640 
          Gly Gln Gly Leu Glu Trp Met Gly Tyr Ile Asn Pro Tyr Asn Asp Gly 
                          645                 650                 655     
          Thr Lys Tyr Asn Glu Lys Phe Lys Gly Arg Val Thr Met Thr Arg Asp 
                      660                 665                 670         
          Thr Ser Thr Ser Thr Val Tyr Met Glu Leu Ser Ser Leu Arg Ser Glu 
                  675                 680                 685             
          Asp Thr Ala Val Tyr Tyr Cys Ala Arg Leu Leu Lys Tyr Arg Arg Phe 
              690                 695                 700                 
          Arg Tyr Tyr Ala Ile Asp Tyr Trp Gly Gln Gly Thr Thr Val Thr Val 
          705                 710                 715                 720 
          Ser Ser 
          <![CDATA[<210> 95]]>
          <![CDATA[<211> 214]]>
          <![CDATA[<212> PRT]]>
          <![CDATA[<213> 智人]]>
          <![CDATA[<400> 95]]>
          Asp Ile Gln Leu Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly 
          1               5                   10                  15      
          Asp Arg Val Thr Ile Thr Cys Ser Ala Ser Gln Asp Ile Ser Asn Tyr 
                      20                  25                  30          
          Leu Asn Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Val Leu Ile 
                  35                  40                  45              
          Tyr Phe Thr Ser Ser Leu His Ser Gly Val Pro Ser Arg Phe Ser Gly 
              50                  55                  60                  
          Ser Gly Ser Gly Thr Gly Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro 
          65                  70                  75                  80  
          Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Tyr Ser Thr Val Pro Trp 
                          85                  90                  95      
          Thr Phe Gly Gln 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 Cys 
              210                 
          <![CDATA[<210> 96]]>
          <![CDATA[<211> 722]]>
          <![CDATA[<212> PRT]]>
          <![CDATA[<213> 智人]]>
          <![CDATA[<400> 96]]>
          Gln Val Gln Leu Val Gln Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 
          1               5                   10                  15      
          Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Tyr Asp Phe Thr His Tyr 
                      20                  25                  30          
          Gly Met Asn Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 
                  35                  40                  45              
          Gly Trp Ile Asn Thr Tyr Thr Gly Glu Pro Thr Tyr Ala Ala Asp Phe 
              50                  55                  60                  
          Lys Arg Arg Phe Thr Phe Ser Leu Asp Thr Ser Lys Ser Thr Ala Tyr 
          65                  70                  75                  80  
          Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 
                          85                  90                  95      
          Ala Lys Tyr Pro Tyr Tyr Tyr Gly Thr Ser His Trp Tyr Phe Asp Val 
                      100                 105                 110         
          Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly 
                  115                 120                 125             
          Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly 
              130                 135                 140                 
          Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val 
          145                 150                 155                 160 
          Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe 
                          165                 170                 175     
          Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val 
                      180                 185                 190         
          Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val 
                  195                 200                 205             
          Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys Arg Val Glu Pro Lys 
              210                 215                 220                 
          Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Ala 
          225                 230                 235                 240 
          Ala Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr 
                          245                 250                 255     
          Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val 
                      260                 265                 270         
          Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val 
                  275                 280                 285             
          Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser 
              290                 295                 300                 
          Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu 
          305                 310                 315                 320 
          Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala 
                          325                 330                 335     
          Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro 
                      340                 345                 350         
          Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln 
                  355                 360                 365             
          Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala 
              370                 375                 380                 
          Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr 
          385                 390                 395                 400 
          Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu 
                          405                 410                 415     
          Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser 
                      420                 425                 430         
          Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser 
                  435                 440                 445             
          Leu Ser Pro Gly Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly 
              450                 455                 460                 
          Gly Gly Ser Gly Gly Gly Gly Ser Asp Ile Gln Met Thr Gln Ser Pro 
          465                 470                 475                 480 
          Ser Ser Leu Ser Ala Ser Val Gly Asp Arg Val Thr Ile Thr Cys Arg 
                          485                 490                 495     
          Thr Ser Glu Asn Val Tyr Ser Asn Leu Ala Trp Tyr Gln Gln Lys Pro 
                      500                 505                 510         
          Gly Lys Ala Pro Lys Leu Leu Ile Tyr Ala Ala Ser Asn Leu Gln Ser 
                  515                 520                 525             
          Gly Val Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Tyr Thr 
              530                 535                 540                 
          Phe Thr Ile Ser Ser Leu Gln Pro Glu Asp Ile Ala Thr Tyr Tyr Cys 
          545                 550                 555                 560 
          Gln His Phe Trp Gly Ser Pro Phe Thr Phe Gly Gln Gly Thr Lys Leu 
                          565                 570                 575     
          Glu Ile Lys Gly Gly Ser Glu Gly Lys Ser Ser Gly Ser Gly Ser Glu 
                      580                 585                 590         
          Ser Lys Ser Thr Gly Gly Ser Gln Val Gln Leu Val Gln Ser Gly Ala 
                  595                 600                 605             
          Glu Val Lys Lys Pro Gly Ala Ser Val Lys Val Ser Cys Lys Ala Ser 
              610                 615                 620                 
          Gly Tyr Thr Phe Thr Asn Tyr Asp Ile Ile Trp Val Arg Gln Ala Pro 
          625                 630                 635                 640 
          Gly Gln Gly Leu Glu Trp Met Gly Tyr Ile Asn Pro Tyr Asn Asp Gly 
                          645                 650                 655     
          Thr Lys Tyr Asn Glu Lys Phe Lys Gly Arg Val Thr Met Thr Arg Asp 
                      660                 665                 670         
          Thr Ser Thr Ser Thr Val Tyr Met Glu Leu Ser Ser Leu Arg Ser Glu 
                  675                 680                 685             
          Asp Thr Ala Val Tyr Tyr Cys Ala Arg Leu Leu Lys Tyr Arg Arg Phe 
              690                 695                 700                 
          Arg Tyr Tyr Ala Ile Asp Tyr Trp Gly Gln Gly Thr Thr Val Thr Val 
          705                 710                 715                 720 
          Ser Ser 
          <![CDATA[<210> 97]]>
          <![CDATA[<211> 214]]>
          <![CDATA[<212> PRT]]>
          <![CDATA[<213> 智人]]>
          <![CDATA[<400> 97]]>
          Asp Ile Gln Leu Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly 
          1               5                   10                  15      
          Asp Arg Val Thr Ile Thr Cys Ser Ala Ser Gln Asp Ile Ser Asn Tyr 
                      20                  25                  30          
          Leu Asn Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Val Leu Ile 
                  35                  40                  45              
          Tyr Phe Thr Ser Ser Leu His 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 Tyr Ser Thr Val Pro Trp 
                          85                  90                  95      
          Thr Phe Gly Gln 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 Cys 
              210                 
          <![CDATA[<210> 98]]>
          <![CDATA[<211> 712]]>
          <![CDATA[<212> PRT]]>
          <![CDATA[<213> 智人]]>
          <![CDATA[<400> 98]]>
          Gln Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 
          1               5                   10                  15      
          Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Tyr Asp Phe Thr His Tyr 
                      20                  25                  30          
          Gly Met Asn Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 
                  35                  40                  45              
          Gly Trp Ile Asn Thr Tyr Thr Gly Glu Pro Thr Tyr Ala Ala Asp Phe 
              50                  55                  60                  
          Lys Arg Arg Phe Thr Phe Ser Leu Asp Thr Ser Lys Ser Thr Ala Tyr 
          65                  70                  75                  80  
          Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 
                          85                  90                  95      
          Ala Lys Tyr Pro Tyr Tyr Tyr Gly Thr Ser His Trp Tyr Phe Asp Val 
                      100                 105                 110         
          Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly 
                  115                 120                 125             
          Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly 
              130                 135                 140                 
          Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val 
          145                 150                 155                 160 
          Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe 
                          165                 170                 175     
          Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val 
                      180                 185                 190         
          Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val 
                  195                 200                 205             
          Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys Arg Val Glu Pro Lys 
              210                 215                 220                 
          Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Ala 
          225                 230                 235                 240 
          Ala Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr 
                          245                 250                 255     
          Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val 
                      260                 265                 270         
          Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val 
                  275                 280                 285             
          Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser 
              290                 295                 300                 
          Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu 
          305                 310                 315                 320 
          Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala 
                          325                 330                 335     
          Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro 
                      340                 345                 350         
          Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln 
                  355                 360                 365             
          Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala 
              370                 375                 380                 
          Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr 
          385                 390                 395                 400 
          Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu 
                          405                 410                 415     
          Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser 
                      420                 425                 430         
          Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser 
                  435                 440                 445             
          Leu Ser Pro Gly Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gln Val 
              450                 455                 460                 
          Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala Ser Val 
          465                 470                 475                 480 
          Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Asn Tyr Asp Ile 
                          485                 490                 495     
          Ile Trp Val Arg Gln Ala Pro Gly Gln Cys Leu Glu Trp Met Gly Tyr 
                      500                 505                 510         
          Ile Asn Pro Tyr Asn Asp Gly Thr Lys Tyr Asn Glu Lys Phe Lys Gly 
                  515                 520                 525             
          Arg Val Thr Met Thr Arg Asp Thr Ser Thr Ser Thr Val Tyr Met Glu 
              530                 535                 540                 
          Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys Ala Arg 
          545                 550                 555                 560 
          Leu Leu Lys Tyr Arg Arg Phe Arg Tyr Tyr Ala Ile Asp Tyr Trp Gly 
                          565                 570                 575     
          Gln Gly Thr Thr Val Thr Val Ser Ser Gly Gly Ser Glu Gly Lys Ser 
                      580                 585                 590         
          Ser Gly Ser Gly Ser Glu Ser Lys Ser Thr Gly Gly Ser Asp Ile Gln 
                  595                 600                 605             
          Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly Asp Arg Val 
              610                 615                 620                 
          Thr Ile Thr Cys Arg Thr Ser Glu Asn Val Tyr Ser Asn Leu Ala Trp 
          625                 630                 635                 640 
          Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile Tyr Ala Ala 
                          645                 650                 655     
          Ser Asn Leu Gln Ser Gly Val Pro Ser Arg Phe Ser Gly Ser Gly Ser 
                      660                 665                 670         
          Gly Thr Asp Tyr Thr Phe Thr Ile Ser Ser Leu Gln Pro Glu Asp Ile 
                  675                 680                 685             
          Ala Thr Tyr Tyr Cys Gln His Phe Trp Gly Ser Pro Phe Thr Phe Gly 
              690                 695                 700                 
          Cys Gly Thr Lys Leu Glu Ile Lys 
          705                 710         
          <![CDATA[<210> 99]]>
          <![CDATA[<211> 214]]>
          <![CDATA[<212> PRT]]>
          <![CDATA[<213> 智人]]>
          <![CDATA[<400> 99]]>
          Asp Ile Gln Leu Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly 
          1               5                   10                  15      
          Asp Arg Val Thr Ile Thr Cys Ser Ala Ser Gln Asp Ile Ser Asn Tyr 
                      20                  25                  30          
          Leu Asn Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Val Leu Ile 
                  35                  40                  45              
          Tyr Phe Thr Ser Ser Leu His 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 Tyr Ser Thr Val Pro Trp 
                          85                  90                  95      
          Thr Phe Gly Gln 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 Cys 
              210                 
          <![CDATA[<210> 100]]>
          <![CDATA[<211> 712]]>
          <![CDATA[<212> PRT]]>
          <![CDATA[<213> 智人]]>
          <![CDATA[<400> 100]]>
          Glu Val Gln Leu Val Gln Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 
          1               5                   10                  15      
          Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Tyr Asp Phe Thr His Tyr 
                      20                  25                  30          
          Gly Met Asn Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 
                  35                  40                  45              
          Gly Trp Ile Asn Thr Tyr Thr Gly Glu Pro Thr Tyr Ala Ala Asp Phe 
              50                  55                  60                  
          Lys Arg Arg Phe Thr Phe Ser Leu Asp Thr Ser Lys Ser Thr Ala Tyr 
          65                  70                  75                  80  
          Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 
                          85                  90                  95      
          Ala Lys Tyr Pro Tyr Tyr Tyr Gly Thr Ser His Trp Tyr Phe Asp Val 
                      100                 105                 110         
          Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly 
                  115                 120                 125             
          Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly 
              130                 135                 140                 
          Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val 
          145                 150                 155                 160 
          Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe 
                          165                 170                 175     
          Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val 
                      180                 185                 190         
          Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val 
                  195                 200                 205             
          Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys Arg Val Glu Pro Lys 
              210                 215                 220                 
          Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Ala 
          225                 230                 235                 240 
          Ala Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr 
                          245                 250                 255     
          Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val 
                      260                 265                 270         
          Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val 
                  275                 280                 285             
          Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser 
              290                 295                 300                 
          Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu 
          305                 310                 315                 320 
          Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala 
                          325                 330                 335     
          Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro 
                      340                 345                 350         
          Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln 
                  355                 360                 365             
          Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala 
              370                 375                 380                 
          Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr 
          385                 390                 395                 400 
          Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu 
                          405                 410                 415     
          Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser 
                      420                 425                 430         
          Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser 
                  435                 440                 445             
          Leu Ser Pro Gly Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gln Val 
              450                 455                 460                 
          Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala Ser Val 
          465                 470                 475                 480 
          Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Asn Tyr Asp Ile 
                          485                 490                 495     
          Ile Trp Val Arg Gln Ala Pro Gly Gln Cys Leu Glu Trp Met Gly Tyr 
                      500                 505                 510         
          Ile Asn Pro Tyr Asn Asp Gly Thr Lys Tyr Asn Glu Lys Phe Lys Gly 
                  515                 520                 525             
          Arg Val Thr Met Thr Arg Asp Thr Ser Thr Ser Thr Val Tyr Met Glu 
              530                 535                 540                 
          Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys Ala Arg 
          545                 550                 555                 560 
          Leu Leu Lys Tyr Arg Arg Phe Arg Tyr Tyr Ala Ile Asp Tyr Trp Gly 
                          565                 570                 575     
          Gln Gly Thr Thr Val Thr Val Ser Ser Gly Gly Ser Glu Gly Lys Ser 
                      580                 585                 590         
          Ser Gly Ser Gly Ser Glu Ser Lys Ser Thr Gly Gly Ser Asp Ile Gln 
                  595                 600                 605             
          Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly Asp Arg Val 
              610                 615                 620                 
          Thr Ile Thr Cys Arg Thr Ser Glu Asn Val Tyr Ser Asn Leu Ala Trp 
          625                 630                 635                 640 
          Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile Tyr Ala Ala 
                          645                 650                 655     
          Ser Asn Leu Gln Ser Gly Val Pro Ser Arg Phe Ser Gly Ser Gly Ser 
                      660                 665                 670         
          Gly Thr Asp Tyr Thr Phe Thr Ile Ser Ser Leu Gln Pro Glu Asp Ile 
                  675                 680                 685             
          Ala Thr Tyr Tyr Cys Gln His Phe Trp Gly Ser Pro Phe Thr Phe Gly 
              690                 695                 700                 
          Cys Gly Thr Lys Leu Glu Ile Lys 
          705                 710         
          <![CDATA[<210> 101]]>
          <![CDATA[<211> 214]]>
          <![CDATA[<212> PRT]]>
          <![CDATA[<213> 智人]]>
          <![CDATA[<400> 101]]>
          Asp Ile Gln Leu Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly 
          1               5                   10                  15      
          Asp Arg Val Thr Ile Thr Cys Ser Ala Ser Gln Asp Ile Ser Asn Tyr 
                      20                  25                  30          
          Leu Asn Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Val Leu Ile 
                  35                  40                  45              
          Tyr Phe Thr Ser Ser Leu His Ser Gly Val Pro Ser Arg Phe Ser Gly 
              50                  55                  60                  
          Ser Gly Ser Gly Thr Gly Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro 
          65                  70                  75                  80  
          Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Tyr Ser Thr Val Pro Trp 
                          85                  90                  95      
          Thr Phe Gly Gln 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 Cys 
              210                 
          <![CDATA[<210> 102]]>
          <![CDATA[<211> 712]]>
          <![CDATA[<212> PRT]]>
          <![CDATA[<213> 智人]]>
          <![CDATA[<400> 102]]>
          Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 
          1               5                   10                  15      
          Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Tyr Asp Phe Thr His Tyr 
                      20                  25                  30          
          Gly Met Asn Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 
                  35                  40                  45              
          Gly Trp Ile Asn Thr Tyr Thr Gly Glu Pro Thr Tyr Ala Ala Asp Phe 
              50                  55                  60                  
          Lys Arg Arg Phe Thr Phe Ser Leu Asp Thr Ser Lys Ser Thr Ala Tyr 
          65                  70                  75                  80  
          Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 
                          85                  90                  95      
          Ala Lys Tyr Pro Tyr Tyr Tyr Gly Thr Ser His Trp Tyr Phe Asp Val 
                      100                 105                 110         
          Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly 
                  115                 120                 125             
          Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly 
              130                 135                 140                 
          Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val 
          145                 150                 155                 160 
          Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe 
                          165                 170                 175     
          Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val 
                      180                 185                 190         
          Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val 
                  195                 200                 205             
          Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys Arg Val Glu Pro Lys 
              210                 215                 220                 
          Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Ala 
          225                 230                 235                 240 
          Ala Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr 
                          245                 250                 255     
          Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val 
                      260                 265                 270         
          Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val 
                  275                 280                 285             
          Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser 
              290                 295                 300                 
          Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu 
          305                 310                 315                 320 
          Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala 
                          325                 330                 335     
          Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro 
                      340                 345                 350         
          Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln 
                  355                 360                 365             
          Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala 
              370                 375                 380                 
          Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr 
          385                 390                 395                 400 
          Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu 
                          405                 410                 415     
          Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser 
                      420                 425                 430         
          Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser 
                  435                 440                 445             
          Leu Ser Pro Gly Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gln Val 
              450                 455                 460                 
          Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala Ser Val 
          465                 470                 475                 480 
          Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Asn Tyr Asp Ile 
                          485                 490                 495     
          Ile Trp Val Arg Gln Ala Pro Gly Gln Cys Leu Glu Trp Met Gly Tyr 
                      500                 505                 510         
          Ile Asn Pro Tyr Asn Asp Gly Thr Lys Tyr Asn Glu Lys Phe Lys Gly 
                  515                 520                 525             
          Arg Val Thr Met Thr Arg Asp Thr Ser Thr Ser Thr Val Tyr Met Glu 
              530                 535                 540                 
          Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys Ala Arg 
          545                 550                 555                 560 
          Leu Leu Lys Tyr Arg Arg Phe Arg Tyr Tyr Ala Ile Asp Tyr Trp Gly 
                          565                 570                 575     
          Gln Gly Thr Thr Val Thr Val Ser Ser Gly Gly Ser Glu Gly Lys Ser 
                      580                 585                 590         
          Ser Gly Ser Gly Ser Glu Ser Lys Ser Thr Gly Gly Ser Asp Ile Gln 
                  595                 600                 605             
          Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly Asp Arg Val 
              610                 615                 620                 
          Thr Ile Thr Cys Arg Thr Ser Glu Asn Val Tyr Ser Asn Leu Ala Trp 
          625                 630                 635                 640 
          Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile Tyr Ala Ala 
                          645                 650                 655     
          Ser Asn Leu Gln Ser Gly Val Pro Ser Arg Phe Ser Gly Ser Gly Ser 
                      660                 665                 670         
          Gly Thr Asp Tyr Thr Phe Thr Ile Ser Ser Leu Gln Pro Glu Asp Ile 
                  675                 680                 685             
          Ala Thr Tyr Tyr Cys Gln His Phe Trp Gly Ser Pro Phe Thr Phe Gly 
              690                 695                 700                 
          Cys Gly Thr Lys Leu Glu Ile Lys 
          705                 710         
          <![CDATA[<210> 103]]>
          <![CDATA[<211> 214]]>
          <![CDATA[<212> PRT]]>
          <![CDATA[<213> 智人]]>
          <![CDATA[<400> 103]]>
          Asp Ile Gln Leu Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly 
          1               5                   10                  15      
          Asp Arg Val Thr Ile Thr Cys Ser Ala Ser Gln Asp Ile Ser Asn Tyr 
                      20                  25                  30          
          Leu Asn Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Val Leu Ile 
                  35                  40                  45              
          Tyr Phe Thr Ser Ser Leu His Ser Gly Val Pro Ser Arg Phe Ser Gly 
              50                  55                  60                  
          Ser Gly Ser Gly Thr Gly Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro 
          65                  70                  75                  80  
          Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Tyr Ser Thr Val Pro Trp 
                          85                  90                  95      
          Thr Phe Gly Gln 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 Cys 
              210                 
          <![CDATA[<210> 104]]>
          <![CDATA[<211> 712]]>
          <![CDATA[<212> PRT]]>
          <![CDATA[<213> 智人]]>
          <![CDATA[<400> 104]]>
          Gln Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 
          1               5                   10                  15      
          Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Tyr Asp Phe Thr His Tyr 
                      20                  25                  30          
          Gly Met Asn Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 
                  35                  40                  45              
          Gly Trp Ile Asn Thr Tyr Thr Gly Glu Pro Thr Tyr Ala Ala Asp Phe 
              50                  55                  60                  
          Lys Arg Arg Phe Thr Phe Ser Leu Asp Thr Ser Lys Ser Thr Ala Tyr 
          65                  70                  75                  80  
          Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 
                          85                  90                  95      
          Ala Lys Tyr Pro Tyr Tyr Tyr Gly Thr Ser His Trp Tyr Phe Asp Val 
                      100                 105                 110         
          Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly 
                  115                 120                 125             
          Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly 
              130                 135                 140                 
          Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val 
          145                 150                 155                 160 
          Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe 
                          165                 170                 175     
          Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val 
                      180                 185                 190         
          Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val 
                  195                 200                 205             
          Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys Arg Val Glu Pro Lys 
              210                 215                 220                 
          Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Ala 
          225                 230                 235                 240 
          Ala Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr 
                          245                 250                 255     
          Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val 
                      260                 265                 270         
          Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val 
                  275                 280                 285             
          Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser 
              290                 295                 300                 
          Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu 
          305                 310                 315                 320 
          Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala 
                          325                 330                 335     
          Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro 
                      340                 345                 350         
          Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln 
                  355                 360                 365             
          Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala 
              370                 375                 380                 
          Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr 
          385                 390                 395                 400 
          Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu 
                          405                 410                 415     
          Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser 
                      420                 425                 430         
          Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser 
                  435                 440                 445             
          Leu Ser Pro Gly Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gln Val 
              450                 455                 460                 
          Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala Ser Val 
          465                 470                 475                 480 
          Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Asn Tyr Asp Ile 
                          485                 490                 495     
          Ile Trp Val Arg Gln Ala Pro Gly Gln Cys Leu Glu Trp Met Gly Tyr 
                      500                 505                 510         
          Ile Asn Pro Tyr Asn Asp Gly Thr Lys Tyr Asn Glu Lys Phe Lys Gly 
                  515                 520                 525             
          Arg Val Thr Met Thr Arg Asp Thr Ser Thr Ser Thr Val Tyr Met Glu 
              530                 535                 540                 
          Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys Ala Arg 
          545                 550                 555                 560 
          Leu Leu Lys Tyr Arg Arg Phe Arg Tyr Tyr Ala Ile Asp Tyr Trp Gly 
                          565                 570                 575     
          Gln Gly Thr Thr Val Thr Val Ser Ser Gly Gly Ser Glu Gly Lys Ser 
                      580                 585                 590         
          Ser Gly Ser Gly Ser Glu Ser Lys Ser Thr Gly Gly Ser Asp Ile Gln 
                  595                 600                 605             
          Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly Asp Arg Val 
              610                 615                 620                 
          Thr Ile Thr Cys Arg Thr Ser Glu Asn Val Tyr Ser Asn Leu Ala Trp 
          625                 630                 635                 640 
          Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile Tyr Ala Ala 
                          645                 650                 655     
          Ser Asn Leu Gln Ser Gly Val Pro Ser Arg Phe Ser Gly Ser Gly Ser 
                      660                 665                 670         
          Gly Thr Asp Tyr Thr Phe Thr Ile Ser Ser Leu Gln Pro Glu Asp Ile 
                  675                 680                 685             
          Ala Thr Tyr Tyr Cys Gln His Phe Trp Gly Ser Pro Phe Thr Phe Gly 
              690                 695                 700                 
          Cys Gly Thr Lys Leu Glu Ile Lys 
          705                 710         
          <![CDATA[<210> 105]]>
          <![CDATA[<211> 214]]>
          <![CDATA[<212> PRT]]>
          <![CDATA[<213> 智人]]>
          <![CDATA[<400> 105]]>
          Asp Ile Gln Leu Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly 
          1               5                   10                  15      
          Asp Arg Val Thr Ile Thr Cys Ser Ala Ser Gln Asp Ile Ser Asn Tyr 
                      20                  25                  30          
          Leu Asn Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Val Leu Ile 
                  35                  40                  45              
          Tyr Phe Thr Ser Ser Leu His Ser Gly Val Pro Ser Arg Phe Ser Gly 
              50                  55                  60                  
          Ser Gly Ser Gly Thr Gly Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro 
          65                  70                  75                  80  
          Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Tyr Ser Thr Val Pro Trp 
                          85                  90                  95      
          Thr Phe Gly Gln 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 Cys 
              210                 
          <![CDATA[<210> 106]]>
          <![CDATA[<211> 712]]>
          <![CDATA[<212> PRT]]>
          <![CDATA[<213> 智人]]>
          <![CDATA[<400> 106]]>
          Glu Val Gln Leu Val Gln Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 
          1               5                   10                  15      
          Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Tyr Asp Phe Thr His Tyr 
                      20                  25                  30          
          Gly Met Asn Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 
                  35                  40                  45              
          Gly Trp Ile Asn Thr Tyr Thr Gly Glu Pro Thr Tyr Ala Ala Asp Phe 
              50                  55                  60                  
          Lys Arg Arg Phe Thr Phe Ser Leu Asp Thr Ser Lys Ser Thr Ala Tyr 
          65                  70                  75                  80  
          Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 
                          85                  90                  95      
          Ala Lys Tyr Pro Tyr Tyr Tyr Gly Thr Ser His Trp Tyr Phe Asp Val 
                      100                 105                 110         
          Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly 
                  115                 120                 125             
          Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly 
              130                 135                 140                 
          Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val 
          145                 150                 155                 160 
          Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe 
                          165                 170                 175     
          Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val 
                      180                 185                 190         
          Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val 
                  195                 200                 205             
          Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys Arg Val Glu Pro Lys 
              210                 215                 220                 
          Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Ala 
          225                 230                 235                 240 
          Ala Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr 
                          245                 250                 255     
          Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val 
                      260                 265                 270         
          Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val 
                  275                 280                 285             
          Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser 
              290                 295                 300                 
          Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu 
          305                 310                 315                 320 
          Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala 
                          325                 330                 335     
          Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro 
                      340                 345                 350         
          Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln 
                  355                 360                 365             
          Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala 
              370                 375                 380                 
          Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr 
          385                 390                 395                 400 
          Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu 
                          405                 410                 415     
          Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser 
                      420                 425                 430         
          Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser 
                  435                 440                 445             
          Leu Ser Pro Gly Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gln Val 
              450                 455                 460                 
          Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala Ser Val 
          465                 470                 475                 480 
          Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Asn Tyr Asp Ile 
                          485                 490                 495     
          Ile Trp Val Arg Gln Ala Pro Gly Gln Cys Leu Glu Trp Met Gly Tyr 
                      500                 505                 510         
          Ile Asn Pro Tyr Asn Asp Gly Thr Lys Tyr Asn Glu Lys Phe Lys Gly 
                  515                 520                 525             
          Arg Val Thr Met Thr Arg Asp Thr Ser Thr Ser Thr Val Tyr Met Glu 
              530                 535                 540                 
          Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys Ala Arg 
          545                 550                 555                 560 
          Leu Leu Lys Tyr Arg Arg Phe Arg Tyr Tyr Ala Ile Asp Tyr Trp Gly 
                          565                 570                 575     
          Gln Gly Thr Thr Val Thr Val Ser Ser Gly Gly Ser Glu Gly Lys Ser 
                      580                 585                 590         
          Ser Gly Ser Gly Ser Glu Ser Lys Ser Thr Gly Gly Ser Asp Ile Gln 
                  595                 600                 605             
          Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly Asp Arg Val 
              610                 615                 620                 
          Thr Ile Thr Cys Arg Thr Ser Glu Asn Val Tyr Ser Asn Leu Ala Trp 
          625                 630                 635                 640 
          Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile Tyr Ala Ala 
                          645                 650                 655     
          Ser Asn Leu Gln Ser Gly Val Pro Ser Arg Phe Ser Gly Ser Gly Ser 
                      660                 665                 670         
          Gly Thr Asp Tyr Thr Phe Thr Ile Ser Ser Leu Gln Pro Glu Asp Ile 
                  675                 680                 685             
          Ala Thr Tyr Tyr Cys Gln His Phe Trp Gly Ser Pro Phe Thr Phe Gly 
              690                 695                 700                 
          Cys Gly Thr Lys Leu Glu Ile Lys 
          705                 710         
          <![CDATA[<210> 107]]>
          <![CDATA[<211> 214]]>
          <![CDATA[<212> PRT]]>
          <![CDATA[<213> 智人]]>
          <![CDATA[<400> 107]]>
          Asp Ile Gln Leu Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly 
          1               5                   10                  15      
          Asp Arg Val Thr Ile Thr Cys Ser Ala Ser Gln Asp Ile Ser Asn Tyr 
                      20                  25                  30          
          Leu Asn Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Val Leu Ile 
                  35                  40                  45              
          Tyr Phe Thr Ser Ser Leu His Ser Gly Val Pro Ser Arg Phe Ser Gly 
              50                  55                  60                  
          Ser Gly Ser Gly Thr Gly Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro 
          65                  70                  75                  80  
          Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Tyr Ser Thr Val Pro Trp 
                          85                  90                  95      
          Thr Phe Gly Gln 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 Cys 
              210                 
          <![CDATA[<210> 108]]>
          <![CDATA[<211> 712]]>
          <![CDATA[<212> PRT]]>
          <![CDATA[<213> 智人]]>
          <![CDATA[<400> 108]]>
          Gln Val Gln Leu Val Gln Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 
          1               5                   10                  15      
          Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Tyr Asp Phe Thr His Tyr 
                      20                  25                  30          
          Gly Met Asn Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 
                  35                  40                  45              
          Gly Trp Ile Asn Thr Tyr Thr Gly Glu Pro Thr Tyr Ala Ala Asp Phe 
              50                  55                  60                  
          Lys Arg Arg Phe Thr Phe Ser Leu Asp Thr Ser Lys Ser Thr Ala Tyr 
          65                  70                  75                  80  
          Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 
                          85                  90                  95      
          Ala Lys Tyr Pro Tyr Tyr Tyr Gly Thr Ser His Trp Tyr Phe Asp Val 
                      100                 105                 110         
          Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly 
                  115                 120                 125             
          Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly 
              130                 135                 140                 
          Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val 
          145                 150                 155                 160 
          Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe 
                          165                 170                 175     
          Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val 
                      180                 185                 190         
          Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val 
                  195                 200                 205             
          Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys Arg Val Glu Pro Lys 
              210                 215                 220                 
          Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Ala 
          225                 230                 235                 240 
          Ala Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr 
                          245                 250                 255     
          Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val 
                      260                 265                 270         
          Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val 
                  275                 280                 285             
          Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser 
              290                 295                 300                 
          Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu 
          305                 310                 315                 320 
          Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala 
                          325                 330                 335     
          Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro 
                      340                 345                 350         
          Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln 
                  355                 360                 365             
          Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala 
              370                 375                 380                 
          Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr 
          385                 390                 395                 400 
          Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu 
                          405                 410                 415     
          Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser 
                      420                 425                 430         
          Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser 
                  435                 440                 445             
          Leu Ser Pro Gly Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gln Val 
              450                 455                 460                 
          Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala Ser Val 
          465                 470                 475                 480 
          Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Asn Tyr Asp Ile 
                          485                 490                 495     
          Ile Trp Val Arg Gln Ala Pro Gly Gln Cys Leu Glu Trp Met Gly Tyr 
                      500                 505                 510         
          Ile Asn Pro Tyr Asn Asp Gly Thr Lys Tyr Asn Glu Lys Phe Lys Gly 
                  515                 520                 525             
          Arg Val Thr Met Thr Arg Asp Thr Ser Thr Ser Thr Val Tyr Met Glu 
              530                 535                 540                 
          Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys Ala Arg 
          545                 550                 555                 560 
          Leu Leu Lys Tyr Arg Arg Phe Arg Tyr Tyr Ala Ile Asp Tyr Trp Gly 
                          565                 570                 575     
          Gln Gly Thr Thr Val Thr Val Ser Ser Gly Gly Ser Glu Gly Lys Ser 
                      580                 585                 590         
          Ser Gly Ser Gly Ser Glu Ser Lys Ser Thr Gly Gly Ser Asp Ile Gln 
                  595                 600                 605             
          Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly Asp Arg Val 
              610                 615                 620                 
          Thr Ile Thr Cys Arg Thr Ser Glu Asn Val Tyr Ser Asn Leu Ala Trp 
          625                 630                 635                 640 
          Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile Tyr Ala Ala 
                          645                 650                 655     
          Ser Asn Leu Gln Ser Gly Val Pro Ser Arg Phe Ser Gly Ser Gly Ser 
                      660                 665                 670         
          Gly Thr Asp Tyr Thr Phe Thr Ile Ser Ser Leu Gln Pro Glu Asp Ile 
                  675                 680                 685             
          Ala Thr Tyr Tyr Cys Gln His Phe Trp Gly Ser Pro Phe Thr Phe Gly 
              690                 695                 700                 
          Cys Gly Thr Lys Leu Glu Ile Lys 
          705                 710         
          <![CDATA[<210> 109]]>
          <![CDATA[<211> 214]]>
          <![CDATA[<212> PRT]]>
          <![CDATA[<213> 智人]]>
          <![CDATA[<400> 109]]>
          Asp Ile Gln Leu Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly 
          1               5                   10                  15      
          Asp Arg Val Thr Ile Thr Cys Ser Ala Ser Gln Asp Ile Ser Asn Tyr 
                      20                  25                  30          
          Leu Asn Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Val Leu Ile 
                  35                  40                  45              
          Tyr Phe Thr Ser Ser Leu His 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 Tyr Ser Thr Val Pro Trp 
                          85                  90                  95      
          Thr Phe Gly Gln 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 Cys 
              210                 
          <![CDATA[<210> 110]]>
          <![CDATA[<211> 722]]>
          <![CDATA[<212> PRT]]>
          <![CDATA[<213> 智人]]>
          <![CDATA[<400> 110]]>
          Gln Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 
          1               5                   10                  15      
          Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Tyr Asp Phe Thr His Tyr 
                      20                  25                  30          
          Gly Met Asn Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 
                  35                  40                  45              
          Gly Trp Ile Asn Thr Tyr Thr Gly Glu Pro Thr Tyr Ala Ala Asp Phe 
              50                  55                  60                  
          Lys Arg Arg Phe Thr Phe Ser Leu Asp Thr Ser Lys Ser Thr Ala Tyr 
          65                  70                  75                  80  
          Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 
                          85                  90                  95      
          Ala Lys Tyr Pro Tyr Tyr Tyr Gly Thr Ser His Trp Tyr Phe Asp Val 
                      100                 105                 110         
          Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly 
                  115                 120                 125             
          Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly 
              130                 135                 140                 
          Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val 
          145                 150                 155                 160 
          Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe 
                          165                 170                 175     
          Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val 
                      180                 185                 190         
          Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val 
                  195                 200                 205             
          Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys Arg Val Glu Pro Lys 
              210                 215                 220                 
          Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Ala 
          225                 230                 235                 240 
          Ala Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr 
                          245                 250                 255     
          Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val 
                      260                 265                 270         
          Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val 
                  275                 280                 285             
          Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser 
              290                 295                 300                 
          Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu 
          305                 310                 315                 320 
          Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala 
                          325                 330                 335     
          Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro 
                      340                 345                 350         
          Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln 
                  355                 360                 365             
          Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala 
              370                 375                 380                 
          Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr 
          385                 390                 395                 400 
          Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu 
                          405                 410                 415     
          Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser 
                      420                 425                 430         
          Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser 
                  435                 440                 445             
          Leu Ser Pro Gly Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly 
              450                 455                 460                 
          Gly Gly Ser Gly Gly Gly Gly Ser Gln Val Gln Leu Val Gln Ser Gly 
          465                 470                 475                 480 
          Ala Glu Val Lys Lys Pro Gly Ala Ser Val Lys Val Ser Cys Lys Ala 
                          485                 490                 495     
          Ser Gly Tyr Thr Phe Thr Asn Tyr Asp Ile Ile Trp Val Arg Gln Ala 
                      500                 505                 510         
          Pro Gly Gln Cys Leu Glu Trp Met Gly Tyr Ile Asn Pro Tyr Asn Asp 
                  515                 520                 525             
          Gly Thr Lys Tyr Asn Glu Lys Phe Lys Gly Arg Val Thr Met Thr Arg 
              530                 535                 540                 
          Asp Thr Ser Thr Ser Thr Val Tyr Met Glu Leu Ser Ser Leu Arg Ser 
          545                 550                 555                 560 
          Glu Asp Thr Ala Val Tyr Tyr Cys Ala Arg Leu Leu Lys Tyr Arg Arg 
                          565                 570                 575     
          Phe Arg Tyr Tyr Ala Ile Asp Tyr Trp Gly Gln Gly Thr Thr Val Thr 
                      580                 585                 590         
          Val Ser Ser Gly Gly Ser Glu Gly Lys Ser Ser Gly Ser Gly Ser Glu 
                  595                 600                 605             
          Ser Lys Ser Thr Gly Gly Ser Asp Ile Gln Met Thr Gln Ser Pro Ser 
              610                 615                 620                 
          Ser Leu Ser Ala Ser Val Gly Asp Arg Val Thr Ile Thr Cys Arg Thr 
          625                 630                 635                 640 
          Ser Glu Asn Val Tyr Ser Asn Leu Ala Trp Tyr Gln Gln Lys Pro Gly 
                          645                 650                 655     
          Lys Ala Pro Lys Leu Leu Ile Tyr Ala Ala Ser Asn Leu Gln Ser Gly 
                      660                 665                 670         
          Val Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Tyr Thr Phe 
                  675                 680                 685             
          Thr Ile Ser Ser Leu Gln Pro Glu Asp Ile Ala Thr Tyr Tyr Cys Gln 
              690                 695                 700                 
          His Phe Trp Gly Ser Pro Phe Thr Phe Gly Cys Gly Thr Lys Leu Glu 
          705                 710                 715                 720 
          Ile Lys 
          <![CDATA[<210> 111]]>
          <![CDATA[<211> 214]]>
          <![CDATA[<212> PRT]]>
          <![CDATA[<213> 智人]]>
          <![CDATA[<400> 111]]>
          Asp Ile Gln Leu Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly 
          1               5                   10                  15      
          Asp Arg Val Thr Ile Thr Cys Ser Ala Ser Gln Asp Ile Ser Asn Tyr 
                      20                  25                  30          
          Leu Asn Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Val Leu Ile 
                  35                  40                  45              
          Tyr Phe Thr Ser Ser Leu His 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 Tyr Ser Thr Val Pro Trp 
                          85                  90                  95      
          Thr Phe Gly Gln 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 Cys 
              210                 
          <![CDATA[<210> 112]]>
          <![CDATA[<211> 722]]>
          <![CDATA[<212> PRT]]>
          <![CDATA[<213> 智人]]>
          <![CDATA[<400> 112]]>
          Glu Val Gln Leu Val Gln Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 
          1               5                   10                  15      
          Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Tyr Asp Phe Thr His Tyr 
                      20                  25                  30          
          Gly Met Asn Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 
                  35                  40                  45              
          Gly Trp Ile Asn Thr Tyr Thr Gly Glu Pro Thr Tyr Ala Ala Asp Phe 
              50                  55                  60                  
          Lys Arg Arg Phe Thr Phe Ser Leu Asp Thr Ser Lys Ser Thr Ala Tyr 
          65                  70                  75                  80  
          Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 
                          85                  90                  95      
          Ala Lys Tyr Pro Tyr Tyr Tyr Gly Thr Ser His Trp Tyr Phe Asp Val 
                      100                 105                 110         
          Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly 
                  115                 120                 125             
          Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly 
              130                 135                 140                 
          Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val 
          145                 150                 155                 160 
          Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe 
                          165                 170                 175     
          Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val 
                      180                 185                 190         
          Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val 
                  195                 200                 205             
          Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys Arg Val Glu Pro Lys 
              210                 215                 220                 
          Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Ala 
          225                 230                 235                 240 
          Ala Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr 
                          245                 250                 255     
          Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val 
                      260                 265                 270         
          Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val 
                  275                 280                 285             
          Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser 
              290                 295                 300                 
          Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu 
          305                 310                 315                 320 
          Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala 
                          325                 330                 335     
          Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro 
                      340                 345                 350         
          Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln 
                  355                 360                 365             
          Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala 
              370                 375                 380                 
          Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr 
          385                 390                 395                 400 
          Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu 
                          405                 410                 415     
          Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser 
                      420                 425                 430         
          Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser 
                  435                 440                 445             
          Leu Ser Pro Gly Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly 
              450                 455                 460                 
          Gly Gly Ser Gly Gly Gly Gly Ser Gln Val Gln Leu Val Gln Ser Gly 
          465                 470                 475                 480 
          Ala Glu Val Lys Lys Pro Gly Ala Ser Val Lys Val Ser Cys Lys Ala 
                          485                 490                 495     
          Ser Gly Tyr Thr Phe Thr Asn Tyr Asp Ile Ile Trp Val Arg Gln Ala 
                      500                 505                 510         
          Pro Gly Gln Cys Leu Glu Trp Met Gly Tyr Ile Asn Pro Tyr Asn Asp 
                  515                 520                 525             
          Gly Thr Lys Tyr Asn Glu Lys Phe Lys Gly Arg Val Thr Met Thr Arg 
              530                 535                 540                 
          Asp Thr Ser Thr Ser Thr Val Tyr Met Glu Leu Ser Ser Leu Arg Ser 
          545                 550                 555                 560 
          Glu Asp Thr Ala Val Tyr Tyr Cys Ala Arg Leu Leu Lys Tyr Arg Arg 
                          565                 570                 575     
          Phe Arg Tyr Tyr Ala Ile Asp Tyr Trp Gly Gln Gly Thr Thr Val Thr 
                      580                 585                 590         
          Val Ser Ser Gly Gly Ser Glu Gly Lys Ser Ser Gly Ser Gly Ser Glu 
                  595                 600                 605             
          Ser Lys Ser Thr Gly Gly Ser Asp Ile Gln Met Thr Gln Ser Pro Ser 
              610                 615                 620                 
          Ser Leu Ser Ala Ser Val Gly Asp Arg Val Thr Ile Thr Cys Arg Thr 
          625                 630                 635                 640 
          Ser Glu Asn Val Tyr Ser Asn Leu Ala Trp Tyr Gln Gln Lys Pro Gly 
                          645                 650                 655     
          Lys Ala Pro Lys Leu Leu Ile Tyr Ala Ala Ser Asn Leu Gln Ser Gly 
                      660                 665                 670         
          Val Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Tyr Thr Phe 
                  675                 680                 685             
          Thr Ile Ser Ser Leu Gln Pro Glu Asp Ile Ala Thr Tyr Tyr Cys Gln 
              690                 695                 700                 
          His Phe Trp Gly Ser Pro Phe Thr Phe Gly Cys Gly Thr Lys Leu Glu 
          705                 710                 715                 720 
          Ile Lys 
          <![CDATA[<210> 113]]>
          <![CDATA[<211> 214]]>
          <![CDATA[<212> PRT]]>
          <![CDATA[<213> 智人]]>
          <![CDATA[<400> 113]]>
          Asp Ile Gln Leu Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly 
          1               5                   10                  15      
          Asp Arg Val Thr Ile Thr Cys Ser Ala Ser Gln Asp Ile Ser Asn Tyr 
                      20                  25                  30          
          Leu Asn Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Val Leu Ile 
                  35                  40                  45              
          Tyr Phe Thr Ser Ser Leu His Ser Gly Val Pro Ser Arg Phe Ser Gly 
              50                  55                  60                  
          Ser Gly Ser Gly Thr Gly Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro 
          65                  70                  75                  80  
          Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Tyr Ser Thr Val Pro Trp 
                          85                  90                  95      
          Thr Phe Gly Gln 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 Cys 
              210                 
          <![CDATA[<210> 114]]>
          <![CDATA[<211> 722]]>
          <![CDATA[<212> PRT]]>
          <![CDATA[<213> 智人]]>
          <![CDATA[<400> 114]]>
          Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 
          1               5                   10                  15      
          Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Tyr Asp Phe Thr His Tyr 
                      20                  25                  30          
          Gly Met Asn Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 
                  35                  40                  45              
          Gly Trp Ile Asn Thr Tyr Thr Gly Glu Pro Thr Tyr Ala Ala Asp Phe 
              50                  55                  60                  
          Lys Arg Arg Phe Thr Phe Ser Leu Asp Thr Ser Lys Ser Thr Ala Tyr 
          65                  70                  75                  80  
          Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 
                          85                  90                  95      
          Ala Lys Tyr Pro Tyr Tyr Tyr Gly Thr Ser His Trp Tyr Phe Asp Val 
                      100                 105                 110         
          Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly 
                  115                 120                 125             
          Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly 
              130                 135                 140                 
          Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val 
          145                 150                 155                 160 
          Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe 
                          165                 170                 175     
          Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val 
                      180                 185                 190         
          Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val 
                  195                 200                 205             
          Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys Arg Val Glu Pro Lys 
              210                 215                 220                 
          Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Ala 
          225                 230                 235                 240 
          Ala Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr 
                          245                 250                 255     
          Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val 
                      260                 265                 270         
          Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val 
                  275                 280                 285             
          Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser 
              290                 295                 300                 
          Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu 
          305                 310                 315                 320 
          Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala 
                          325                 330                 335     
          Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro 
                      340                 345                 350         
          Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln 
                  355                 360                 365             
          Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala 
              370                 375                 380                 
          Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr 
          385                 390                 395                 400 
          Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu 
                          405                 410                 415     
          Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser 
                      420                 425                 430         
          Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser 
                  435                 440                 445             
          Leu Ser Pro Gly Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly 
              450                 455                 460                 
          Gly Gly Ser Gly Gly Gly Gly Ser Gln Val Gln Leu Val Gln Ser Gly 
          465                 470                 475                 480 
          Ala Glu Val Lys Lys Pro Gly Ala Ser Val Lys Val Ser Cys Lys Ala 
                          485                 490                 495     
          Ser Gly Tyr Thr Phe Thr Asn Tyr Asp Ile Ile Trp Val Arg Gln Ala 
                      500                 505                 510         
          Pro Gly Gln Cys Leu Glu Trp Met Gly Tyr Ile Asn Pro Tyr Asn Asp 
                  515                 520                 525             
          Gly Thr Lys Tyr Asn Glu Lys Phe Lys Gly Arg Val Thr Met Thr Arg 
              530                 535                 540                 
          Asp Thr Ser Thr Ser Thr Val Tyr Met Glu Leu Ser Ser Leu Arg Ser 
          545                 550                 555                 560 
          Glu Asp Thr Ala Val Tyr Tyr Cys Ala Arg Leu Leu Lys Tyr Arg Arg 
                          565                 570                 575     
          Phe Arg Tyr Tyr Ala Ile Asp Tyr Trp Gly Gln Gly Thr Thr Val Thr 
                      580                 585                 590         
          Val Ser Ser Gly Gly Ser Glu Gly Lys Ser Ser Gly Ser Gly Ser Glu 
                  595                 600                 605             
          Ser Lys Ser Thr Gly Gly Ser Asp Ile Gln Met Thr Gln Ser Pro Ser 
              610                 615                 620                 
          Ser Leu Ser Ala Ser Val Gly Asp Arg Val Thr Ile Thr Cys Arg Thr 
          625                 630                 635                 640 
          Ser Glu Asn Val Tyr Ser Asn Leu Ala Trp Tyr Gln Gln Lys Pro Gly 
                          645                 650                 655     
          Lys Ala Pro Lys Leu Leu Ile Tyr Ala Ala Ser Asn Leu Gln Ser Gly 
                      660                 665                 670         
          Val Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Tyr Thr Phe 
                  675                 680                 685             
          Thr Ile Ser Ser Leu Gln Pro Glu Asp Ile Ala Thr Tyr Tyr Cys Gln 
              690                 695                 700                 
          His Phe Trp Gly Ser Pro Phe Thr Phe Gly Cys Gly Thr Lys Leu Glu 
          705                 710                 715                 720 
          Ile Lys 
          <![CDATA[<210> 115]]>
          <![CDATA[<211> 214]]>
          <![CDATA[<212> PRT]]>
          <![CDATA[<213> 智人]]>
          <![CDATA[<400> 115]]>
          Asp Ile Gln Leu Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly 
          1               5                   10                  15      
          Asp Arg Val Thr Ile Thr Cys Ser Ala Ser Gln Asp Ile Ser Asn Tyr 
                      20                  25                  30          
          Leu Asn Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Val Leu Ile 
                  35                  40                  45              
          Tyr Phe Thr Ser Ser Leu His Ser Gly Val Pro Ser Arg Phe Ser Gly 
              50                  55                  60                  
          Ser Gly Ser Gly Thr Gly Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro 
          65                  70                  75                  80  
          Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Tyr Ser Thr Val Pro Trp 
                          85                  90                  95      
          Thr Phe Gly Gln 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 Cys 
              210                 
          <![CDATA[<210> 116]]>
          <![CDATA[<211> 722]]>
          <![CDATA[<212> PRT]]>
          <![CDATA[<213> 智人]]>
          <![CDATA[<400> 116]]>
          Gln Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 
          1               5                   10                  15      
          Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Tyr Asp Phe Thr His Tyr 
                      20                  25                  30          
          Gly Met Asn Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 
                  35                  40                  45              
          Gly Trp Ile Asn Thr Tyr Thr Gly Glu Pro Thr Tyr Ala Ala Asp Phe 
              50                  55                  60                  
          Lys Arg Arg Phe Thr Phe Ser Leu Asp Thr Ser Lys Ser Thr Ala Tyr 
          65                  70                  75                  80  
          Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 
                          85                  90                  95      
          Ala Lys Tyr Pro Tyr Tyr Tyr Gly Thr Ser His Trp Tyr Phe Asp Val 
                      100                 105                 110         
          Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly 
                  115                 120                 125             
          Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly 
              130                 135                 140                 
          Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val 
          145                 150                 155                 160 
          Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe 
                          165                 170                 175     
          Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val 
                      180                 185                 190         
          Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val 
                  195                 200                 205             
          Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys Arg Val Glu Pro Lys 
              210                 215                 220                 
          Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Ala 
          225                 230                 235                 240 
          Ala Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr 
                          245                 250                 255     
          Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val 
                      260                 265                 270         
          Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val 
                  275                 280                 285             
          Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser 
              290                 295                 300                 
          Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu 
          305                 310                 315                 320 
          Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala 
                          325                 330                 335     
          Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro 
                      340                 345                 350         
          Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln 
                  355                 360                 365             
          Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala 
              370                 375                 380                 
          Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr 
          385                 390                 395                 400 
          Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu 
                          405                 410                 415     
          Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser 
                      420                 425                 430         
          Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser 
                  435                 440                 445             
          Leu Ser Pro Gly Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly 
              450                 455                 460                 
          Gly Gly Ser Gly Gly Gly Gly Ser Gln Val Gln Leu Val Gln Ser Gly 
          465                 470                 475                 480 
          Ala Glu Val Lys Lys Pro Gly Ala Ser Val Lys Val Ser Cys Lys Ala 
                          485                 490                 495     
          Ser Gly Tyr Thr Phe Thr Asn Tyr Asp Ile Ile Trp Val Arg Gln Ala 
                      500                 505                 510         
          Pro Gly Gln Cys Leu Glu Trp Met Gly Tyr Ile Asn Pro Tyr Asn Asp 
                  515                 520                 525             
          Gly Thr Lys Tyr Asn Glu Lys Phe Lys Gly Arg Val Thr Met Thr Arg 
              530                 535                 540                 
          Asp Thr Ser Thr Ser Thr Val Tyr Met Glu Leu Ser Ser Leu Arg Ser 
          545                 550                 555                 560 
          Glu Asp Thr Ala Val Tyr Tyr Cys Ala Arg Leu Leu Lys Tyr Arg Arg 
                          565                 570                 575     
          Phe Arg Tyr Tyr Ala Ile Asp Tyr Trp Gly Gln Gly Thr Thr Val Thr 
                      580                 585                 590         
          Val Ser Ser Gly Gly Ser Glu Gly Lys Ser Ser Gly Ser Gly Ser Glu 
                  595                 600                 605             
          Ser Lys Ser Thr Gly Gly Ser Asp Ile Gln Met Thr Gln Ser Pro Ser 
              610                 615                 620                 
          Ser Leu Ser Ala Ser Val Gly Asp Arg Val Thr Ile Thr Cys Arg Thr 
          625                 630                 635                 640 
          Ser Glu Asn Val Tyr Ser Asn Leu Ala Trp Tyr Gln Gln Lys Pro Gly 
                          645                 650                 655     
          Lys Ala Pro Lys Leu Leu Ile Tyr Ala Ala Ser Asn Leu Gln Ser Gly 
                      660                 665                 670         
          Val Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Tyr Thr Phe 
                  675                 680                 685             
          Thr Ile Ser Ser Leu Gln Pro Glu Asp Ile Ala Thr Tyr Tyr Cys Gln 
              690                 695                 700                 
          His Phe Trp Gly Ser Pro Phe Thr Phe Gly Cys Gly Thr Lys Leu Glu 
          705                 710                 715                 720 
          Ile Lys 
          <![CDATA[<210> 117]]>
          <![CDATA[<211> 214]]>
          <![CDATA[<212> PRT]]>
          <![CDATA[<213> 智人]]>
          <![CDATA[<400> 117]]>
          Asp Ile Gln Leu Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly 
          1               5                   10                  15      
          Asp Arg Val Thr Ile Thr Cys Ser Ala Ser Gln Asp Ile Ser Asn Tyr 
                      20                  25                  30          
          Leu Asn Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Val Leu Ile 
                  35                  40                  45              
          Tyr Phe Thr Ser Ser Leu His Ser Gly Val Pro Ser Arg Phe Ser Gly 
              50                  55                  60                  
          Ser Gly Ser Gly Thr Gly Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro 
          65                  70                  75                  80  
          Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Tyr Ser Thr Val Pro Trp 
                          85                  90                  95      
          Thr Phe Gly Gln 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 Cys 
              210                 
          <![CDATA[<210> 118]]>
          <![CDATA[<211> 722]]>
          <![CDATA[<212> PRT]]>
          <![CDATA[<213> 智人]]>
          <![CDATA[<400> 118]]>
          Glu Val Gln Leu Val Gln Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 
          1               5                   10                  15      
          Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Tyr Asp Phe Thr His Tyr 
                      20                  25                  30          
          Gly Met Asn Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 
                  35                  40                  45              
          Gly Trp Ile Asn Thr Tyr Thr Gly Glu Pro Thr Tyr Ala Ala Asp Phe 
              50                  55                  60                  
          Lys Arg Arg Phe Thr Phe Ser Leu Asp Thr Ser Lys Ser Thr Ala Tyr 
          65                  70                  75                  80  
          Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 
                          85                  90                  95      
          Ala Lys Tyr Pro Tyr Tyr Tyr Gly Thr Ser His Trp Tyr Phe Asp Val 
                      100                 105                 110         
          Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly 
                  115                 120                 125             
          Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly 
              130                 135                 140                 
          Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val 
          145                 150                 155                 160 
          Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe 
                          165                 170                 175     
          Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val 
                      180                 185                 190         
          Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val 
                  195                 200                 205             
          Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys Arg Val Glu Pro Lys 
              210                 215                 220                 
          Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Ala 
          225                 230                 235                 240 
          Ala Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr 
                          245                 250                 255     
          Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val 
                      260                 265                 270         
          Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val 
                  275                 280                 285             
          Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser 
              290                 295                 300                 
          Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu 
          305                 310                 315                 320 
          Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala 
                          325                 330                 335     
          Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro 
                      340                 345                 350         
          Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln 
                  355                 360                 365             
          Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala 
              370                 375                 380                 
          Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr 
          385                 390                 395                 400 
          Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu 
                          405                 410                 415     
          Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser 
                      420                 425                 430         
          Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser 
                  435                 440                 445             
          Leu Ser Pro Gly Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly 
              450                 455                 460                 
          Gly Gly Ser Gly Gly Gly Gly Ser Gln Val Gln Leu Val Gln Ser Gly 
          465                 470                 475                 480 
          Ala Glu Val Lys Lys Pro Gly Ala Ser Val Lys Val Ser Cys Lys Ala 
                          485                 490                 495     
          Ser Gly Tyr Thr Phe Thr Asn Tyr Asp Ile Ile Trp Val Arg Gln Ala 
                      500                 505                 510         
          Pro Gly Gln Cys Leu Glu Trp Met Gly Tyr Ile Asn Pro Tyr Asn Asp 
                  515                 520                 525             
          Gly Thr Lys Tyr Asn Glu Lys Phe Lys Gly Arg Val Thr Met Thr Arg 
              530                 535                 540                 
          Asp Thr Ser Thr Ser Thr Val Tyr Met Glu Leu Ser Ser Leu Arg Ser 
          545                 550                 555                 560 
          Glu Asp Thr Ala Val Tyr Tyr Cys Ala Arg Leu Leu Lys Tyr Arg Arg 
                          565                 570                 575     
          Phe Arg Tyr Tyr Ala Ile Asp Tyr Trp Gly Gln Gly Thr Thr Val Thr 
                      580                 585                 590         
          Val Ser Ser Gly Gly Ser Glu Gly Lys Ser Ser Gly Ser Gly Ser Glu 
                  595                 600                 605             
          Ser Lys Ser Thr Gly Gly Ser Asp Ile Gln Met Thr Gln Ser Pro Ser 
              610                 615                 620                 
          Ser Leu Ser Ala Ser Val Gly Asp Arg Val Thr Ile Thr Cys Arg Thr 
          625                 630                 635                 640 
          Ser Glu Asn Val Tyr Ser Asn Leu Ala Trp Tyr Gln Gln Lys Pro Gly 
                          645                 650                 655     
          Lys Ala Pro Lys Leu Leu Ile Tyr Ala Ala Ser Asn Leu Gln Ser Gly 
                      660                 665                 670         
          Val Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Tyr Thr Phe 
                  675                 680                 685             
          Thr Ile Ser Ser Leu Gln Pro Glu Asp Ile Ala Thr Tyr Tyr Cys Gln 
              690                 695                 700                 
          His Phe Trp Gly Ser Pro Phe Thr Phe Gly Cys Gly Thr Lys Leu Glu 
          705                 710                 715                 720 
          Ile Lys 
          <![CDATA[<210> 119]]>
          <![CDATA[<211> 214]]>
          <![CDATA[<212> PRT]]>
          <![CDATA[<213> 智人]]>
          <![CDATA[<400> 119]]>
          Asp Ile Gln Leu Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly 
          1               5                   10                  15      
          Asp Arg Val Thr Ile Thr Cys Ser Ala Ser Gln Asp Ile Ser Asn Tyr 
                      20                  25                  30          
          Leu Asn Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Val Leu Ile 
                  35                  40                  45              
          Tyr Phe Thr Ser Ser Leu His Ser Gly Val Pro Ser Arg Phe Ser Gly 
              50                  55                  60                  
          Ser Gly Ser Gly Thr Gly Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro 
          65                  70                  75                  80  
          Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Tyr Ser Thr Val Pro Trp 
                          85                  90                  95      
          Thr Phe Gly Gln 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 Cys 
              210                 
          <![CDATA[<210> 120]]>
          <![CDATA[<211> 722]]>
          <![CDATA[<212> PRT]]>
          <![CDATA[<213> 智人]]>
          <![CDATA[<400> 120]]>
          Gln Val Gln Leu Val Gln Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 
          1               5                   10                  15      
          Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Tyr Asp Phe Thr His Tyr 
                      20                  25                  30          
          Gly Met Asn Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 
                  35                  40                  45              
          Gly Trp Ile Asn Thr Tyr Thr Gly Glu Pro Thr Tyr Ala Ala Asp Phe 
              50                  55                  60                  
          Lys Arg Arg Phe Thr Phe Ser Leu Asp Thr Ser Lys Ser Thr Ala Tyr 
          65                  70                  75                  80  
          Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 
                          85                  90                  95      
          Ala Lys Tyr Pro Tyr Tyr Tyr Gly Thr Ser His Trp Tyr Phe Asp Val 
                      100                 105                 110         
          Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly 
                  115                 120                 125             
          Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly 
              130                 135                 140                 
          Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val 
          145                 150                 155                 160 
          Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe 
                          165                 170                 175     
          Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val 
                      180                 185                 190         
          Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val 
                  195                 200                 205             
          Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys Arg Val Glu Pro Lys 
              210                 215                 220                 
          Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Ala 
          225                 230                 235                 240 
          Ala Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr 
                          245                 250                 255     
          Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val 
                      260                 265                 270         
          Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val 
                  275                 280                 285             
          Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser 
              290                 295                 300                 
          Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu 
          305                 310                 315                 320 
          Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala 
                          325                 330                 335     
          Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro 
                      340                 345                 350         
          Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln 
                  355                 360                 365             
          Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala 
              370                 375                 380                 
          Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr 
          385                 390                 395                 400 
          Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu 
                          405                 410                 415     
          Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser 
                      420                 425                 430         
          Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser 
                  435                 440                 445             
          Leu Ser Pro Gly Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly 
              450                 455                 460                 
          Gly Gly Ser Gly Gly Gly Gly Ser Gln Val Gln Leu Val Gln Ser Gly 
          465                 470                 475                 480 
          Ala Glu Val Lys Lys Pro Gly Ala Ser Val Lys Val Ser Cys Lys Ala 
                          485                 490                 495     
          Ser Gly Tyr Thr Phe Thr Asn Tyr Asp Ile Ile Trp Val Arg Gln Ala 
                      500                 505                 510         
          Pro Gly Gln Cys Leu Glu Trp Met Gly Tyr Ile Asn Pro Tyr Asn Asp 
                  515                 520                 525             
          Gly Thr Lys Tyr Asn Glu Lys Phe Lys Gly Arg Val Thr Met Thr Arg 
              530                 535                 540                 
          Asp Thr Ser Thr Ser Thr Val Tyr Met Glu Leu Ser Ser Leu Arg Ser 
          545                 550                 555                 560 
          Glu Asp Thr Ala Val Tyr Tyr Cys Ala Arg Leu Leu Lys Tyr Arg Arg 
                          565                 570                 575     
          Phe Arg Tyr Tyr Ala Ile Asp Tyr Trp Gly Gln Gly Thr Thr Val Thr 
                      580                 585                 590         
          Val Ser Ser Gly Gly Ser Glu Gly Lys Ser Ser Gly Ser Gly Ser Glu 
                  595                 600                 605             
          Ser Lys Ser Thr Gly Gly Ser Asp Ile Gln Met Thr Gln Ser Pro Ser 
              610                 615                 620                 
          Ser Leu Ser Ala Ser Val Gly Asp Arg Val Thr Ile Thr Cys Arg Thr 
          625                 630                 635                 640 
          Ser Glu Asn Val Tyr Ser Asn Leu Ala Trp Tyr Gln Gln Lys Pro Gly 
                          645                 650                 655     
          Lys Ala Pro Lys Leu Leu Ile Tyr Ala Ala Ser Asn Leu Gln Ser Gly 
                      660                 665                 670         
          Val Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Tyr Thr Phe 
                  675                 680                 685             
          Thr Ile Ser Ser Leu Gln Pro Glu Asp Ile Ala Thr Tyr Tyr Cys Gln 
              690                 695                 700                 
          His Phe Trp Gly Ser Pro Phe Thr Phe Gly Cys Gly Thr Lys Leu Glu 
          705                 710                 715                 720 
          Ile Lys 
          <![CDATA[<210> 121]]>
          <![CDATA[<211> 214]]>
          <![CDATA[<212> PRT]]>
          <![CDATA[<213> 智人]]>
          <![CDATA[<400> 121]]>
          Asp Ile Gln Leu Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly 
          1               5                   10                  15      
          Asp Arg Val Thr Ile Thr Cys Ser Ala Ser Gln Asp Ile Ser Asn Tyr 
                      20                  25                  30          
          Leu Asn Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Val Leu Ile 
                  35                  40                  45              
          Tyr Phe Thr Ser Ser Leu His 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 Tyr Ser Thr Val Pro Trp 
                          85                  90                  95      
          Thr Phe Gly Gln 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 Cys 
              210                 
          <![CDATA[<210> 122]]>
          <![CDATA[<211> 712]]>
          <![CDATA[<212> PRT]]>
          <![CDATA[<213> 智人]]>
          <![CDATA[<400> 122]]>
          Gln Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 
          1               5                   10                  15      
          Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Tyr Asp Phe Thr His Tyr 
                      20                  25                  30          
          Gly Met Asn Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 
                  35                  40                  45              
          Gly Trp Ile Asn Thr Tyr Thr Gly Glu Pro Thr Tyr Ala Ala Asp Phe 
              50                  55                  60                  
          Lys Arg Arg Phe Thr Phe Ser Leu Asp Thr Ser Lys Ser Thr Ala Tyr 
          65                  70                  75                  80  
          Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 
                          85                  90                  95      
          Ala Lys Tyr Pro Tyr Tyr Tyr Gly Thr Ser His Trp Tyr Phe Asp Val 
                      100                 105                 110         
          Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly 
                  115                 120                 125             
          Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly 
              130                 135                 140                 
          Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val 
          145                 150                 155                 160 
          Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe 
                          165                 170                 175     
          Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val 
                      180                 185                 190         
          Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val 
                  195                 200                 205             
          Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys Arg Val Glu Pro Lys 
              210                 215                 220                 
          Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Ala 
          225                 230                 235                 240 
          Ala Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr 
                          245                 250                 255     
          Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val 
                      260                 265                 270         
          Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val 
                  275                 280                 285             
          Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser 
              290                 295                 300                 
          Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu 
          305                 310                 315                 320 
          Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala 
                          325                 330                 335     
          Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro 
                      340                 345                 350         
          Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln 
                  355                 360                 365             
          Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala 
              370                 375                 380                 
          Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr 
          385                 390                 395                 400 
          Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu 
                          405                 410                 415     
          Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser 
                      420                 425                 430         
          Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser 
                  435                 440                 445             
          Leu Ser Pro Gly Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Asp Ile 
              450                 455                 460                 
          Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly Asp Arg 
          465                 470                 475                 480 
          Val Thr Ile Thr Cys Arg Thr Ser Glu Asn Val Tyr Ser Asn Leu Ala 
                          485                 490                 495     
          Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile Tyr Ala 
                      500                 505                 510         
          Ala Ser Asn Leu Gln Ser Gly Val Pro Ser Arg Phe Ser Gly Ser Gly 
                  515                 520                 525             
          Ser Gly Thr Asp Tyr Thr Phe Thr Ile Ser Ser Leu Gln Pro Glu Asp 
              530                 535                 540                 
          Ile Ala Thr Tyr Tyr Cys Gln His Phe Trp Gly Ser Pro Phe Thr Phe 
          545                 550                 555                 560 
          Gly Cys Gly Thr Lys Leu Glu Ile Lys Gly Gly Ser Glu Gly Lys Ser 
                          565                 570                 575     
          Ser Gly Ser Gly Ser Glu Ser Lys Ser Thr Gly Gly Ser Gln Val Gln 
                      580                 585                 590         
          Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala Ser Val Lys 
                  595                 600                 605             
          Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Asn Tyr Asp Ile Ile 
              610                 615                 620                 
          Trp Val Arg Gln Ala Pro Gly Gln Cys Leu Glu Trp Met Gly Tyr Ile 
          625                 630                 635                 640 
          Asn Pro Tyr Asn Asp Gly Thr Lys Tyr Asn Glu Lys Phe Lys Gly Arg 
                          645                 650                 655     
          Val Thr Met Thr Arg Asp Thr Ser Thr Ser Thr Val Tyr Met Glu Leu 
                      660                 665                 670         
          Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys Ala Arg Leu 
                  675                 680                 685             
          Leu Lys Tyr Arg Arg Phe Arg Tyr Tyr Ala Ile Asp Tyr Trp Gly Gln 
              690                 695                 700                 
          Gly Thr Thr Val Thr Val Ser Ser 
          705                 710         
          <![CDATA[<210> 123]]>
          <![CDATA[<211> 214]]>
          <![CDATA[<212> PRT]]>
          <![CDATA[<213> 智人]]>
          <![CDATA[<400> 123]]>
          Asp Ile Gln Leu Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly 
          1               5                   10                  15      
          Asp Arg Val Thr Ile Thr Cys Ser Ala Ser Gln Asp Ile Ser Asn Tyr 
                      20                  25                  30          
          Leu Asn Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Val Leu Ile 
                  35                  40                  45              
          Tyr Phe Thr Ser Ser Leu His 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 Tyr Ser Thr Val Pro Trp 
                          85                  90                  95      
          Thr Phe Gly Gln 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 Cys 
              210                 
          <![CDATA[<210> 124]]>
          <![CDATA[<211> 712]]>
          <![CDATA[<212> PRT]]>
          <![CDATA[<213> 智人]]>
          <![CDATA[<400> 124]]>
          Glu Val Gln Leu Val Gln Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 
          1               5                   10                  15      
          Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Tyr Asp Phe Thr His Tyr 
                      20                  25                  30          
          Gly Met Asn Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 
                  35                  40                  45              
          Gly Trp Ile Asn Thr Tyr Thr Gly Glu Pro Thr Tyr Ala Ala Asp Phe 
              50                  55                  60                  
          Lys Arg Arg Phe Thr Phe Ser Leu Asp Thr Ser Lys Ser Thr Ala Tyr 
          65                  70                  75                  80  
          Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 
                          85                  90                  95      
          Ala Lys Tyr Pro Tyr Tyr Tyr Gly Thr Ser His Trp Tyr Phe Asp Val 
                      100                 105                 110         
          Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly 
                  115                 120                 125             
          Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly 
              130                 135                 140                 
          Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val 
          145                 150                 155                 160 
          Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe 
                          165                 170                 175     
          Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val 
                      180                 185                 190         
          Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val 
                  195                 200                 205             
          Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys Arg Val Glu Pro Lys 
              210                 215                 220                 
          Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Ala 
          225                 230                 235                 240 
          Ala Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr 
                          245                 250                 255     
          Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val 
                      260                 265                 270         
          Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val 
                  275                 280                 285             
          Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser 
              290                 295                 300                 
          Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu 
          305                 310                 315                 320 
          Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala 
                          325                 330                 335     
          Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro 
                      340                 345                 350         
          Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln 
                  355                 360                 365             
          Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala 
              370                 375                 380                 
          Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr 
          385                 390                 395                 400 
          Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu 
                          405                 410                 415     
          Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser 
                      420                 425                 430         
          Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser 
                  435                 440                 445             
          Leu Ser Pro Gly Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Asp Ile 
              450                 455                 460                 
          Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly Asp Arg 
          465                 470                 475                 480 
          Val Thr Ile Thr Cys Arg Thr Ser Glu Asn Val Tyr Ser Asn Leu Ala 
                          485                 490                 495     
          Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile Tyr Ala 
                      500                 505                 510         
          Ala Ser Asn Leu Gln Ser Gly Val Pro Ser Arg Phe Ser Gly Ser Gly 
                  515                 520                 525             
          Ser Gly Thr Asp Tyr Thr Phe Thr Ile Ser Ser Leu Gln Pro Glu Asp 
              530                 535                 540                 
          Ile Ala Thr Tyr Tyr Cys Gln His Phe Trp Gly Ser Pro Phe Thr Phe 
          545                 550                 555                 560 
          Gly Cys Gly Thr Lys Leu Glu Ile Lys Gly Gly Ser Glu Gly Lys Ser 
                          565                 570                 575     
          Ser Gly Ser Gly Ser Glu Ser Lys Ser Thr Gly Gly Ser Gln Val Gln 
                      580                 585                 590         
          Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala Ser Val Lys 
                  595                 600                 605             
          Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Asn Tyr Asp Ile Ile 
              610                 615                 620                 
          Trp Val Arg Gln Ala Pro Gly Gln Cys Leu Glu Trp Met Gly Tyr Ile 
          625                 630                 635                 640 
          Asn Pro Tyr Asn Asp Gly Thr Lys Tyr Asn Glu Lys Phe Lys Gly Arg 
                          645                 650                 655     
          Val Thr Met Thr Arg Asp Thr Ser Thr Ser Thr Val Tyr Met Glu Leu 
                      660                 665                 670         
          Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys Ala Arg Leu 
                  675                 680                 685             
          Leu Lys Tyr Arg Arg Phe Arg Tyr Tyr Ala Ile Asp Tyr Trp Gly Gln 
              690                 695                 700                 
          Gly Thr Thr Val Thr Val Ser Ser 
          705                 710         
          <![CDATA[<210> 125]]>
          <![CDATA[<211> 214]]>
          <![CDATA[<212> PRT]]>
          <![CDATA[<213> 智人]]>
          <![CDATA[<400> 125]]>
          Asp Ile Gln Leu Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly 
          1               5                   10                  15      
          Asp Arg Val Thr Ile Thr Cys Ser Ala Ser Gln Asp Ile Ser Asn Tyr 
                      20                  25                  30          
          Leu Asn Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Val Leu Ile 
                  35                  40                  45              
          Tyr Phe Thr Ser Ser Leu His Ser Gly Val Pro Ser Arg Phe Ser Gly 
              50                  55                  60                  
          Ser Gly Ser Gly Thr Gly Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro 
          65                  70                  75                  80  
          Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Tyr Ser Thr Val Pro Trp 
                          85                  90                  95      
          Thr Phe Gly Gln 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 Cys 
              210                 
          <![CDATA[<210> 126]]>
          <![CDATA[<211> 712]]>
          <![CDATA[<212> PRT]]>
          <![CDATA[<213> 智人]]>
          <![CDATA[<400> 126]]>
          Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 
          1               5                   10                  15      
          Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Tyr Asp Phe Thr His Tyr 
                      20                  25                  30          
          Gly Met Asn Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 
                  35                  40                  45              
          Gly Trp Ile Asn Thr Tyr Thr Gly Glu Pro Thr Tyr Ala Ala Asp Phe 
              50                  55                  60                  
          Lys Arg Arg Phe Thr Phe Ser Leu Asp Thr Ser Lys Ser Thr Ala Tyr 
          65                  70                  75                  80  
          Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 
                          85                  90                  95      
          Ala Lys Tyr Pro Tyr Tyr Tyr Gly Thr Ser His Trp Tyr Phe Asp Val 
                      100                 105                 110         
          Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly 
                  115                 120                 125             
          Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly 
              130                 135                 140                 
          Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val 
          145                 150                 155                 160 
          Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe 
                          165                 170                 175     
          Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val 
                      180                 185                 190         
          Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val 
                  195                 200                 205             
          Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys Arg Val Glu Pro Lys 
              210                 215                 220                 
          Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Ala 
          225                 230                 235                 240 
          Ala Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr 
                          245                 250                 255     
          Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val 
                      260                 265                 270         
          Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val 
                  275                 280                 285             
          Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser 
              290                 295                 300                 
          Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu 
          305                 310                 315                 320 
          Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala 
                          325                 330                 335     
          Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro 
                      340                 345                 350         
          Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln 
                  355                 360                 365             
          Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala 
              370                 375                 380                 
          Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr 
          385                 390                 395                 400 
          Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu 
                          405                 410                 415     
          Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser 
                      420                 425                 430         
          Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser 
                  435                 440                 445             
          Leu Ser Pro Gly Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Asp Ile 
              450                 455                 460                 
          Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly Asp Arg 
          465                 470                 475                 480 
          Val Thr Ile Thr Cys Arg Thr Ser Glu Asn Val Tyr Ser Asn Leu Ala 
                          485                 490                 495     
          Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile Tyr Ala 
                      500                 505                 510         
          Ala Ser Asn Leu Gln Ser Gly Val Pro Ser Arg Phe Ser Gly Ser Gly 
                  515                 520                 525             
          Ser Gly Thr Asp Tyr Thr Phe Thr Ile Ser Ser Leu Gln Pro Glu Asp 
              530                 535                 540                 
          Ile Ala Thr Tyr Tyr Cys Gln His Phe Trp Gly Ser Pro Phe Thr Phe 
          545                 550                 555                 560 
          Gly Cys Gly Thr Lys Leu Glu Ile Lys Gly Gly Ser Glu Gly Lys Ser 
                          565                 570                 575     
          Ser Gly Ser Gly Ser Glu Ser Lys Ser Thr Gly Gly Ser Gln Val Gln 
                      580                 585                 590         
          Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala Ser Val Lys 
                  595                 600                 605             
          Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Asn Tyr Asp Ile Ile 
              610                 615                 620                 
          Trp Val Arg Gln Ala Pro Gly Gln Cys Leu Glu Trp Met Gly Tyr Ile 
          625                 630                 635                 640 
          Asn Pro Tyr Asn Asp Gly Thr Lys Tyr Asn Glu Lys Phe Lys Gly Arg 
                          645                 650                 655     
          Val Thr Met Thr Arg Asp Thr Ser Thr Ser Thr Val Tyr Met Glu Leu 
                      660                 665                 670         
          Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys Ala Arg Leu 
                  675                 680                 685             
          Leu Lys Tyr Arg Arg Phe Arg Tyr Tyr Ala Ile Asp Tyr Trp Gly Gln 
              690                 695                 700                 
          Gly Thr Thr Val Thr Val Ser Ser 
          705                 710         
          <![CDATA[<210> 127]]>
          <![CDATA[<211> 214]]>
          <![CDATA[<212> PRT]]>
          <![CDATA[<213> 智人]]>
          <![CDATA[<400> 127]]>
          Asp Ile Gln Leu Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly 
          1               5                   10                  15      
          Asp Arg Val Thr Ile Thr Cys Ser Ala Ser Gln Asp Ile Ser Asn Tyr 
                      20                  25                  30          
          Leu Asn Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Val Leu Ile 
                  35                  40                  45              
          Tyr Phe Thr Ser Ser Leu His Ser Gly Val Pro Ser Arg Phe Ser Gly 
              50                  55                  60                  
          Ser Gly Ser Gly Thr Gly Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro 
          65                  70                  75                  80  
          Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Tyr Ser Thr Val Pro Trp 
                          85                  90                  95      
          Thr Phe Gly Gln 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 Cys 
              210                 
          <![CDATA[<210> 128]]>
          <![CDATA[<211> 712]]>
          <![CDATA[<212> PRT]]>
          <![CDATA[<213> 智人]]>
          <![CDATA[<400> 128]]>
          Gln Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 
          1               5                   10                  15      
          Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Tyr Asp Phe Thr His Tyr 
                      20                  25                  30          
          Gly Met Asn Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 
                  35                  40                  45              
          Gly Trp Ile Asn Thr Tyr Thr Gly Glu Pro Thr Tyr Ala Ala Asp Phe 
              50                  55                  60                  
          Lys Arg Arg Phe Thr Phe Ser Leu Asp Thr Ser Lys Ser Thr Ala Tyr 
          65                  70                  75                  80  
          Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 
                          85                  90                  95      
          Ala Lys Tyr Pro Tyr Tyr Tyr Gly Thr Ser His Trp Tyr Phe Asp Val 
                      100                 105                 110         
          Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly 
                  115                 120                 125             
          Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly 
              130                 135                 140                 
          Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val 
          145                 150                 155                 160 
          Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe 
                          165                 170                 175     
          Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val 
                      180                 185                 190         
          Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val 
                  195                 200                 205             
          Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys Arg Val Glu Pro Lys 
              210                 215                 220                 
          Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Ala 
          225                 230                 235                 240 
          Ala Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr 
                          245                 250                 255     
          Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val 
                      260                 265                 270         
          Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val 
                  275                 280                 285             
          Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser 
              290                 295                 300                 
          Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu 
          305                 310                 315                 320 
          Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala 
                          325                 330                 335     
          Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro 
                      340                 345                 350         
          Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln 
                  355                 360                 365             
          Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala 
              370                 375                 380                 
          Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr 
          385                 390                 395                 400 
          Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu 
                          405                 410                 415     
          Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser 
                      420                 425                 430         
          Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser 
                  435                 440                 445             
          Leu Ser Pro Gly Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Asp Ile 
              450                 455                 460                 
          Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly Asp Arg 
          465                 470                 475                 480 
          Val Thr Ile Thr Cys Arg Thr Ser Glu Asn Val Tyr Ser Asn Leu Ala 
                          485                 490                 495     
          Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile Tyr Ala 
                      500                 505                 510         
          Ala Ser Asn Leu Gln Ser Gly Val Pro Ser Arg Phe Ser Gly Ser Gly 
                  515                 520                 525             
          Ser Gly Thr Asp Tyr Thr Phe Thr Ile Ser Ser Leu Gln Pro Glu Asp 
              530                 535                 540                 
          Ile Ala Thr Tyr Tyr Cys Gln His Phe Trp Gly Ser Pro Phe Thr Phe 
          545                 550                 555                 560 
          Gly Cys Gly Thr Lys Leu Glu Ile Lys Gly Gly Ser Glu Gly Lys Ser 
                          565                 570                 575     
          Ser Gly Ser Gly Ser Glu Ser Lys Ser Thr Gly Gly Ser Gln Val Gln 
                      580                 585                 590         
          Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala Ser Val Lys 
                  595                 600                 605             
          Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Asn Tyr Asp Ile Ile 
              610                 615                 620                 
          Trp Val Arg Gln Ala Pro Gly Gln Cys Leu Glu Trp Met Gly Tyr Ile 
          625                 630                 635                 640 
          Asn Pro Tyr Asn Asp Gly Thr Lys Tyr Asn Glu Lys Phe Lys Gly Arg 
                          645                 650                 655     
          Val Thr Met Thr Arg Asp Thr Ser Thr Ser Thr Val Tyr Met Glu Leu 
                      660                 665                 670         
          Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys Ala Arg Leu 
                  675                 680                 685             
          Leu Lys Tyr Arg Arg Phe Arg Tyr Tyr Ala Ile Asp Tyr Trp Gly Gln 
              690                 695                 700                 
          Gly Thr Thr Val Thr Val Ser Ser 
          705                 710         
          <![CDATA[<210> 129]]>
          <![CDATA[<211> 214]]>
          <![CDATA[<212> PRT]]>
          <![CDATA[<213> 智人]]>
          <![CDATA[<400> 129]]>
          Asp Ile Gln Leu Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly 
          1               5                   10                  15      
          Asp Arg Val Thr Ile Thr Cys Ser Ala Ser Gln Asp Ile Ser Asn Tyr 
                      20                  25                  30          
          Leu Asn Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Val Leu Ile 
                  35                  40                  45              
          Tyr Phe Thr Ser Ser Leu His Ser Gly Val Pro Ser Arg Phe Ser Gly 
              50                  55                  60                  
          Ser Gly Ser Gly Thr Gly Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro 
          65                  70                  75                  80  
          Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Tyr Ser Thr Val Pro Trp 
                          85                  90                  95      
          Thr Phe Gly Gln 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 Cys 
              210                 
          <![CDATA[<210> 130]]>
          <![CDATA[<211> 712]]>
          <![CDATA[<212> PRT]]>
          <![CDATA[<213> 智人]]>
          <![CDATA[<400> 130]]>
          Glu Val Gln Leu Val Gln Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 
          1               5                   10                  15      
          Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Tyr Asp Phe Thr His Tyr 
                      20                  25                  30          
          Gly Met Asn Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 
                  35                  40                  45              
          Gly Trp Ile Asn Thr Tyr Thr Gly Glu Pro Thr Tyr Ala Ala Asp Phe 
              50                  55                  60                  
          Lys Arg Arg Phe Thr Phe Ser Leu Asp Thr Ser Lys Ser Thr Ala Tyr 
          65                  70                  75                  80  
          Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 
                          85                  90                  95      
          Ala Lys Tyr Pro Tyr Tyr Tyr Gly Thr Ser His Trp Tyr Phe Asp Val 
                      100                 105                 110         
          Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly 
                  115                 120                 125             
          Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly 
              130                 135                 140                 
          Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val 
          145                 150                 155                 160 
          Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe 
                          165                 170                 175     
          Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val 
                      180                 185                 190         
          Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val 
                  195                 200                 205             
          Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys Arg Val Glu Pro Lys 
              210                 215                 220                 
          Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Ala 
          225                 230                 235                 240 
          Ala Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr 
                          245                 250                 255     
          Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val 
                      260                 265                 270         
          Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val 
                  275                 280                 285             
          Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser 
              290                 295                 300                 
          Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu 
          305                 310                 315                 320 
          Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala 
                          325                 330                 335     
          Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro 
                      340                 345                 350         
          Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln 
                  355                 360                 365             
          Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala 
              370                 375                 380                 
          Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr 
          385                 390                 395                 400 
          Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu 
                          405                 410                 415     
          Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser 
                      420                 425                 430         
          Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser 
                  435                 440                 445             
          Leu Ser Pro Gly Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Asp Ile 
              450                 455                 460                 
          Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly Asp Arg 
          465                 470                 475                 480 
          Val Thr Ile Thr Cys Arg Thr Ser Glu Asn Val Tyr Ser Asn Leu Ala 
                          485                 490                 495     
          Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile Tyr Ala 
                      500                 505                 510         
          Ala Ser Asn Leu Gln Ser Gly Val Pro Ser Arg Phe Ser Gly Ser Gly 
                  515                 520                 525             
          Ser Gly Thr Asp Tyr Thr Phe Thr Ile Ser Ser Leu Gln Pro Glu Asp 
              530                 535                 540                 
          Ile Ala Thr Tyr Tyr Cys Gln His Phe Trp Gly Ser Pro Phe Thr Phe 
          545                 550                 555                 560 
          Gly Cys Gly Thr Lys Leu Glu Ile Lys Gly Gly Ser Glu Gly Lys Ser 
                          565                 570                 575     
          Ser Gly Ser Gly Ser Glu Ser Lys Ser Thr Gly Gly Ser Gln Val Gln 
                      580                 585                 590         
          Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala Ser Val Lys 
                  595                 600                 605             
          Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Asn Tyr Asp Ile Ile 
              610                 615                 620                 
          Trp Val Arg Gln Ala Pro Gly Gln Cys Leu Glu Trp Met Gly Tyr Ile 
          625                 630                 635                 640 
          Asn Pro Tyr Asn Asp Gly Thr Lys Tyr Asn Glu Lys Phe Lys Gly Arg 
                          645                 650                 655     
          Val Thr Met Thr Arg Asp Thr Ser Thr Ser Thr Val Tyr Met Glu Leu 
                      660                 665                 670         
          Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys Ala Arg Leu 
                  675                 680                 685             
          Leu Lys Tyr Arg Arg Phe Arg Tyr Tyr Ala Ile Asp Tyr Trp Gly Gln 
              690                 695                 700                 
          Gly Thr Thr Val Thr Val Ser Ser 
          705                 710         
          <![CDATA[<210> 131]]>
          <![CDATA[<211> 214]]>
          <![CDATA[<212> PRT]]>
          <![CDATA[<213> 智人]]>
          <![CDATA[<400> 131]]>
          Asp Ile Gln Leu Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly 
          1               5                   10                  15      
          Asp Arg Val Thr Ile Thr Cys Ser Ala Ser Gln Asp Ile Ser Asn Tyr 
                      20                  25                  30          
          Leu Asn Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Val Leu Ile 
                  35                  40                  45              
          Tyr Phe Thr Ser Ser Leu His Ser Gly Val Pro Ser Arg Phe Ser Gly 
              50                  55                  60                  
          Ser Gly Ser Gly Thr Gly Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro 
          65                  70                  75                  80  
          Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Tyr Ser Thr Val Pro Trp 
                          85                  90                  95      
          Thr Phe Gly Gln 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 Cys 
              210                 
          <![CDATA[<210> 132]]>
          <![CDATA[<211> 712]]>
          <![CDATA[<212> PRT]]>
          <![CDATA[<213> 智人]]>
          <![CDATA[<400> 132]]>
          Gln Val Gln Leu Val Gln Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 
          1               5                   10                  15      
          Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Tyr Asp Phe Thr His Tyr 
                      20                  25                  30          
          Gly Met Asn Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 
                  35                  40                  45              
          Gly Trp Ile Asn Thr Tyr Thr Gly Glu Pro Thr Tyr Ala Ala Asp Phe 
              50                  55                  60                  
          Lys Arg Arg Phe Thr Phe Ser Leu Asp Thr Ser Lys Ser Thr Ala Tyr 
          65                  70                  75                  80  
          Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 
                          85                  90                  95      
          Ala Lys Tyr Pro Tyr Tyr Tyr Gly Thr Ser His Trp Tyr Phe Asp Val 
                      100                 105                 110         
          Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly 
                  115                 120                 125             
          Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly 
              130                 135                 140                 
          Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val 
          145                 150                 155                 160 
          Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe 
                          165                 170                 175     
          Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val 
                      180                 185                 190         
          Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val 
                  195                 200                 205             
          Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys Arg Val Glu Pro Lys 
              210                 215                 220                 
          Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Ala 
          225                 230                 235                 240 
          Ala Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr 
                          245                 250                 255     
          Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val 
                      260                 265                 270         
          Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val 
                  275                 280                 285             
          Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser 
              290                 295                 300                 
          Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu 
          305                 310                 315                 320 
          Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala 
                          325                 330                 335     
          Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro 
                      340                 345                 350         
          Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln 
                  355                 360                 365             
          Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala 
              370                 375                 380                 
          Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr 
          385                 390                 395                 400 
          Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu 
                          405                 410                 415     
          Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser 
                      420                 425                 430         
          Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser 
                  435                 440                 445             
          Leu Ser Pro Gly Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Asp Ile 
              450                 455                 460                 
          Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly Asp Arg 
          465                 470                 475                 480 
          Val Thr Ile Thr Cys Arg Thr Ser Glu Asn Val Tyr Ser Asn Leu Ala 
                          485                 490                 495     
          Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile Tyr Ala 
                      500                 505                 510         
          Ala Ser Asn Leu Gln Ser Gly Val Pro Ser Arg Phe Ser Gly Ser Gly 
                  515                 520                 525             
          Ser Gly Thr Asp Tyr Thr Phe Thr Ile Ser Ser Leu Gln Pro Glu Asp 
              530                 535                 540                 
          Ile Ala Thr Tyr Tyr Cys Gln His Phe Trp Gly Ser Pro Phe Thr Phe 
          545                 550                 555                 560 
          Gly Cys Gly Thr Lys Leu Glu Ile Lys Gly Gly Ser Glu Gly Lys Ser 
                          565                 570                 575     
          Ser Gly Ser Gly Ser Glu Ser Lys Ser Thr Gly Gly Ser Gln Val Gln 
                      580                 585                 590         
          Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala Ser Val Lys 
                  595                 600                 605             
          Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Asn Tyr Asp Ile Ile 
              610                 615                 620                 
          Trp Val Arg Gln Ala Pro Gly Gln Cys Leu Glu Trp Met Gly Tyr Ile 
          625                 630                 635                 640 
          Asn Pro Tyr Asn Asp Gly Thr Lys Tyr Asn Glu Lys Phe Lys Gly Arg 
                          645                 650                 655     
          Val Thr Met Thr Arg Asp Thr Ser Thr Ser Thr Val Tyr Met Glu Leu 
                      660                 665                 670         
          Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys Ala Arg Leu 
                  675                 680                 685             
          Leu Lys Tyr Arg Arg Phe Arg Tyr Tyr Ala Ile Asp Tyr Trp Gly Gln 
              690                 695                 700                 
          Gly Thr Thr Val Thr Val Ser Ser 
          705                 710         
          <![CDATA[<210> 133]]>
          <![CDATA[<211> 214]]>
          <![CDATA[<212> PRT]]>
          <![CDATA[<213> 智人]]>
          <![CDATA[<400> 133]]>
          Asp Ile Gln Leu Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly 
          1               5                   10                  15      
          Asp Arg Val Thr Ile Thr Cys Ser Ala Ser Gln Asp Ile Ser Asn Tyr 
                      20                  25                  30          
          Leu Asn Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Val Leu Ile 
                  35                  40                  45              
          Tyr Phe Thr Ser Ser Leu His 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 Tyr Ser Thr Val Pro Trp 
                          85                  90                  95      
          Thr Phe Gly Gln 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 Cys 
              210                 
          <![CDATA[<210> 134]]>
          <![CDATA[<211> 722]]>
          <![CDATA[<212> PRT]]>
          <![CDATA[<213> 智人]]>
          <![CDATA[<400> 134]]>
          Gln Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 
          1               5                   10                  15      
          Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Tyr Asp Phe Thr His Tyr 
                      20                  25                  30          
          Gly Met Asn Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 
                  35                  40                  45              
          Gly Trp Ile Asn Thr Tyr Thr Gly Glu Pro Thr Tyr Ala Ala Asp Phe 
              50                  55                  60                  
          Lys Arg Arg Phe Thr Phe Ser Leu Asp Thr Ser Lys Ser Thr Ala Tyr 
          65                  70                  75                  80  
          Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 
                          85                  90                  95      
          Ala Lys Tyr Pro Tyr Tyr Tyr Gly Thr Ser His Trp Tyr Phe Asp Val 
                      100                 105                 110         
          Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly 
                  115                 120                 125             
          Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly 
              130                 135                 140                 
          Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val 
          145                 150                 155                 160 
          Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe 
                          165                 170                 175     
          Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val 
                      180                 185                 190         
          Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val 
                  195                 200                 205             
          Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys Arg Val Glu Pro Lys 
              210                 215                 220                 
          Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Ala 
          225                 230                 235                 240 
          Ala Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr 
                          245                 250                 255     
          Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val 
                      260                 265                 270         
          Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val 
                  275                 280                 285             
          Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser 
              290                 295                 300                 
          Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu 
          305                 310                 315                 320 
          Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala 
                          325                 330                 335     
          Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro 
                      340                 345                 350         
          Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln 
                  355                 360                 365             
          Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala 
              370                 375                 380                 
          Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr 
          385                 390                 395                 400 
          Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu 
                          405                 410                 415     
          Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser 
                      420                 425                 430         
          Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser 
                  435                 440                 445             
          Leu Ser Pro Gly Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly 
              450                 455                 460                 
          Gly Gly Ser Gly Gly Gly Gly Ser Asp Ile Gln Met Thr Gln Ser Pro 
          465                 470                 475                 480 
          Ser Ser Leu Ser Ala Ser Val Gly Asp Arg Val Thr Ile Thr Cys Arg 
                          485                 490                 495     
          Thr Ser Glu Asn Val Tyr Ser Asn Leu Ala Trp Tyr Gln Gln Lys Pro 
                      500                 505                 510         
          Gly Lys Ala Pro Lys Leu Leu Ile Tyr Ala Ala Ser Asn Leu Gln Ser 
                  515                 520                 525             
          Gly Val Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Tyr Thr 
              530                 535                 540                 
          Phe Thr Ile Ser Ser Leu Gln Pro Glu Asp Ile Ala Thr Tyr Tyr Cys 
          545                 550                 555                 560 
          Gln His Phe Trp Gly Ser Pro Phe Thr Phe Gly Cys Gly Thr Lys Leu 
                          565                 570                 575     
          Glu Ile Lys Gly Gly Ser Glu Gly Lys Ser Ser Gly Ser Gly Ser Glu 
                      580                 585                 590         
          Ser Lys Ser Thr Gly Gly Ser Gln Val Gln Leu Val Gln Ser Gly Ala 
                  595                 600                 605             
          Glu Val Lys Lys Pro Gly Ala Ser Val Lys Val Ser Cys Lys Ala Ser 
              610                 615                 620                 
          Gly Tyr Thr Phe Thr Asn Tyr Asp Ile Ile Trp Val Arg Gln Ala Pro 
          625                 630                 635                 640 
          Gly Gln Cys Leu Glu Trp Met Gly Tyr Ile Asn Pro Tyr Asn Asp Gly 
                          645                 650                 655     
          Thr Lys Tyr Asn Glu Lys Phe Lys Gly Arg Val Thr Met Thr Arg Asp 
                      660                 665                 670         
          Thr Ser Thr Ser Thr Val Tyr Met Glu Leu Ser Ser Leu Arg Ser Glu 
                  675                 680                 685             
          Asp Thr Ala Val Tyr Tyr Cys Ala Arg Leu Leu Lys Tyr Arg Arg Phe 
              690                 695                 700                 
          Arg Tyr Tyr Ala Ile Asp Tyr Trp Gly Gln Gly Thr Thr Val Thr Val 
          705                 710                 715                 720 
          Ser Ser 
          <![CDATA[<210> 135]]>
          <![CDATA[<211> 214]]>
          <![CDATA[<212> PRT]]>
          <![CDATA[<213> 智人]]>
          <![CDATA[<400> 135]]>
          Asp Ile Gln Leu Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly 
          1               5                   10                  15      
          Asp Arg Val Thr Ile Thr Cys Ser Ala Ser Gln Asp Ile Ser Asn Tyr 
                      20                  25                  30          
          Leu Asn Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Val Leu Ile 
                  35                  40                  45              
          Tyr Phe Thr Ser Ser Leu His 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 Tyr Ser Thr Val Pro Trp 
                          85                  90                  95      
          Thr Phe Gly Gln 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 Cys 
              210                 
          <![CDATA[<210> 136]]>
          <![CDATA[<211> 722]]>
          <![CDATA[<212> PRT]]>
          <![CDATA[<213> 智人]]>
          <![CDATA[<400> 136]]>
          Glu Val Gln Leu Val Gln Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 
          1               5                   10                  15      
          Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Tyr Asp Phe Thr His Tyr 
                      20                  25                  30          
          Gly Met Asn Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 
                  35                  40                  45              
          Gly Trp Ile Asn Thr Tyr Thr Gly Glu Pro Thr Tyr Ala Ala Asp Phe 
              50                  55                  60                  
          Lys Arg Arg Phe Thr Phe Ser Leu Asp Thr Ser Lys Ser Thr Ala Tyr 
          65                  70                  75                  80  
          Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 
                          85                  90                  95      
          Ala Lys Tyr Pro Tyr Tyr Tyr Gly Thr Ser His Trp Tyr Phe Asp Val 
                      100                 105                 110         
          Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly 
                  115                 120                 125             
          Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly 
              130                 135                 140                 
          Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val 
          145                 150                 155                 160 
          Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe 
                          165                 170                 175     
          Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val 
                      180                 185                 190         
          Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val 
                  195                 200                 205             
          Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys Arg Val Glu Pro Lys 
              210                 215                 220                 
          Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Ala 
          225                 230                 235                 240 
          Ala Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr 
                          245                 250                 255     
          Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val 
                      260                 265                 270         
          Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val 
                  275                 280                 285             
          Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser 
              290                 295                 300                 
          Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu 
          305                 310                 315                 320 
          Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala 
                          325                 330                 335     
          Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro 
                      340                 345                 350         
          Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln 
                  355                 360                 365             
          Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala 
              370                 375                 380                 
          Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr 
          385                 390                 395                 400 
          Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu 
                          405                 410                 415     
          Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser 
                      420                 425                 430         
          Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser 
                  435                 440                 445             
          Leu Ser Pro Gly Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly 
              450                 455                 460                 
          Gly Gly Ser Gly Gly Gly Gly Ser Asp Ile Gln Met Thr Gln Ser Pro 
          465                 470                 475                 480 
          Ser Ser Leu Ser Ala Ser Val Gly Asp Arg Val Thr Ile Thr Cys Arg 
                          485                 490                 495     
          Thr Ser Glu Asn Val Tyr Ser Asn Leu Ala Trp Tyr Gln Gln Lys Pro 
                      500                 505                 510         
          Gly Lys Ala Pro Lys Leu Leu Ile Tyr Ala Ala Ser Asn Leu Gln Ser 
                  515                 520                 525             
          Gly Val Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Tyr Thr 
              530                 535                 540                 
          Phe Thr Ile Ser Ser Leu Gln Pro Glu Asp Ile Ala Thr Tyr Tyr Cys 
          545                 550                 555                 560 
          Gln His Phe Trp Gly Ser Pro Phe Thr Phe Gly Cys Gly Thr Lys Leu 
                          565                 570                 575     
          Glu Ile Lys Gly Gly Ser Glu Gly Lys Ser Ser Gly Ser Gly Ser Glu 
                      580                 585                 590         
          Ser Lys Ser Thr Gly Gly Ser Gln Val Gln Leu Val Gln Ser Gly Ala 
                  595                 600                 605             
          Glu Val Lys Lys Pro Gly Ala Ser Val Lys Val Ser Cys Lys Ala Ser 
              610                 615                 620                 
          Gly Tyr Thr Phe Thr Asn Tyr Asp Ile Ile Trp Val Arg Gln Ala Pro 
          625                 630                 635                 640 
          Gly Gln Cys Leu Glu Trp Met Gly Tyr Ile Asn Pro Tyr Asn Asp Gly 
                          645                 650                 655     
          Thr Lys Tyr Asn Glu Lys Phe Lys Gly Arg Val Thr Met Thr Arg Asp 
                      660                 665                 670         
          Thr Ser Thr Ser Thr Val Tyr Met Glu Leu Ser Ser Leu Arg Ser Glu 
                  675                 680                 685             
          Asp Thr Ala Val Tyr Tyr Cys Ala Arg Leu Leu Lys Tyr Arg Arg Phe 
              690                 695                 700                 
          Arg Tyr Tyr Ala Ile Asp Tyr Trp Gly Gln Gly Thr Thr Val Thr Val 
          705                 710                 715                 720 
          Ser Ser 
          <![CDATA[<210> 137]]>
          <![CDATA[<211> 214]]>
          <![CDATA[<212> PRT]]>
          <![CDATA[<213> 智人]]>
          <![CDATA[<400> 137]]>
          Asp Ile Gln Leu Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly 
          1               5                   10                  15      
          Asp Arg Val Thr Ile Thr Cys Ser Ala Ser Gln Asp Ile Ser Asn Tyr 
                      20                  25                  30          
          Leu Asn Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Val Leu Ile 
                  35                  40                  45              
          Tyr Phe Thr Ser Ser Leu His Ser Gly Val Pro Ser Arg Phe Ser Gly 
              50                  55                  60                  
          Ser Gly Ser Gly Thr Gly Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro 
          65                  70                  75                  80  
          Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Tyr Ser Thr Val Pro Trp 
                          85                  90                  95      
          Thr Phe Gly Gln 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 Cys 
              210                 
          <![CDATA[<210> 138]]>
          <![CDATA[<211> 722]]>
          <![CDATA[<212> PRT]]>
          <![CDATA[<213> 智人]]>
          <![CDATA[<400> 138]]>
          Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 
          1               5                   10                  15      
          Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Tyr Asp Phe Thr His Tyr 
                      20                  25                  30          
          Gly Met Asn Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 
                  35                  40                  45              
          Gly Trp Ile Asn Thr Tyr Thr Gly Glu Pro Thr Tyr Ala Ala Asp Phe 
              50                  55                  60                  
          Lys Arg Arg Phe Thr Phe Ser Leu Asp Thr Ser Lys Ser Thr Ala Tyr 
          65                  70                  75                  80  
          Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 
                          85                  90                  95      
          Ala Lys Tyr Pro Tyr Tyr Tyr Gly Thr Ser His Trp Tyr Phe Asp Val 
                      100                 105                 110         
          Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly 
                  115                 120                 125             
          Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly 
              130                 135                 140                 
          Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val 
          145                 150                 155                 160 
          Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe 
                          165                 170                 175     
          Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val 
                      180                 185                 190         
          Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val 
                  195                 200                 205             
          Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys Arg Val Glu Pro Lys 
              210                 215                 220                 
          Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Ala 
          225                 230                 235                 240 
          Ala Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr 
                          245                 250                 255     
          Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val 
                      260                 265                 270         
          Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val 
                  275                 280                 285             
          Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser 
              290                 295                 300                 
          Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu 
          305                 310                 315                 320 
          Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala 
                          325                 330                 335     
          Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro 
                      340                 345                 350         
          Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln 
                  355                 360                 365             
          Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala 
              370                 375                 380                 
          Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr 
          385                 390                 395                 400 
          Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu 
                          405                 410                 415     
          Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser 
                      420                 425                 430         
          Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser 
                  435                 440                 445             
          Leu Ser Pro Gly Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly 
              450                 455                 460                 
          Gly Gly Ser Gly Gly Gly Gly Ser Asp Ile Gln Met Thr Gln Ser Pro 
          465                 470                 475                 480 
          Ser Ser Leu Ser Ala Ser Val Gly Asp Arg Val Thr Ile Thr Cys Arg 
                          485                 490                 495     
          Thr Ser Glu Asn Val Tyr Ser Asn Leu Ala Trp Tyr Gln Gln Lys Pro 
                      500                 505                 510         
          Gly Lys Ala Pro Lys Leu Leu Ile Tyr Ala Ala Ser Asn Leu Gln Ser 
                  515                 520                 525             
          Gly Val Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Tyr Thr 
              530                 535                 540                 
          Phe Thr Ile Ser Ser Leu Gln Pro Glu Asp Ile Ala Thr Tyr Tyr Cys 
          545                 550                 555                 560 
          Gln His Phe Trp Gly Ser Pro Phe Thr Phe Gly Cys Gly Thr Lys Leu 
                          565                 570                 575     
          Glu Ile Lys Gly Gly Ser Glu Gly Lys Ser Ser Gly Ser Gly Ser Glu 
                      580                 585                 590         
          Ser Lys Ser Thr Gly Gly Ser Gln Val Gln Leu Val Gln Ser Gly Ala 
                  595                 600                 605             
          Glu Val Lys Lys Pro Gly Ala Ser Val Lys Val Ser Cys Lys Ala Ser 
              610                 615                 620                 
          Gly Tyr Thr Phe Thr Asn Tyr Asp Ile Ile Trp Val Arg Gln Ala Pro 
          625                 630                 635                 640 
          Gly Gln Cys Leu Glu Trp Met Gly Tyr Ile Asn Pro Tyr Asn Asp Gly 
                          645                 650                 655     
          Thr Lys Tyr Asn Glu Lys Phe Lys Gly Arg Val Thr Met Thr Arg Asp 
                      660                 665                 670         
          Thr Ser Thr Ser Thr Val Tyr Met Glu Leu Ser Ser Leu Arg Ser Glu 
                  675                 680                 685             
          Asp Thr Ala Val Tyr Tyr Cys Ala Arg Leu Leu Lys Tyr Arg Arg Phe 
              690                 695                 700                 
          Arg Tyr Tyr Ala Ile Asp Tyr Trp Gly Gln Gly Thr Thr Val Thr Val 
          705                 710                 715                 720 
          Ser Ser 
          <![CDATA[<210> 139]]>
          <![CDATA[<211> 214]]>
          <![CDATA[<212> PRT]]>
          <![CDATA[<213> 智人]]>
          <![CDATA[<400> 139]]>
          Asp Ile Gln Leu Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly 
          1               5                   10                  15      
          Asp Arg Val Thr Ile Thr Cys Ser Ala Ser Gln Asp Ile Ser Asn Tyr 
                      20                  25                  30          
          Leu Asn Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Val Leu Ile 
                  35                  40                  45              
          Tyr Phe Thr Ser Ser Leu His Ser Gly Val Pro Ser Arg Phe Ser Gly 
              50                  55                  60                  
          Ser Gly Ser Gly Thr Gly Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro 
          65                  70                  75                  80  
          Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Tyr Ser Thr Val Pro Trp 
                          85                  90                  95      
          Thr Phe Gly Gln 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 Cys 
              210                 
          <![CDATA[<210> 140]]>
          <![CDATA[<211> 722]]>
          <![CDATA[<212> PRT]]>
          <![CDATA[<213> 智人]]>
          <![CDATA[<400> 140]]>
          Gln Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 
          1               5                   10                  15      
          Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Tyr Asp Phe Thr His Tyr 
                      20                  25                  30          
          Gly Met Asn Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 
                  35                  40                  45              
          Gly Trp Ile Asn Thr Tyr Thr Gly Glu Pro Thr Tyr Ala Ala Asp Phe 
              50                  55                  60                  
          Lys Arg Arg Phe Thr Phe Ser Leu Asp Thr Ser Lys Ser Thr Ala Tyr 
          65                  70                  75                  80  
          Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 
                          85                  90                  95      
          Ala Lys Tyr Pro Tyr Tyr Tyr Gly Thr Ser His Trp Tyr Phe Asp Val 
                      100                 105                 110         
          Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly 
                  115                 120                 125             
          Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly 
              130                 135                 140                 
          Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val 
          145                 150                 155                 160 
          Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe 
                          165                 170                 175     
          Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val 
                      180                 185                 190         
          Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val 
                  195                 200                 205             
          Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys Arg Val Glu Pro Lys 
              210                 215                 220                 
          Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Ala 
          225                 230                 235                 240 
          Ala Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr 
                          245                 250                 255     
          Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val 
                      260                 265                 270         
          Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val 
                  275                 280                 285             
          Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser 
              290                 295                 300                 
          Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu 
          305                 310                 315                 320 
          Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala 
                          325                 330                 335     
          Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro 
                      340                 345                 350         
          Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln 
                  355                 360                 365             
          Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala 
              370                 375                 380                 
          Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr 
          385                 390                 395                 400 
          Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu 
                          405                 410                 415     
          Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser 
                      420                 425                 430         
          Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser 
                  435                 440                 445             
          Leu Ser Pro Gly Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly 
              450                 455                 460                 
          Gly Gly Ser Gly Gly Gly Gly Ser Asp Ile Gln Met Thr Gln Ser Pro 
          465                 470                 475                 480 
          Ser Ser Leu Ser Ala Ser Val Gly Asp Arg Val Thr Ile Thr Cys Arg 
                          485                 490                 495     
          Thr Ser Glu Asn Val Tyr Ser Asn Leu Ala Trp Tyr Gln Gln Lys Pro 
                      500                 505                 510         
          Gly Lys Ala Pro Lys Leu Leu Ile Tyr Ala Ala Ser Asn Leu Gln Ser 
                  515                 520                 525             
          Gly Val Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Tyr Thr 
              530                 535                 540                 
          Phe Thr Ile Ser Ser Leu Gln Pro Glu Asp Ile Ala Thr Tyr Tyr Cys 
          545                 550                 555                 560 
          Gln His Phe Trp Gly Ser Pro Phe Thr Phe Gly Cys Gly Thr Lys Leu 
                          565                 570                 575     
          Glu Ile Lys Gly Gly Ser Glu Gly Lys Ser Ser Gly Ser Gly Ser Glu 
                      580                 585                 590         
          Ser Lys Ser Thr Gly Gly Ser Gln Val Gln Leu Val Gln Ser Gly Ala 
                  595                 600                 605             
          Glu Val Lys Lys Pro Gly Ala Ser Val Lys Val Ser Cys Lys Ala Ser 
              610                 615                 620                 
          Gly Tyr Thr Phe Thr Asn Tyr Asp Ile Ile Trp Val Arg Gln Ala Pro 
          625                 630                 635                 640 
          Gly Gln Cys Leu Glu Trp Met Gly Tyr Ile Asn Pro Tyr Asn Asp Gly 
                          645                 650                 655     
          Thr Lys Tyr Asn Glu Lys Phe Lys Gly Arg Val Thr Met Thr Arg Asp 
                      660                 665                 670         
          Thr Ser Thr Ser Thr Val Tyr Met Glu Leu Ser Ser Leu Arg Ser Glu 
                  675                 680                 685             
          Asp Thr Ala Val Tyr Tyr Cys Ala Arg Leu Leu Lys Tyr Arg Arg Phe 
              690                 695                 700                 
          Arg Tyr Tyr Ala Ile Asp Tyr Trp Gly Gln Gly Thr Thr Val Thr Val 
          705                 710                 715                 720 
          Ser Ser 
          <![CDATA[<210> 141]]>
          <![CDATA[<211> 214]]>
          <![CDATA[<212> PRT]]>
          <![CDATA[<213> 智人]]>
          <![CDATA[<400> 141]]>
          Asp Ile Gln Leu Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly 
          1               5                   10                  15      
          Asp Arg Val Thr Ile Thr Cys Ser Ala Ser Gln Asp Ile Ser Asn Tyr 
                      20                  25                  30          
          Leu Asn Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Val Leu Ile 
                  35                  40                  45              
          Tyr Phe Thr Ser Ser Leu His Ser Gly Val Pro Ser Arg Phe Ser Gly 
              50                  55                  60                  
          Ser Gly Ser Gly Thr Gly Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro 
          65                  70                  75                  80  
          Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Tyr Ser Thr Val Pro Trp 
                          85                  90                  95      
          Thr Phe Gly Gln 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 Cys 
              210                 
          <![CDATA[<210> 142]]>
          <![CDATA[<211> 722]]>
          <![CDATA[<212> PRT]]>
          <![CDATA[<213> 智人]]>
          <![CDATA[<400> 142]]>
          Glu Val Gln Leu Val Gln Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 
          1               5                   10                  15      
          Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Tyr Asp Phe Thr His Tyr 
                      20                  25                  30          
          Gly Met Asn Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 
                  35                  40                  45              
          Gly Trp Ile Asn Thr Tyr Thr Gly Glu Pro Thr Tyr Ala Ala Asp Phe 
              50                  55                  60                  
          Lys Arg Arg Phe Thr Phe Ser Leu Asp Thr Ser Lys Ser Thr Ala Tyr 
          65                  70                  75                  80  
          Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 
                          85                  90                  95      
          Ala Lys Tyr Pro Tyr Tyr Tyr Gly Thr Ser His Trp Tyr Phe Asp Val 
                      100                 105                 110         
          Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly 
                  115                 120                 125             
          Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly 
              130                 135                 140                 
          Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val 
          145                 150                 155                 160 
          Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe 
                          165                 170                 175     
          Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val 
                      180                 185                 190         
          Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val 
                  195                 200                 205             
          Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys Arg Val Glu Pro Lys 
              210                 215                 220                 
          Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Ala 
          225                 230                 235                 240 
          Ala Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr 
                          245                 250                 255     
          Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val 
                      260                 265                 270         
          Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val 
                  275                 280                 285             
          Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser 
              290                 295                 300                 
          Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu 
          305                 310                 315                 320 
          Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala 
                          325                 330                 335     
          Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro 
                      340                 345                 350         
          Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln 
                  355                 360                 365             
          Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala 
              370                 375                 380                 
          Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr 
          385                 390                 395                 400 
          Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu 
                          405                 410                 415     
          Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser 
                      420                 425                 430         
          Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser 
                  435                 440                 445             
          Leu Ser Pro Gly Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly 
              450                 455                 460                 
          Gly Gly Ser Gly Gly Gly Gly Ser Asp Ile Gln Met Thr Gln Ser Pro 
          465                 470                 475                 480 
          Ser Ser Leu Ser Ala Ser Val Gly Asp Arg Val Thr Ile Thr Cys Arg 
                          485                 490                 495     
          Thr Ser Glu Asn Val Tyr Ser Asn Leu Ala Trp Tyr Gln Gln Lys Pro 
                      500                 505                 510         
          Gly Lys Ala Pro Lys Leu Leu Ile Tyr Ala Ala Ser Asn Leu Gln Ser 
                  515                 520                 525             
          Gly Val Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Tyr Thr 
              530                 535                 540                 
          Phe Thr Ile Ser Ser Leu Gln Pro Glu Asp Ile Ala Thr Tyr Tyr Cys 
          545                 550                 555                 560 
          Gln His Phe Trp Gly Ser Pro Phe Thr Phe Gly Cys Gly Thr Lys Leu 
                          565                 570                 575     
          Glu Ile Lys Gly Gly Ser Glu Gly Lys Ser Ser Gly Ser Gly Ser Glu 
                      580                 585                 590         
          Ser Lys Ser Thr Gly Gly Ser Gln Val Gln Leu Val Gln Ser Gly Ala 
                  595                 600                 605             
          Glu Val Lys Lys Pro Gly Ala Ser Val Lys Val Ser Cys Lys Ala Ser 
              610                 615                 620                 
          Gly Tyr Thr Phe Thr Asn Tyr Asp Ile Ile Trp Val Arg Gln Ala Pro 
          625                 630                 635                 640 
          Gly Gln Cys Leu Glu Trp Met Gly Tyr Ile Asn Pro Tyr Asn Asp Gly 
                          645                 650                 655     
          Thr Lys Tyr Asn Glu Lys Phe Lys Gly Arg Val Thr Met Thr Arg Asp 
                      660                 665                 670         
          Thr Ser Thr Ser Thr Val Tyr Met Glu Leu Ser Ser Leu Arg Ser Glu 
                  675                 680                 685             
          Asp Thr Ala Val Tyr Tyr Cys Ala Arg Leu Leu Lys Tyr Arg Arg Phe 
              690                 695                 700                 
          Arg Tyr Tyr Ala Ile Asp Tyr Trp Gly Gln Gly Thr Thr Val Thr Val 
          705                 710                 715                 720 
          Ser Ser 
          <![CDATA[<210> 143]]>
          <![CDATA[<211> 214]]>
          <![CDATA[<212> PRT]]>
          <![CDATA[<213> 智人]]>
          <![CDATA[<400> 143]]>
          Asp Ile Gln Leu Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly 
          1               5                   10                  15      
          Asp Arg Val Thr Ile Thr Cys Ser Ala Ser Gln Asp Ile Ser Asn Tyr 
                      20                  25                  30          
          Leu Asn Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Val Leu Ile 
                  35                  40                  45              
          Tyr Phe Thr Ser Ser Leu His Ser Gly Val Pro Ser Arg Phe Ser Gly 
              50                  55                  60                  
          Ser Gly Ser Gly Thr Gly Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro 
          65                  70                  75                  80  
          Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Tyr Ser Thr Val Pro Trp 
                          85                  90                  95      
          Thr Phe Gly Gln 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 Cys 
              210                 
          <![CDATA[<210> 144]]>
          <![CDATA[<211> 722]]>
          <![CDATA[<212> PRT]]>
          <![CDATA[<213> 智人]]>
          <![CDATA[<400> 144]]>
          Gln Val Gln Leu Val Gln Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 
          1               5                   10                  15      
          Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Tyr Asp Phe Thr His Tyr 
                      20                  25                  30          
          Gly Met Asn Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 
                  35                  40                  45              
          Gly Trp Ile Asn Thr Tyr Thr Gly Glu Pro Thr Tyr Ala Ala Asp Phe 
              50                  55                  60                  
          Lys Arg Arg Phe Thr Phe Ser Leu Asp Thr Ser Lys Ser Thr Ala Tyr 
          65                  70                  75                  80  
          Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 
                          85                  90                  95      
          Ala Lys Tyr Pro Tyr Tyr Tyr Gly Thr Ser His Trp Tyr Phe Asp Val 
                      100                 105                 110         
          Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly 
                  115                 120                 125             
          Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly 
              130                 135                 140                 
          Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val 
          145                 150                 155                 160 
          Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe 
                          165                 170                 175     
          Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val 
                      180                 185                 190         
          Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val 
                  195                 200                 205             
          Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys Arg Val Glu Pro Lys 
              210                 215                 220                 
          Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Ala 
          225                 230                 235                 240 
          Ala Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr 
                          245                 250                 255     
          Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val 
                      260                 265                 270         
          Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val 
                  275                 280                 285             
          Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser 
              290                 295                 300                 
          Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu 
          305                 310                 315                 320 
          Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala 
                          325                 330                 335     
          Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro 
                      340                 345                 350         
          Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln 
                  355                 360                 365             
          Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala 
              370                 375                 380                 
          Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr 
          385                 390                 395                 400 
          Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu 
                          405                 410                 415     
          Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser 
                      420                 425                 430         
          Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser 
                  435                 440                 445             
          Leu Ser Pro Gly Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly 
              450                 455                 460                 
          Gly Gly Ser Gly Gly Gly Gly Ser Asp Ile Gln Met Thr Gln Ser Pro 
          465                 470                 475                 480 
          Ser Ser Leu Ser Ala Ser Val Gly Asp Arg Val Thr Ile Thr Cys Arg 
                          485                 490                 495     
          Thr Ser Glu Asn Val Tyr Ser Asn Leu Ala Trp Tyr Gln Gln Lys Pro 
                      500                 505                 510         
          Gly Lys Ala Pro Lys Leu Leu Ile Tyr Ala Ala Ser Asn Leu Gln Ser 
                  515                 520                 525             
          Gly Val Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Tyr Thr 
              530                 535                 540                 
          Phe Thr Ile Ser Ser Leu Gln Pro Glu Asp Ile Ala Thr Tyr Tyr Cys 
          545                 550                 555                 560 
          Gln His Phe Trp Gly Ser Pro Phe Thr Phe Gly Cys Gly Thr Lys Leu 
                          565                 570                 575     
          Glu Ile Lys Gly Gly Ser Glu Gly Lys Ser Ser Gly Ser Gly Ser Glu 
                      580                 585                 590         
          Ser Lys Ser Thr Gly Gly Ser Gln Val Gln Leu Val Gln Ser Gly Ala 
                  595                 600                 605             
          Glu Val Lys Lys Pro Gly Ala Ser Val Lys Val Ser Cys Lys Ala Ser 
              610                 615                 620                 
          Gly Tyr Thr Phe Thr Asn Tyr Asp Ile Ile Trp Val Arg Gln Ala Pro 
          625                 630                 635                 640 
          Gly Gln Cys Leu Glu Trp Met Gly Tyr Ile Asn Pro Tyr Asn Asp Gly 
                          645                 650                 655     
          Thr Lys Tyr Asn Glu Lys Phe Lys Gly Arg Val Thr Met Thr Arg Asp 
                      660                 665                 670         
          Thr Ser Thr Ser Thr Val Tyr Met Glu Leu Ser Ser Leu Arg Ser Glu 
                  675                 680                 685             
          Asp Thr Ala Val Tyr Tyr Cys Ala Arg Leu Leu Lys Tyr Arg Arg Phe 
              690                 695                 700                 
          Arg Tyr Tyr Ala Ile Asp Tyr Trp Gly Gln Gly Thr Thr Val Thr Val 
          705                 710                 715                 720 
          Ser Ser 
          <![CDATA[<210> 145]]>
          <![CDATA[<211> 11]]>
          <![CDATA[<212> PRT]]>
          <![CDATA[<213> 智人]]>
          <![CDATA[<400> 145]]>
          Ser Ala Ser Gln Asp Ile Ser Asn Tyr Leu Asn 
          1               5                   10      
          <![CDATA[<210> 146]]>
          <![CDATA[<211> 7]]>
          <![CDATA[<212> PRT]]>
          <![CDATA[<213> 智人]]>
          <![CDATA[<400> 146]]>
          Phe Thr Ser Ser Leu His Ser 
          1               5           
          <![CDATA[<210> 147]]>
          <![CDATA[<211> 9]]>
          <![CDATA[<212> PRT]]>
          <![CDATA[<213> 智人]]>
          <![CDATA[<400> 147]]>
          Gln Gln Tyr Ser Thr Val Pro Trp Thr 
          1               5                   
          <![CDATA[<210> 148]]>
          <![CDATA[<211> 10]]>
          <![CDATA[<212> PRT]]>
          <![CDATA[<213> 智人]]>
          <![CDATA[<400> 148]]>
          Gly Tyr Asp Phe Thr His Tyr Gly Met Asn 
          1               5                   10  
          <![CDATA[<210> 149]]>
          <![CDATA[<211> 17]]>
          <![CDATA[<212> PRT]]>
          <![CDATA[<213> 智人]]>
          <![CDATA[<400> 149]]>
          Trp Ile Asn Thr Tyr Thr Gly Glu Pro Thr Tyr Ala Ala Asp Phe Lys 
          1               5                   10                  15      
          Arg 
          <![CDATA[<210> 150]]>
          <![CDATA[<211> 14]]>
          <![CDATA[<212> PRT]]>
          <![CDATA[<213> 智人]]>
          <![CDATA[<400> 150]]>
          Tyr Pro Tyr Tyr Tyr Gly Thr Ser His Trp Tyr Phe Asp Val 
          1               5                   10                  
          <![CDATA[<210> 151]]>
          <![CDATA[<211> 5]]>
          <![CDATA[<212> PRT]]>
          <![CDATA[<213> 智人]]>
          <![CDATA[<400> 151]]>
          His Tyr Gly Met Asn 
          1               5   
          <![CDATA[<210> 152]]>
          <![CDATA[<211> 17]]>
          <![CDATA[<212> PRT]]>
          <![CDATA[<213> 智人]]>
          <![CDATA[<400> 152]]>
          Trp Ile Asn Thr Tyr Thr Gly Glu Pro Thr Tyr Ala Ala Asp Phe Lys 
          1               5                   10                  15      
          Arg 
          <![CDATA[<210> 153]]>
          <![CDATA[<211> 14]]>
          <![CDATA[<212> PRT]]>
          <![CDATA[<213> 智人]]>
          <![CDATA[<400> 153]]>
          Tyr Pro Tyr Tyr Tyr Gly Thr Ser His Trp Tyr Phe Asp Val 
          1               5                   10                  
          <![CDATA[<210> 154]]>
          <![CDATA[<211> 7]]>
          <![CDATA[<212> PRT]]>
          <![CDATA[<213> 智人]]>
          <![CDATA[<400> 154]]>
          Gly Tyr Asp Phe Thr His Tyr 
          1               5           
          <![CDATA[<210> 155]]>
          <![CDATA[<211> 6]]>
          <![CDATA[<212> PRT]]>
          <![CDATA[<213> 智人]]>
          <![CDATA[<400> 155]]>
          Asn Thr Tyr Thr Gly Glu 
          1               5       
          <![CDATA[<210> 156]]>
          <![CDATA[<211> 14]]>
          <![CDATA[<212> PRT]]>
          <![CDATA[<213> 智人]]>
          <![CDATA[<400> 156]]>
          Tyr Pro Tyr Tyr Tyr Gly Thr Ser His Trp Tyr Phe Asp Val 
          1               5                   10                  
          <![CDATA[<210> 157]]>
          <![CDATA[<211> 11]]>
          <![CDATA[<212> PRT]]>
          <![CDATA[<213> 智人]]>
          <![CDATA[<400> 157]]>
          Arg Ala Ser Gln Val Ile Arg Arg Ser Leu Ala 
          1               5                   10      
          <![CDATA[<210> 158]]>
          <![CDATA[<211> 7]]>
          <![CDATA[<212> PRT]]>
          <![CDATA[<213> 智人]]>
          <![CDATA[<400> 158]]>
          Ala Ala Ser Asn Leu Ala Ser 
          1               5           
          <![CDATA[<210> 159]]>
          <![CDATA[<211> 9]]>
          <![CDATA[<212> PRT]]>
          <![CDATA[<213> 智人]]>
          <![CDATA[<400> 159]]>
          Gln Gln Ser Asn Thr Ser Pro Leu Thr 
          1               5                   
          <![CDATA[<210> 160]]>
          <![CDATA[<211> 10]]>
          <![CDATA[<212> PRT]]>
          <![CDATA[<213> 智人]]>
          <![CDATA[<400> 160]]>
          Gly Phe Thr Ile Asn Ala Ser Trp Ile His 
          1               5                   10  
          <![CDATA[<210> 161]]>
          <![CDATA[<211> 17]]>
          <![CDATA[<212> PRT]]>
          <![CDATA[<213> 智人]]>
          <![CDATA[<400> 161]]>
          Ala Ile Tyr Pro Tyr Ser Gly Tyr Thr Asn Tyr Ala Asp Ser Val Lys 
          1               5                   10                  15      
          Gly 
          <![CDATA[<210> 162]]>
          <![CDATA[<211> 12]]>
          <![CDATA[<212> PRT]]>
          <![CDATA[<213> 智人]]>
          <![CDATA[<400> 162]]>
          Trp Gly His Ser Thr Ser Pro Trp Ala Met Asp Tyr 
          1               5                   10          
          <![CDATA[<210> 163]]>
          <![CDATA[<211> 5]]>
          <![CDATA[<212> PRT]]>
          <![CDATA[<213> 智人]]>
          <![CDATA[<400> 163]]>
          Ala Ser Trp Ile His 
          1               5   
          <![CDATA[<210> 164]]>
          <![CDATA[<211> 17]]>
          <![CDATA[<212> PRT]]>
          <![CDATA[<213> 智人]]>
          <![CDATA[<400> 164]]>
          Ala Ile Tyr Pro Tyr Ser Gly Tyr Thr Asn Tyr Ala Asp Ser Val Lys 
          1               5                   10                  15      
          Gly 
          <![CDATA[<210> 165]]>
          <![CDATA[<211> 12]]>
          <![CDATA[<212> PRT]]>
          <![CDATA[<213> 智人]]>
          <![CDATA[<400> 165]]>
          Trp Gly His Ser Thr Ser Pro Trp Ala Met Asp Tyr 
          1               5                   10          
          <![CDATA[<210> 166]]>
          <![CDATA[<211> 7]]>
          <![CDATA[<212> PRT]]>
          <![CDATA[<213> 智人]]>
          <![CDATA[<400> 166]]>
          Gly Phe Thr Ile Asn Ala Ser 
          1               5           
          <![CDATA[<210> 167]]>
          <![CDATA[<211> 6]]>
          <![CDATA[<212> PRT]]>
          <![CDATA[<213> 智人]]>
          <![CDATA[<400> 167]]>
          Tyr Pro Tyr Ser Gly Tyr 
          1               5       
          <![CDATA[<210> 168]]>
          <![CDATA[<211> 12]]>
          <![CDATA[<212> PRT]]>
          <![CDATA[<213> 智人]]>
          <![CDATA[<400> 168]]>
          Trp Gly His Ser Thr Ser Pro Trp Ala Met Asp Tyr 
          1               5                   10          
          <![CDATA[<210> 169]]>
          <![CDATA[<211> 11]]>
          <![CDATA[<212> PRT]]>
          <![CDATA[<213> 智人]]>
          <![CDATA[<400> 169]]>
          Arg Ala Ser Gln Asp Val Ser Thr Ala Val Ala 
          1               5                   10      
          <![CDATA[<210> 170]]>
          <![CDATA[<211> 7]]>
          <![CDATA[<212> PRT]]>
          <![CDATA[<213> 智人]]>
          <![CDATA[<400> 170]]>
          Ser Ala Ser Phe Leu Tyr Ser 
          1               5           
          <![CDATA[<210> 171]]>
          <![CDATA[<211> 9]]>
          <![CDATA[<212> PRT]]>
          <![CDATA[<213> 智人]]>
          <![CDATA[<400> 171]]>
          Gln Gln Ser Tyr Thr Thr Pro Pro Thr 
          1               5                   
          <![CDATA[<210> 172]]>
          <![CDATA[<211> 10]]>
          <![CDATA[<212> PRT]]>
          <![CDATA[<213> 智人]]>
          <![CDATA[<400> 172]]>
          Gly Phe Thr Ile Ser Asp Tyr Trp Ile His 
          1               5                   10  
          <![CDATA[<210> 173]]>
          <![CDATA[<211> 17]]>
          <![CDATA[<212> PRT]]>
          <![CDATA[<213> 智人]]>
          <![CDATA[<400> 173]]>
          Gly Ile Thr Pro Ala Gly Gly Tyr Thr Tyr Tyr Ala Asp Ser Val Lys 
          1               5                   10                  15      
          Gly 
          <![CDATA[<210> 174]]>
          <![CDATA[<211> 11]]>
          <![CDATA[<212> PRT]]>
          <![CDATA[<213> 智人]]>
          <![CDATA[<400> 174]]>
          Phe Val Phe Phe Leu Pro Tyr Ala Met Asp Tyr 
          1               5                   10      
          <![CDATA[<210> 175]]>
          <![CDATA[<211> 5]]>
          <![CDATA[<212> PRT]]>
          <![CDATA[<213> 智人]]>
          <![CDATA[<400> 175]]>
          Asp Tyr Trp Ile His 
          1               5   
          <![CDATA[<210> 176]]>
          <![CDATA[<211> 17]]>
          <![CDATA[<212> PRT]]>
          <![CDATA[<213> 智人]]>
          <![CDATA[<400> 176]]>
          Gly Ile Thr Pro Ala Gly Gly Tyr Thr Tyr Tyr Ala Asp Ser Val Lys 
          1               5                   10                  15      
          Gly 
          <![CDATA[<210> 177]]>
          <![CDATA[<211> 11]]>
          <![CDATA[<212> PRT]]>
          <![CDATA[<213> 智人]]>
          <![CDATA[<400> 177]]>
          Phe Val Phe Phe Leu Pro Tyr Ala Met Asp Tyr 
          1               5                   10      
          <![CDATA[<210> 178]]>
          <![CDATA[<211> 7]]>
          <![CDATA[<212> PRT]]>
          <![CDATA[<213> 智人]]>
          <![CDATA[<400> 178]]>
          Gly Phe Thr Ile Ser Asp Tyr 
          1               5           
          <![CDATA[<210> 179]]>
          <![CDATA[<211> 6]]>
          <![CDATA[<212> PRT]]>
          <![CDATA[<213> 智人]]>
          <![CDATA[<400> 179]]>
          Thr Pro Ala Gly Gly Tyr 
          1               5       
          <![CDATA[<210> 180]]>
          <![CDATA[<211> 11]]>
          <![CDATA[<212> PRT]]>
          <![CDATA[<213> 智人]]>
          <![CDATA[<400> 180]]>
          Phe Val Phe Phe Leu Pro Tyr Ala Met Asp Tyr 
          1               5                   10      
          <![CDATA[<210> 181]]>
          <![CDATA[<211> 107]]>
          <![CDATA[<212> PRT]]>
          <![CDATA[<213> 智人]]>
          <![CDATA[<400> 181]]>
          Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly 
          1               5                   10                  15      
          Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Val Ile Arg Arg Ser 
                      20                  25                  30          
          Leu Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile 
                  35                  40                  45              
          Tyr Ala Ala Ser Asn Leu Ala 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 Ser Asn Thr Ser Pro Leu 
                          85                  90                  95      
          Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys 
                      100                 105         
          <![CDATA[<210> 182]]>
          <![CDATA[<211> 121]]>
          <![CDATA[<212> PRT]]>
          <![CDATA[<213> 智人]]>
          <![CDATA[<400> 182]]>
          Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 
          1               5                   10                  15      
          Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Ile Asn Ala Ser 
                      20                  25                  30          
          Trp Ile His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 
                  35                  40                  45              
          Gly Ala Ile Tyr Pro Tyr Ser Gly Tyr Thr Asn Tyr Ala Asp Ser Val 
              50                  55                  60                  
          Lys Gly Arg Phe Thr Ile Ser Ala Asp Thr Ser Lys Asn Thr Ala Tyr 
          65                  70                  75                  80  
          Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 
                          85                  90                  95      
          Ala Arg Trp Gly His Ser Thr Ser Pro Trp Ala Met Asp Tyr Trp Gly 
                      100                 105                 110         
          Gln Gly Thr Leu Val Thr Val Ser Ser 
                  115                 120     
          <![CDATA[<210> 183]]>
          <![CDATA[<211> 107]]>
          <![CDATA[<212> PRT]]>
          <![CDATA[<213> 智人]]>
          <![CDATA[<400> 183]]>
          Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly 
          1               5                   10                  15      
          Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Asp Val Ser Thr Ala 
                      20                  25                  30          
          Val Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile 
                  35                  40                  45              
          Tyr Ser Ala Ser Phe Leu Tyr 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 Ser Tyr Thr Thr Pro Pro 
                          85                  90                  95      
          Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys 
                      100                 105         
          <![CDATA[<210> 184]]>
          <![CDATA[<211> 120]]>
          <![CDATA[<212> PRT]]>
          <![CDATA[<213> 智人]]>
          <![CDATA[<400> 184]]>
          Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 
          1               5                   10                  15      
          Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Ile Ser Asp Tyr 
                      20                  25                  30          
          Trp Ile His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 
                  35                  40                  45              
          Ala Gly Ile Thr Pro Ala Gly Gly Tyr Thr Tyr Tyr Ala Asp Ser Val 
              50                  55                  60                  
          Lys Gly Arg Phe Thr Ile Ser Ala Asp Thr Ser Lys Asn Thr Ala Tyr 
          65                  70                  75                  80  
          Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 
                          85                  90                  95      
          Ala Arg Phe Val Phe Phe Leu Pro Tyr Ala Met Asp Tyr Trp Gly Gln 
                      100                 105                 110         
          Gly Thr Leu Val Thr Val Ser Ser 
                  115                 120 
          <![CDATA[<210> 185]]>
          <![CDATA[<211> 214]]>
          <![CDATA[<212> PRT]]>
          <![CDATA[<213> 智人]]>
          <![CDATA[<400> 185]]>
          Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly 
          1               5                   10                  15      
          Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Val Ile Arg Arg Ser 
                      20                  25                  30          
          Leu Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile 
                  35                  40                  45              
          Tyr Ala Ala Ser Asn Leu Ala 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 Ser Asn Thr Ser Pro Leu 
                          85                  90                  95      
          Thr Phe Gly Gln 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 Cys 
              210                 
          <![CDATA[<210> 186]]>
          <![CDATA[<211> 450]]>
          <![CDATA[<212> PRT]]>
          <![CDATA[<213> 智人]]>
          <![CDATA[<400> 186]]>
          Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 
          1               5                   10                  15      
          Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Ile Asn Ala Ser 
                      20                  25                  30          
          Trp Ile His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 
                  35                  40                  45              
          Gly Ala Ile Tyr Pro Tyr Ser Gly Tyr Thr Asn Tyr Ala Asp Ser Val 
              50                  55                  60                  
          Lys Gly Arg Phe Thr Ile Ser Ala Asp Thr Ser Lys Asn Thr Ala Tyr 
          65                  70                  75                  80  
          Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 
                          85                  90                  95      
          Ala Arg Trp Gly His Ser Thr Ser Pro Trp Ala Met Asp Tyr Trp Gly 
                      100                 105                 110         
          Gln Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser 
                  115                 120                 125             
          Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala 
              130                 135                 140                 
          Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val 
          145                 150                 155                 160 
          Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala 
                          165                 170                 175     
          Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val 
                      180                 185                 190         
          Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His 
                  195                 200                 205             
          Lys Pro Ser Asn Thr Lys Val Asp Lys Arg Val Glu Pro Lys Ser Cys 
              210                 215                 220                 
          Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Ala Ala Gly 
          225                 230                 235                 240 
          Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met 
                          245                 250                 255     
          Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His 
                      260                 265                 270         
          Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val 
                  275                 280                 285             
          His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr 
              290                 295                 300                 
          Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly 
          305                 310                 315                 320 
          Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile 
                          325                 330                 335     
          Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val 
                      340                 345                 350         
          Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser 
                  355                 360                 365             
          Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu 
              370                 375                 380                 
          Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro 
          385                 390                 395                 400 
          Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val 
                          405                 410                 415     
          Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met 
                      420                 425                 430         
          His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser 
                  435                 440                 445             
          Pro Gly 
              450 
          <![CDATA[<210> 187]]>
          <![CDATA[<211> 214]]>
          <![CDATA[<212> PRT]]>
          <![CDATA[<213> 智人]]>
          <![CDATA[<400> 187]]>
          Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly 
          1               5                   10                  15      
          Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Asp Val Ser Thr Ala 
                      20                  25                  30          
          Val Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile 
                  35                  40                  45              
          Tyr Ser Ala Ser Phe Leu Tyr 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 Ser Tyr Thr Thr Pro Pro 
                          85                  90                  95      
          Thr Phe Gly Gln 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 Cys 
              210                 
          <![CDATA[<210> 188]]>
          <![CDATA[<211> 449]]>
          <![CDATA[<212> PRT]]>
          <![CDATA[<213> 智人]]>
          <![CDATA[<400> 188]]>
          Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 
          1               5                   10                  15      
          Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Ile Ser Asp Tyr 
                      20                  25                  30          
          Trp Ile His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 
                  35                  40                  45              
          Ala Gly Ile Thr Pro Ala Gly Gly Tyr Thr Tyr Tyr Ala Asp Ser Val 
              50                  55                  60                  
          Lys Gly Arg Phe Thr Ile Ser Ala Asp Thr Ser Lys Asn Thr Ala Tyr 
          65                  70                  75                  80  
          Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 
                          85                  90                  95      
          Ala Arg Phe Val Phe Phe Leu Pro Tyr Ala Met Asp Tyr Trp Gly Gln 
                      100                 105                 110         
          Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val 
                  115                 120                 125             
          Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala 
              130                 135                 140                 
          Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser 
          145                 150                 155                 160 
          Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val 
                          165                 170                 175     
          Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro 
                      180                 185                 190         
          Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys 
                  195                 200                 205             
          Pro Ser Asn Thr Lys Val Asp Lys Arg Val Glu Pro Lys Ser Cys Asp 
              210                 215                 220                 
          Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Ala Ala Gly Gly 
          225                 230                 235                 240 
          Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile 
                          245                 250                 255     
          Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu 
                      260                 265                 270         
          Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His 
                  275                 280                 285             
          Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg 
              290                 295                 300                 
          Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys 
          305                 310                 315                 320 
          Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu 
                          325                 330                 335     
          Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr 
                      340                 345                 350         
          Thr Leu Pro Pro Ser Arg 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 
          <![CDATA[<210> 189]]>
          <![CDATA[<211> 107]]>
          <![CDATA[<212> PRT]]>
          <![CDATA[<213> 智人]]>
          <![CDATA[<400> 189]]>
          Asp Ile Gln Leu Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly 
          1               5                   10                  15      
          Asp Arg Val Thr Ile Thr Cys Ser Ala Ser Gln Asp Ile Ser Asn Tyr 
                      20                  25                  30          
          Leu Asn Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Val Leu Ile 
                  35                  40                  45              
          Tyr Phe Thr Ser Ser Leu His 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 Tyr Ser Thr Val Pro Trp 
                          85                  90                  95      
          Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys 
                      100                 105         
          <![CDATA[<210> 190]]>
          <![CDATA[<211> 123]]>
          <![CDATA[<212> PRT]]>
          <![CDATA[<213> 智人]]>
          <![CDATA[<400> 190]]>
          Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 
          1               5                   10                  15      
          Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Tyr Asp Phe Thr His Tyr 
                      20                  25                  30          
          Gly Met Asn Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 
                  35                  40                  45              
          Gly Trp Ile Asn Thr Tyr Thr Gly Glu Pro Thr Tyr Ala Ala Asp Phe 
              50                  55                  60                  
          Lys Arg Arg Phe Thr Phe Ser Leu Asp Thr Ser Lys Ser Thr Ala Tyr 
          65                  70                  75                  80  
          Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 
                          85                  90                  95      
          Ala Lys Tyr Pro Tyr Tyr Tyr Gly Thr Ser His Trp Tyr Phe Asp Val 
                      100                 105                 110         
          Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser 
                  115                 120             
          <![CDATA[<210> 191]]>
          <![CDATA[<211> 123]]>
          <![CDATA[<212> PRT]]>
          <![CDATA[<213> 智人]]>
          <![CDATA[<400> 191]]>
          Gln Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 
          1               5                   10                  15      
          Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Tyr Asp Phe Thr His Tyr 
                      20                  25                  30          
          Gly Met Asn Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 
                  35                  40                  45              
          Gly Trp Ile Asn Thr Tyr Thr Gly Glu Pro Thr Tyr Ala Ala Asp Phe 
              50                  55                  60                  
          Lys Arg Arg Phe Thr Phe Ser Leu Asp Thr Ser Lys Ser Thr Ala Tyr 
          65                  70                  75                  80  
          Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 
                          85                  90                  95      
          Ala Lys Tyr Pro Tyr Tyr Tyr Gly Thr Ser His Trp Tyr Phe Asp Val 
                      100                 105                 110         
          Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser 
                  115                 120             
          <![CDATA[<210> 192]]>
          <![CDATA[<211> 123]]>
          <![CDATA[<212> PRT]]>
          <![CDATA[<213> 智人]]>
          <![CDATA[<400> 192]]>
          Glu Val Gln Leu Val Gln Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 
          1               5                   10                  15      
          Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Tyr Asp Phe Thr His Tyr 
                      20                  25                  30          
          Gly Met Asn Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 
                  35                  40                  45              
          Gly Trp Ile Asn Thr Tyr Thr Gly Glu Pro Thr Tyr Ala Ala Asp Phe 
              50                  55                  60                  
          Lys Arg Arg Phe Thr Phe Ser Leu Asp Thr Ser Lys Ser Thr Ala Tyr 
          65                  70                  75                  80  
          Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 
                          85                  90                  95      
          Ala Lys Tyr Pro Tyr Tyr Tyr Gly Thr Ser His Trp Tyr Phe Asp Val 
                      100                 105                 110         
          Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser 
                  115                 120             
          <![CDATA[<210> 193]]>
          <![CDATA[<211> 107]]>
          <![CDATA[<212> PRT]]>
          <![CDATA[<213> 智人]]>
          <![CDATA[<400> 193]]>
          Asp Ile Gln Leu Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly 
          1               5                   10                  15      
          Asp Arg Val Thr Ile Thr Cys Ser Ala Ser Gln Asp Ile Ser Asn Tyr 
                      20                  25                  30          
          Leu Asn Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Val Leu Ile 
                  35                  40                  45              
          Tyr Phe Thr Ser Ser Leu His Ser Gly Val Pro Ser Arg Phe Ser Gly 
              50                  55                  60                  
          Ser Gly Ser Gly Thr Gly Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro 
          65                  70                  75                  80  
          Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Tyr Ser Thr Val Pro Trp 
                          85                  90                  95      
          Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys 
                      100                 105         
          <![CDATA[<210> 194]]>
          <![CDATA[<211> 123]]>
          <![CDATA[<212> PRT]]>
          <![CDATA[<213> 智人]]>
          <![CDATA[<400> 194]]>
          Gln Val Gln Leu Val Gln Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 
          1               5                   10                  15      
          Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Tyr Asp Phe Thr His Tyr 
                      20                  25                  30          
          Gly Met Asn Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 
                  35                  40                  45              
          Gly Trp Ile Asn Thr Tyr Thr Gly Glu Pro Thr Tyr Ala Ala Asp Phe 
              50                  55                  60                  
          Lys Arg Arg Phe Thr Phe Ser Leu Asp Thr Ser Lys Ser Thr Ala Tyr 
          65                  70                  75                  80  
          Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 
                          85                  90                  95      
          Ala Lys Tyr Pro Tyr Tyr Tyr Gly Thr Ser His Trp Tyr Phe Asp Val 
                      100                 105                 110         
          Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser 
                  115                 120             
          <![CDATA[<210> 195]]>
          <![CDATA[<211> 214]]>
          <![CDATA[<212> PRT]]>
          <![CDATA[<213> 智人]]>
          <![CDATA[<400> 195]]>
          Asp Ile Gln Leu Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly 
          1               5                   10                  15      
          Asp Arg Val Thr Ile Thr Cys Ser Ala Ser Gln Asp Ile Ser Asn Tyr 
                      20                  25                  30          
          Leu Asn Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Val Leu Ile 
                  35                  40                  45              
          Tyr Phe Thr Ser Ser Leu His 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 Tyr Ser Thr Val Pro Trp 
                          85                  90                  95      
          Thr Phe Gly Gln 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 Cys 
              210                 
          <![CDATA[<210> 196]]>
          <![CDATA[<211> 452]]>
          <![CDATA[<212> PRT]]>
          <![CDATA[<213> 智人]]>
          <![CDATA[<400> 196]]>
          Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 
          1               5                   10                  15      
          Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Tyr Asp Phe Thr His Tyr 
                      20                  25                  30          
          Gly Met Asn Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 
                  35                  40                  45              
          Gly Trp Ile Asn Thr Tyr Thr Gly Glu Pro Thr Tyr Ala Ala Asp Phe 
              50                  55                  60                  
          Lys Arg Arg Phe Thr Phe Ser Leu Asp Thr Ser Lys Ser Thr Ala Tyr 
          65                  70                  75                  80  
          Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 
                          85                  90                  95      
          Ala Lys Tyr Pro Tyr Tyr Tyr Gly Thr Ser His Trp Tyr Phe Asp Val 
                      100                 105                 110         
          Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly 
                  115                 120                 125             
          Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly 
              130                 135                 140                 
          Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val 
          145                 150                 155                 160 
          Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe 
                          165                 170                 175     
          Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val 
                      180                 185                 190         
          Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val 
                  195                 200                 205             
          Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys Arg Val Glu Pro Lys 
              210                 215                 220                 
          Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Ala 
          225                 230                 235                 240 
          Ala Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr 
                          245                 250                 255     
          Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val 
                      260                 265                 270         
          Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val 
                  275                 280                 285             
          Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser 
              290                 295                 300                 
          Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu 
          305                 310                 315                 320 
          Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala 
                          325                 330                 335     
          Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro 
                      340                 345                 350         
          Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln 
                  355                 360                 365             
          Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala 
              370                 375                 380                 
          Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr 
          385                 390                 395                 400 
          Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu 
                          405                 410                 415     
          Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser 
                      420                 425                 430         
          Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser 
                  435                 440                 445             
          Leu Ser Pro Gly 
              450         
          <![CDATA[<210> 197]]>
          <![CDATA[<211> 452]]>
          <![CDATA[<212> PRT]]>
          <![CDATA[<213> 智人]]>
          <![CDATA[<400> 197]]>
          Gln Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 
          1               5                   10                  15      
          Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Tyr Asp Phe Thr His Tyr 
                      20                  25                  30          
          Gly Met Asn Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 
                  35                  40                  45              
          Gly Trp Ile Asn Thr Tyr Thr Gly Glu Pro Thr Tyr Ala Ala Asp Phe 
              50                  55                  60                  
          Lys Arg Arg Phe Thr Phe Ser Leu Asp Thr Ser Lys Ser Thr Ala Tyr 
          65                  70                  75                  80  
          Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 
                          85                  90                  95      
          Ala Lys Tyr Pro Tyr Tyr Tyr Gly Thr Ser His Trp Tyr Phe Asp Val 
                      100                 105                 110         
          Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly 
                  115                 120                 125             
          Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly 
              130                 135                 140                 
          Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val 
          145                 150                 155                 160 
          Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe 
                          165                 170                 175     
          Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val 
                      180                 185                 190         
          Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val 
                  195                 200                 205             
          Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys Arg Val Glu Pro Lys 
              210                 215                 220                 
          Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Ala 
          225                 230                 235                 240 
          Ala Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr 
                          245                 250                 255     
          Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val 
                      260                 265                 270         
          Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val 
                  275                 280                 285             
          Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser 
              290                 295                 300                 
          Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu 
          305                 310                 315                 320 
          Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala 
                          325                 330                 335     
          Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro 
                      340                 345                 350         
          Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln 
                  355                 360                 365             
          Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala 
              370                 375                 380                 
          Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr 
          385                 390                 395                 400 
          Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu 
                          405                 410                 415     
          Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser 
                      420                 425                 430         
          Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser 
                  435                 440                 445             
          Leu Ser Pro Gly 
              450         
          <![CDATA[<210> 198]]>
          <![CDATA[<211> 452]]>
          <![CDATA[<212> PRT]]>
          <![CDATA[<213> 智人]]>
          <![CDATA[<400> 198]]>
          Glu Val Gln Leu Val Gln Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 
          1               5                   10                  15      
          Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Tyr Asp Phe Thr His Tyr 
                      20                  25                  30          
          Gly Met Asn Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 
                  35                  40                  45              
          Gly Trp Ile Asn Thr Tyr Thr Gly Glu Pro Thr Tyr Ala Ala Asp Phe 
              50                  55                  60                  
          Lys Arg Arg Phe Thr Phe Ser Leu Asp Thr Ser Lys Ser Thr Ala Tyr 
          65                  70                  75                  80  
          Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 
                          85                  90                  95      
          Ala Lys Tyr Pro Tyr Tyr Tyr Gly Thr Ser His Trp Tyr Phe Asp Val 
                      100                 105                 110         
          Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly 
                  115                 120                 125             
          Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly 
              130                 135                 140                 
          Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val 
          145                 150                 155                 160 
          Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe 
                          165                 170                 175     
          Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val 
                      180                 185                 190         
          Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val 
                  195                 200                 205             
          Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys Arg Val Glu Pro Lys 
              210                 215                 220                 
          Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Ala 
          225                 230                 235                 240 
          Ala Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr 
                          245                 250                 255     
          Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val 
                      260                 265                 270         
          Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val 
                  275                 280                 285             
          Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser 
              290                 295                 300                 
          Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu 
          305                 310                 315                 320 
          Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala 
                          325                 330                 335     
          Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro 
                      340                 345                 350         
          Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln 
                  355                 360                 365             
          Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala 
              370                 375                 380                 
          Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr 
          385                 390                 395                 400 
          Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu 
                          405                 410                 415     
          Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser 
                      420                 425                 430         
          Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser 
                  435                 440                 445             
          Leu Ser Pro Gly 
              450         
          <![CDATA[<210> 199]]>
          <![CDATA[<211> 214]]>
          <![CDATA[<212> PRT]]>
          <![CDATA[<213> 智人]]>
          <![CDATA[<400> 199]]>
          Asp Ile Gln Leu Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly 
          1               5                   10                  15      
          Asp Arg Val Thr Ile Thr Cys Ser Ala Ser Gln Asp Ile Ser Asn Tyr 
                      20                  25                  30          
          Leu Asn Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Val Leu Ile 
                  35                  40                  45              
          Tyr Phe Thr Ser Ser Leu His Ser Gly Val Pro Ser Arg Phe Ser Gly 
              50                  55                  60                  
          Ser Gly Ser Gly Thr Gly Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro 
          65                  70                  75                  80  
          Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Tyr Ser Thr Val Pro Trp 
                          85                  90                  95      
          Thr Phe Gly Gln 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 Cys 
              210                 
          <![CDATA[<210> 200]]>
          <![CDATA[<211> 452]]>
          <![CDATA[<212> PRT]]>
          <![CDATA[<213> 智人]]>
          <![CDATA[<400> 200]]>
          Gln Val Gln Leu Val Gln Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 
          1               5                   10                  15      
          Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Tyr Asp Phe Thr His Tyr 
                      20                  25                  30          
          Gly Met Asn Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 
                  35                  40                  45              
          Gly Trp Ile Asn Thr Tyr Thr Gly Glu Pro Thr Tyr Ala Ala Asp Phe 
              50                  55                  60                  
          Lys Arg Arg Phe Thr Phe Ser Leu Asp Thr Ser Lys Ser Thr Ala Tyr 
          65                  70                  75                  80  
          Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 
                          85                  90                  95      
          Ala Lys Tyr Pro Tyr Tyr Tyr Gly Thr Ser His Trp Tyr Phe Asp Val 
                      100                 105                 110         
          Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly 
                  115                 120                 125             
          Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly 
              130                 135                 140                 
          Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val 
          145                 150                 155                 160 
          Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe 
                          165                 170                 175     
          Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val 
                      180                 185                 190         
          Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val 
                  195                 200                 205             
          Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys Arg Val Glu Pro Lys 
              210                 215                 220                 
          Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Ala 
          225                 230                 235                 240 
          Ala Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr 
                          245                 250                 255     
          Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val 
                      260                 265                 270         
          Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val 
                  275                 280                 285             
          Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser 
              290                 295                 300                 
          Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu 
          305                 310                 315                 320 
          Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala 
                          325                 330                 335     
          Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro 
                      340                 345                 350         
          Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln 
                  355                 360                 365             
          Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala 
              370                 375                 380                 
          Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr 
          385                 390                 395                 400 
          Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu 
                          405                 410                 415     
          Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser 
                      420                 425                 430         
          Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser 
                  435                 440                 445             
          Leu Ser Pro Gly 
              450         
          <![CDATA[<210> 201]]>
          <![CDATA[<211> 11]]>
          <![CDATA[<212> PRT]]>
          <![CDATA[<213> 智人]]>
          <![CDATA[<400> 201]]>
          Arg Thr Ser Glu Asn Val Tyr Ser Asn Leu Ala 
          1               5                   10      
          <![CDATA[<210> 202]]>
          <![CDATA[<211> 7]]>
          <![CDATA[<212> PRT]]>
          <![CDATA[<213> 智人]]>
          <![CDATA[<400> 202]]>
          Ala Ala Ser Asn Leu Gln Ser 
          1               5           
          <![CDATA[<210> 203]]>
          <![CDATA[<211> 9]]>
          <![CDATA[<212> PRT]]>
          <![CDATA[<213> 智人]]>
          <![CDATA[<400> 203]]>
          Gln His Phe Trp Gly Ser Pro Phe Thr 
          1               5                   
          <![CDATA[<210> 204]]>
          <![CDATA[<211> 10]]>
          <![CDATA[<212> PRT]]>
          <![CDATA[<213> 智人]]>
          <![CDATA[<400> 204]]>
          Gly Tyr Thr Phe Thr Asn Tyr Asp Ile Ile 
          1               5                   10  
          <![CDATA[<210> 205]]>
          <![CDATA[<211> 17]]>
          <![CDATA[<212> PRT]]>
          <![CDATA[<213> 智人]]>
          <![CDATA[<400> 205]]>
          Tyr Ile Asn Pro Tyr Asn Asp Gly Thr Lys Tyr Asn Glu Lys Phe Lys 
          1               5                   10                  15      
          Gly 
          <![CDATA[<210> 206]]>
          <![CDATA[<211> 14]]>
          <![CDATA[<212> PRT]]>
          <![CDATA[<213> 智人]]>
          <![CDATA[<400> 206]]>
          Leu Leu Lys Tyr Arg Arg Phe Arg Tyr Tyr Ala Ile Asp Tyr 
          1               5                   10                  
          <![CDATA[<210> 207]]>
          <![CDATA[<211> 5]]>
          <![CDATA[<212> PRT]]>
          <![CDATA[<213> 智人]]>
          <![CDATA[<400> 207]]>
          Asn Tyr Asp Ile Ile 
          1               5   
          <![CDATA[<210> 208]]>
          <![CDATA[<211> 17]]>
          <![CDATA[<212> PRT]]>
          <![CDATA[<213> 智人]]>
          <![CDATA[<400> 208]]>
          Tyr Ile Asn Pro Tyr Asn Asp Gly Thr Lys Tyr Asn Glu Lys Phe Lys 
          1               5                   10                  15      
          Gly 
          <![CDATA[<210> 209]]>
          <![CDATA[<211> 14]]>
          <![CDATA[<212> PRT]]>
          <![CDATA[<213> 智人]]>
          <![CDATA[<400> 209]]>
          Leu Leu Lys Tyr Arg Arg Phe Arg Tyr Tyr Ala Ile Asp Tyr 
          1               5                   10                  
          <![CDATA[<210> 210]]>
          <![CDATA[<211> 7]]>
          <![CDATA[<212> PRT]]>
          <![CDATA[<213> 智人]]>
          <![CDATA[<400> 210]]>
          Gly Tyr Thr Phe Thr Asn Tyr 
          1               5           
          <![CDATA[<210> 211]]>
          <![CDATA[<211> 6]]>
          <![CDATA[<212> PRT]]>
          <![CDATA[<213> 智人]]>
          <![CDATA[<400> 211]]>
          Asn Pro Tyr Asn Asp Gly 
          1               5       
          <![CDATA[<210> 212]]>
          <![CDATA[<211> 14]]>
          <![CDATA[<212> PRT]]>
          <![CDATA[<213> 智人]]>
          <![CDATA[<400> 212]]>
          Leu Leu Lys Tyr Arg Arg Phe Arg Tyr Tyr Ala Ile Asp Tyr 
          1               5                   10                  
          <![CDATA[<210> 213]]>
          <![CDATA[<211> 107]]>
          <![CDATA[<212> PRT]]>
          <![CDATA[<213> 智人]]>
          <![CDATA[<400> 213]]>
          Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly 
          1               5                   10                  15      
          Asp Arg Val Thr Ile Thr Cys Arg Thr Ser Glu Asn Val Tyr Ser Asn 
                      20                  25                  30          
          Leu Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile 
                  35                  40                  45              
          Tyr Ala Ala Ser Asn Leu Gln Ser Gly Val Pro Ser Arg Phe Ser Gly 
              50                  55                  60                  
          Ser Gly Ser Gly Thr Asp Tyr Thr Phe Thr Ile Ser Ser Leu Gln Pro 
          65                  70                  75                  80  
          Glu Asp Ile Ala Thr Tyr Tyr Cys Gln His Phe Trp Gly Ser Pro Phe 
                          85                  90                  95      
          Thr Phe Gly Cys Gly Thr Lys Leu Glu Ile Lys 
                      100                 105         
          <![CDATA[<210> 214]]>
          <![CDATA[<211> 123]]>
          <![CDATA[<212> PRT]]>
          <![CDATA[<213> 智人]]>
          <![CDATA[<400> 214]]>
          Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala 
          1               5                   10                  15      
          Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Asn Tyr 
                      20                  25                  30          
          Asp Ile Ile Trp Val Arg Gln Ala Pro Gly Gln Cys Leu Glu Trp Met 
                  35                  40                  45              
          Gly Tyr Ile Asn Pro Tyr Asn Asp Gly Thr Lys Tyr Asn Glu Lys Phe 
              50                  55                  60                  
          Lys Gly Arg Val Thr Met Thr Arg Asp Thr Ser Thr Ser Thr Val Tyr 
          65                  70                  75                  80  
          Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys 
                          85                  90                  95      
          Ala Arg Leu Leu Lys Tyr Arg Arg Phe Arg Tyr Tyr Ala Ile Asp Tyr 
                      100                 105                 110         
          Trp Gly Gln Gly Thr Thr Val Thr Val Ser Ser 
                  115                 120             
          <![CDATA[<210> 215]]>
          <![CDATA[<211> 107]]>
          <![CDATA[<212> PRT]]>
          <![CDATA[<213> 智人]]>
          <![CDATA[<400> 215]]>
          Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly 
          1               5                   10                  15      
          Asp Arg Val Thr Ile Thr Cys Arg Thr Ser Glu Asn Val Tyr Ser Asn 
                      20                  25                  30          
          Leu Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile 
                  35                  40                  45              
          Tyr Ala Ala Ser Asn Leu Gln Ser Gly Val Pro Ser Arg Phe Ser Gly 
              50                  55                  60                  
          Ser Gly Ser Gly Thr Asp Tyr Thr Phe Thr Ile Ser Ser Leu Gln Pro 
          65                  70                  75                  80  
          Glu Asp Ile Ala Thr Tyr Tyr Cys Gln His Phe Trp Gly Ser Pro Phe 
                          85                  90                  95      
          Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys 
                      100                 105         
          <![CDATA[<210> 216]]>
          <![CDATA[<211> 123]]>
          <![CDATA[<212> PRT]]>
          <![CDATA[<213> 智人]]>
          <![CDATA[<400> 216]]>
          Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala 
          1               5                   10                  15      
          Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Asn Tyr 
                      20                  25                  30          
          Asp Ile Ile Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met 
                  35                  40                  45              
          Gly Tyr Ile Asn Pro Tyr Asn Asp Gly Thr Lys Tyr Asn Glu Lys Phe 
              50                  55                  60                  
          Lys Gly Arg Val Thr Met Thr Arg Asp Thr Ser Thr Ser Thr Val Tyr 
          65                  70                  75                  80  
          Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys 
                          85                  90                  95      
          Ala Arg Leu Leu Lys Tyr Arg Arg Phe Arg Tyr Tyr Ala Ile Asp Tyr 
                      100                 105                 110         
          Trp Gly Gln Gly Thr Thr Val Thr Val Ser Ser 
                  115                 120             
          <![CDATA[<210> 217]]>
          <![CDATA[<211> 6]]>
          <![CDATA[<212> PRT]]>
          <![CDATA[<213> 智人]]>
          <![CDATA[<400> 217]]>
          Gly Gly Ser Gly Gly Ser 
          1               5       
          <![CDATA[<210> 218]]>
          <![CDATA[<211> 10]]>
          <![CDATA[<212> PRT]]>
          <![CDATA[<213> 智人]]>
          <![CDATA[<400> 218]]>
          Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser 
          1               5                   10  
          <![CDATA[<210> 219]]>
          <![CDATA[<211> 15]]>
          <![CDATA[<212> PRT]]>
          <![CDATA[<213> 智人]]>
          <![CDATA[<400> 219]]>
          Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser 
          1               5                   10                  15  
          <![CDATA[<210> 220]]>
          <![CDATA[<211> 20]]>
          <![CDATA[<212> PRT]]>
          <![CDATA[<213> 智人]]>
          <![CDATA[<400> 220]]>
          Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly 
          1               5                   10                  15      
          Gly Gly Gly Ser 
                      20  
          <![CDATA[<210> 221]]>
          <![CDATA[<211> 20]]>
          <![CDATA[<212> PRT]]>
          <![CDATA[<213> 智人]]>
          <![CDATA[<400> 221]]>
          Gly Gly Ser Glu Gly Lys Ser Ser Gly Ser Gly Ser Glu Ser Lys Ser 
          1               5                   10                  15      
          Thr Gly Gly Ser 
                      20  
          <![CDATA[<210> 222]]>
          <![CDATA[<211> 250]]>
          <![CDATA[<212> PRT]]>
          <![CDATA[<213> 智人]]>
          <![CDATA[<400> 222]]>
          Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly 
          1               5                   10                  15      
          Asp Arg Val Thr Ile Thr Cys Arg Thr Ser Glu Asn Val Tyr Ser Asn 
                      20                  25                  30          
          Leu Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile 
                  35                  40                  45              
          Tyr Ala Ala Ser Asn Leu Gln Ser Gly Val Pro Ser Arg Phe Ser Gly 
              50                  55                  60                  
          Ser Gly Ser Gly Thr Asp Tyr Thr Phe Thr Ile Ser Ser Leu Gln Pro 
          65                  70                  75                  80  
          Glu Asp Ile Ala Thr Tyr Tyr Cys Gln His Phe Trp Gly Ser Pro Phe 
                          85                  90                  95      
          Thr Phe Gly Cys Gly Thr Lys Leu Glu Ile Lys Gly Gly Ser Glu Gly 
                      100                 105                 110         
          Lys Ser Ser Gly Ser Gly Ser Glu Ser Lys Ser Thr Gly Gly Ser Gln 
                  115                 120                 125             
          Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala Ser 
              130                 135                 140                 
          Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Asn Tyr Asp 
          145                 150                 155                 160 
          Ile Ile Trp Val Arg Gln Ala Pro Gly Gln Cys Leu Glu Trp Met Gly 
                          165                 170                 175     
          Tyr Ile Asn Pro Tyr Asn Asp Gly Thr Lys Tyr Asn Glu Lys Phe Lys 
                      180                 185                 190         
          Gly Arg Val Thr Met Thr Arg Asp Thr Ser Thr Ser Thr Val Tyr Met 
                  195                 200                 205             
          Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys Ala 
              210                 215                 220                 
          Arg Leu Leu Lys Tyr Arg Arg Phe Arg Tyr Tyr Ala Ile Asp Tyr Trp 
          225                 230                 235                 240 
          Gly Gln Gly Thr Thr Val Thr Val Ser Ser 
                          245                 250 
          <![CDATA[<210> 223]]>
          <![CDATA[<211> 250]]>
          <![CDATA[<212> PRT]]>
          <![CDATA[<213> 智人]]>
          <![CDATA[<400> 223]]>
          Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala 
          1               5                   10                  15      
          Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Asn Tyr 
                      20                  25                  30          
          Asp Ile Ile Trp Val Arg Gln Ala Pro Gly Gln Cys Leu Glu Trp Met 
                  35                  40                  45              
          Gly Tyr Ile Asn Pro Tyr Asn Asp Gly Thr Lys Tyr Asn Glu Lys Phe 
              50                  55                  60                  
          Lys Gly Arg Val Thr Met Thr Arg Asp Thr Ser Thr Ser Thr Val Tyr 
          65                  70                  75                  80  
          Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys 
                          85                  90                  95      
          Ala Arg Leu Leu Lys Tyr Arg Arg Phe Arg Tyr Tyr Ala Ile Asp Tyr 
                      100                 105                 110         
          Trp Gly Gln Gly Thr Thr Val Thr Val Ser Ser Gly Gly Ser Glu Gly 
                  115                 120                 125             
          Lys Ser Ser Gly Ser Gly Ser Glu Ser Lys Ser Thr Gly Gly Ser Asp 
              130                 135                 140                 
          Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly Asp 
          145                 150                 155                 160 
          Arg Val Thr Ile Thr Cys Arg Thr Ser Glu Asn Val Tyr Ser Asn Leu 
                          165                 170                 175     
          Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile Tyr 
                      180                 185                 190         
          Ala Ala Ser Asn Leu Gln Ser Gly Val Pro Ser Arg Phe Ser Gly Ser 
                  195                 200                 205             
          Gly Ser Gly Thr Asp Tyr Thr Phe Thr Ile Ser Ser Leu Gln Pro Glu 
              210                 215                 220                 
          Asp Ile Ala Thr Tyr Tyr Cys Gln His Phe Trp Gly Ser Pro Phe Thr 
          225                 230                 235                 240 
          Phe Gly Cys Gly Thr Lys Leu Glu Ile Lys 
                          245                 250 
          <![CDATA[<210> 224]]>
          <![CDATA[<211> 250]]>
          <![CDATA[<212> PRT]]>
          <![CDATA[<213> 智人]]>
          <![CDATA[<400> 224]]>
          Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly 
          1               5                   10                  15      
          Asp Arg Val Thr Ile Thr Cys Arg Thr Ser Glu Asn Val Tyr Ser Asn 
                      20                  25                  30          
          Leu Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile 
                  35                  40                  45              
          Tyr Ala Ala Ser Asn Leu Gln Ser Gly Val Pro Ser Arg Phe Ser Gly 
              50                  55                  60                  
          Ser Gly Ser Gly Thr Asp Tyr Thr Phe Thr Ile Ser Ser Leu Gln Pro 
          65                  70                  75                  80  
          Glu Asp Ile Ala Thr Tyr Tyr Cys Gln His Phe Trp Gly Ser Pro Phe 
                          85                  90                  95      
          Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys Gly Gly Ser Glu Gly 
                      100                 105                 110         
          Lys Ser Ser Gly Ser Gly Ser Glu Ser Lys Ser Thr Gly Gly Ser Gln 
                  115                 120                 125             
          Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala Ser 
              130                 135                 140                 
          Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Asn Tyr Asp 
          145                 150                 155                 160 
          Ile Ile Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met Gly 
                          165                 170                 175     
          Tyr Ile Asn Pro Tyr Asn Asp Gly Thr Lys Tyr Asn Glu Lys Phe Lys 
                      180                 185                 190         
          Gly Arg Val Thr Met Thr Arg Asp Thr Ser Thr Ser Thr Val Tyr Met 
                  195                 200                 205             
          Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys Ala 
              210                 215                 220                 
          Arg Leu Leu Lys Tyr Arg Arg Phe Arg Tyr Tyr Ala Ile Asp Tyr Trp 
          225                 230                 235                 240 
          Gly Gln Gly Thr Thr Val Thr Val Ser Ser 
                          245                 250 
          <![CDATA[<210> 225]]>
          <![CDATA[<211> 250]]>
          <![CDATA[<212> PRT]]>
          <![CDATA[<213> 智人]]>
          <![CDATA[<400> 225]]>
          Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala 
          1               5                   10                  15      
          Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Asn Tyr 
                      20                  25                  30          
          Asp Ile Ile Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met 
                  35                  40                  45              
          Gly Tyr Ile Asn Pro Tyr Asn Asp Gly Thr Lys Tyr Asn Glu Lys Phe 
              50                  55                  60                  
          Lys Gly Arg Val Thr Met Thr Arg Asp Thr Ser Thr Ser Thr Val Tyr 
          65                  70                  75                  80  
          Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys 
                          85                  90                  95      
          Ala Arg Leu Leu Lys Tyr Arg Arg Phe Arg Tyr Tyr Ala Ile Asp Tyr 
                      100                 105                 110         
          Trp Gly Gln Gly Thr Thr Val Thr Val Ser Ser Gly Gly Ser Glu Gly 
                  115                 120                 125             
          Lys Ser Ser Gly Ser Gly Ser Glu Ser Lys Ser Thr Gly Gly Ser Asp 
              130                 135                 140                 
          Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly Asp 
          145                 150                 155                 160 
          Arg Val Thr Ile Thr Cys Arg Thr Ser Glu Asn Val Tyr Ser Asn Leu 
                          165                 170                 175     
          Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile Tyr 
                      180                 185                 190         
          Ala Ala Ser Asn Leu Gln Ser Gly Val Pro Ser Arg Phe Ser Gly Ser 
                  195                 200                 205             
          Gly Ser Gly Thr Asp Tyr Thr Phe Thr Ile Ser Ser Leu Gln Pro Glu 
              210                 215                 220                 
          Asp Ile Ala Thr Tyr Tyr Cys Gln His Phe Trp Gly Ser Pro Phe Thr 
          225                 230                 235                 240 
          Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys 
                          245                 250 
          <![CDATA[<210> 226]]>
          <![CDATA[<211> 399]]>
          <![CDATA[<212> PRT]]>
          <![CDATA[<213> 智人]]>
          <![CDATA[<400> 226]]>
          Cys Pro Thr Ser Cys Lys Cys Ser Ala Ser Arg Ile Trp Cys Ser Asp 
          1               5                   10                  15      
          Pro Ser Pro Gly Ile Val Ala Phe Pro Arg Leu Glu Pro Asn Ser Val 
                      20                  25                  30          
          Asp Pro Glu Asn Ile Thr Glu Ile Phe Ile Ala Asn Gln Lys Arg Leu 
                  35                  40                  45              
          Glu Ile Ile Asn Glu Asp Asp Val Glu Ala Tyr Val Gly Leu Arg Asn 
              50                  55                  60                  
          Leu Thr Ile Val Asp Ser Gly Leu Lys Phe Val Ala His Lys Ala Phe 
          65                  70                  75                  80  
          Leu Lys Asn Ser Asn Leu Gln His Ile Asn Phe Thr Arg Asn Lys Leu 
                          85                  90                  95      
          Thr Ser Leu Ser Arg Lys His Phe Arg His Leu Asp Leu Ser Glu Leu 
                      100                 105                 110         
          Ile Leu Val Gly Asn Pro Phe Thr Cys Ser Cys Asp Ile Met Trp Ile 
                  115                 120                 125             
          Lys Thr Leu Gln Glu Ala Lys Ser Ser Pro Asp Thr Gln Asp Leu Tyr 
              130                 135                 140                 
          Cys Leu Asn Glu Ser Ser Lys Asn Ile Pro Leu Ala Asn Leu Gln Ile 
          145                 150                 155                 160 
          Pro Asn Cys Gly Leu Pro Ser Ala Asn Leu Ala Ala Pro Asn Leu Thr 
                          165                 170                 175     
          Val Glu Glu Gly Lys Ser Ile Thr Leu Ser Cys Ser Val Ala Gly Asp 
                      180                 185                 190         
          Pro Val Pro Asn Met Tyr Trp Asp Val Gly Asn Leu Val Ser Lys His 
                  195                 200                 205             
          Met Asn Glu Thr Ser His Thr Gln Gly Ser Leu Arg Ile Thr Asn Ile 
              210                 215                 220                 
          Ser Ser Asp Asp Ser Gly Lys Gln Ile Ser Cys Val Ala Glu Asn Leu 
          225                 230                 235                 240 
          Val Gly Glu Asp Gln Asp Ser Val Asn Leu Thr Val His Phe Ala Pro 
                          245                 250                 255     
          Thr Ile Thr Phe Leu Glu Ser Pro Thr Ser Asp His His Trp Cys Ile 
                      260                 265                 270         
          Pro Phe Thr Val Lys Gly Asn Pro Lys Pro Ala Leu Gln Trp Phe Tyr 
                  275                 280                 285             
          Asn Gly Ala Ile Leu Asn Glu Ser Lys Tyr Ile Cys Thr Lys Ile His 
              290                 295                 300                 
          Val Thr Asn His Thr Glu Tyr His Gly Cys Leu Gln Leu Asp Asn Pro 
          305                 310                 315                 320 
          Thr His Met Asn Asn Gly Asp Tyr Thr Leu Ile Ala Lys Asn Glu Tyr 
                          325                 330                 335     
          Gly Lys Asp Glu Lys Gln Ile Ser Ala His Phe Met Gly Trp Pro Gly 
                      340                 345                 350         
          Ile Asp Asp Gly Ala Asn Pro Asn Tyr Pro Asp Val Ile Tyr Glu Asp 
                  355                 360                 365             
          Tyr Gly Thr Ala Ala Asn Asp Ile Gly Asp Thr Thr Asn Arg Ser Asn 
              370                 375                 380                 
          Glu Ile Pro Ser Thr Asp Val Thr Asp Lys Thr Gly Arg Glu His 
          385                 390                 395                 
          <![CDATA[<210> 227]]>
          <![CDATA[<211> 4]]>
          <![CDATA[<212> PRT]]>
          <![CDATA[<213> 智人]]>
          <![CDATA[<400> 227]]>
          Gly Gly Gly Ser 
          1               
          <![CDATA[<210> 228]]>
          <![CDATA[<211> 17]]>
          <![CDATA[<212> PRT]]>
          <![CDATA[<213> 智人]]>
          <![CDATA[<400> 228]]>
          Lys Ser Ser Gln Ser Leu Leu Tyr Ser Ser Asn Gln Lys Asn Tyr Leu 
          1               5                   10                  15      
          Ala 
          <![CDATA[<210> 229]]>
          <![CDATA[<211> 7]]>
          <![CDATA[<212> PRT]]>
          <![CDATA[<213> 智人]]>
          <![CDATA[<400> 229]]>
          Trp Ala Ser Thr Arg Glu Ser 
          1               5           
          <![CDATA[<210> 230]]>
          <![CDATA[<211> 9]]>
          <![CDATA[<212> PRT]]>
          <![CDATA[<213> 智人]]>
          <![CDATA[<400> 230]]>
          Gln Gln Tyr Tyr Ser Tyr Pro Tyr Thr 
          1               5                   
          <![CDATA[<210> 231]]>
          <![CDATA[<211> 10]]>
          <![CDATA[<212> PRT]]>
          <![CDATA[<213> 智人]]>
          <![CDATA[<400> 231]]>
          Gly Tyr Thr Phe Thr Gly Tyr Trp Met His 
          1               5                   10  
          <![CDATA[<210> 232]]>
          <![CDATA[<211> 17]]>
          <![CDATA[<212> PRT]]>
          <![CDATA[<213> 智人]]>
          <![CDATA[<400> 232]]>
          Tyr Ile Asn Pro Ser Thr Asp Tyr Thr Glu Tyr Asn Gln Lys Phe Lys 
          1               5                   10                  15      
          Asp 
          <![CDATA[<210> 233]]>
          <![CDATA[<211> 6]]>
          <![CDATA[<212> PRT]]>
          <![CDATA[<213> 智人]]>
          <![CDATA[<400> 233]]>
          Ser Arg Thr Gly Asn Tyr 
          1               5       
          <![CDATA[<210> 234]]>
          <![CDATA[<211> 5]]>
          <![CDATA[<212> PRT]]>
          <![CDATA[<213> 智人]]>
          <![CDATA[<400> 234]]>
          Gly Tyr Trp Met His 
          1               5   
          <![CDATA[<210> 235]]>
          <![CDATA[<211> 17]]>
          <![CDATA[<212> PRT]]>
          <![CDATA[<213> 智人]]>
          <![CDATA[<400> 235]]>
          Tyr Ile Asn Pro Ser Thr Asp Tyr Thr Glu Tyr Asn Gln Lys Phe Lys 
          1               5                   10                  15      
          Asp 
          <![CDATA[<210> 236]]>
          <![CDATA[<211> 6]]>
          <![CDATA[<212> PRT]]>
          <![CDATA[<213> 智人]]>
          <![CDATA[<400> 236]]>
          Ser Arg Thr Gly Asn Tyr 
          1               5       
          <![CDATA[<210> 237]]>
          <![CDATA[<211> 7]]>
          <![CDATA[<212> PRT]]>
          <![CDATA[<213> 智人]]>
          <![CDATA[<400> 237]]>
          Gly Tyr Thr Phe Thr Gly Tyr 
          1               5           
          <![CDATA[<210> 238]]>
          <![CDATA[<211> 6]]>
          <![CDATA[<212> PRT]]>
          <![CDATA[<213> 智人]]>
          <![CDATA[<400> 238]]>
          Asn Pro Ser Thr Asp Tyr 
          1               5       
          <![CDATA[<210> 239]]>
          <![CDATA[<211> 6]]>
          <![CDATA[<212> PRT]]>
          <![CDATA[<213> 智人]]>
          <![CDATA[<400> 239]]>
          Ser Arg Thr Gly Asn Tyr 
          1               5       
          <![CDATA[<210> 240]]>
          <![CDATA[<211> 113]]>
          <![CDATA[<212> PRT]]>
          <![CDATA[<213> 智人]]>
          <![CDATA[<400> 240]]>
          Asp Ile Val Met Thr Gln Ser Pro Asp Ser Leu Ala Val Ser Leu Gly 
          1               5                   10                  15      
          Glu Arg Ala Thr Ile Asn Cys Lys Ser Ser Gln Ser Leu Leu Tyr Ser 
                      20                  25                  30          
          Ser Asn Gln Lys Asn Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln 
                  35                  40                  45              
          Pro Pro Lys Leu Leu Ile Tyr Trp Ala Ser Thr Arg Glu Ser Gly Val 
              50                  55                  60                  
          Pro Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr 
          65                  70                  75                  80  
          Ile Ser Ser Leu Gln Ala Glu Asp Val Ala Val Tyr Tyr Cys Gln Gln 
                          85                  90                  95      
          Tyr Tyr Ser Tyr Pro Tyr Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile 
                      100                 105                 110         
          Lys 
          <![CDATA[<210> 241]]>
          <![CDATA[<211> 115]]>
          <![CDATA[<212> PRT]]>
          <![CDATA[<213> 智人]]>
          <![CDATA[<400> 241]]>
          Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala 
          1               5                   10                  15      
          Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Gly Tyr 
                      20                  25                  30          
          Trp Met His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met 
                  35                  40                  45              
          Gly Tyr Ile Asn Pro Ser Thr Asp Tyr Thr Glu Tyr Asn Gln Lys Phe 
              50                  55                  60                  
          Lys Asp Arg Val Thr Met Thr Arg Asp Thr Ser Thr Ser Thr Val Tyr 
          65                  70                  75                  80  
          Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys 
                          85                  90                  95      
          Ala Arg Ser Arg Thr Gly Asn Tyr Trp Gly Gln Gly Thr Leu Val Thr 
                      100                 105                 110         
          Val Ser Ser 
                  115 
          <![CDATA[<210> 242]]>
          <![CDATA[<211> 113]]>
          <![CDATA[<212> PRT]]>
          <![CDATA[<213> 智人]]>
          <![CDATA[<400> 242]]>
          Asp Ile Val Met Thr Gln Ser Pro Asp Ser Leu Ala Val Ser Leu Gly 
          1               5                   10                  15      
          Glu Arg Ala Thr Ile Ser Cys Lys Ser Ser Gln Ser Leu Leu Tyr Ser 
                      20                  25                  30          
          Ser Asn Gln Lys Asn Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln 
                  35                  40                  45              
          Pro Pro Lys Leu Leu Ile Tyr Trp Ala Ser Thr Arg Glu Ser Gly Val 
              50                  55                  60                  
          Pro Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr 
          65                  70                  75                  80  
          Ile Ser Ser Leu Gln Ala Glu Asp Val Ala Val Tyr Tyr Cys Gln Gln 
                          85                  90                  95      
          Tyr Tyr Ser Tyr Pro Tyr Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile 
                      100                 105                 110         
          Lys 
          <![CDATA[<210> 243]]>
          <![CDATA[<211> 115]]>
          <![CDATA[<212> PRT]]>
          <![CDATA[<213> 智人]]>
          <![CDATA[<400> 243]]>
          Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala 
          1               5                   10                  15      
          Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Gly Tyr 
                      20                  25                  30          
          Trp Met His Trp Val Arg Gln Arg Pro Gly Gln Gly Leu Glu Trp Ile 
                  35                  40                  45              
          Gly Tyr Ile Asn Pro Ser Thr Asp Tyr Thr Glu Tyr Asn Gln Lys Phe 
              50                  55                  60                  
          Lys Asp Arg Val Thr Leu Thr Arg Asp Thr Ser Thr Ser Thr Val Tyr 
          65                  70                  75                  80  
          Met Glu Leu Ser Ser Leu Thr Ser Glu Asp Thr Ala Val Tyr Tyr Cys 
                          85                  90                  95      
          Ala Arg Ser Arg Thr Gly Asn Tyr Trp Gly Gln Gly Thr Thr Val Thr 
                      100                 105                 110         
          Val Ser Ser 
                  115 
          <![CDATA[<210> 244]]>
          <![CDATA[<211> 113]]>
          <![CDATA[<212> PRT]]>
          <![CDATA[<213> 智人]]>
          <![CDATA[<400> 244]]>
          Asp Ile Val Met Thr Gln Ser Pro Asp Ser Leu Ala Val Ser Leu Gly 
          1               5                   10                  15      
          Glu Arg Ala Thr Ile Ser Cys Lys Ser Ser Gln Ser Leu Leu Tyr Ser 
                      20                  25                  30          
          Ser Asn Gln Lys Asn Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln 
                  35                  40                  45              
          Pro Pro Lys Leu Leu Ile Tyr Trp Ala Ser Thr Arg Glu Ser Gly Val 
              50                  55                  60                  
          Pro Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr 
          65                  70                  75                  80  
          Ile Ser Ser Leu Gln Ala Glu Asp Val Ala Val Tyr Tyr Cys Gln Gln 
                          85                  90                  95      
          Tyr Tyr Ser Tyr Pro Tyr Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile 
                      100                 105                 110         
          Lys 
          <![CDATA[<210> 245]]>
          <![CDATA[<211> 115]]>
          <![CDATA[<212> PRT]]>
          <![CDATA[<213> 智人]]>
          <![CDATA[<400> 245]]>
          Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala 
          1               5                   10                  15      
          Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Gly Tyr 
                      20                  25                  30          
          Trp Met His Trp Val Arg Gln Arg Pro Gly Gln Gly Leu Glu Trp Ile 
                  35                  40                  45              
          Gly Tyr Ile Asn Pro Ser Thr Asp Tyr Thr Glu Tyr Asn Gln Lys Phe 
              50                  55                  60                  
          Lys Asp Arg Val Thr Leu Thr Arg Asp Thr Ser Thr Ser Thr Val Tyr 
          65                  70                  75                  80  
          Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys 
                          85                  90                  95      
          Ala Arg Ser Arg Thr Gly Asn Tyr Trp Gly Gln Gly Thr Thr Val Thr 
                      100                 105                 110         
          Val Ser Ser 
                  115 
          <![CDATA[<210> 246]]>
          <![CDATA[<211> 113]]>
          <![CDATA[<212> PRT]]>
          <![CDATA[<213> 智人]]>
          <![CDATA[<400> 246]]>
          Asp Ile Val Met Thr Gln Ser Pro Asp Ser Leu Ala Val Ser Leu Gly 
          1               5                   10                  15      
          Glu Arg Ala Thr Ile Asn Cys Lys Ser Ser Gln Ser Leu Leu Tyr Ser 
                      20                  25                  30          
          Ser Asn Gln Lys Asn Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln 
                  35                  40                  45              
          Pro Pro Lys Leu Leu Ile Tyr Trp Ala Ser Thr Arg Glu Ser Gly Val 
              50                  55                  60                  
          Pro Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr 
          65                  70                  75                  80  
          Ile Ser Ser Leu Gln Ala Glu Asp Val Ala Val Tyr Tyr Cys Gln Gln 
                          85                  90                  95      
          Tyr Tyr Ser Tyr Pro Tyr Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile 
                      100                 105                 110         
          Lys 
          <![CDATA[<210> 247]]>
          <![CDATA[<211> 115]]>
          <![CDATA[<212> PRT]]>
          <![CDATA[<213> 智人]]>
          <![CDATA[<400> 247]]>
          Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala 
          1               5                   10                  15      
          Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Gly Tyr 
                      20                  25                  30          
          Trp Met His Trp Val Arg Gln Arg Pro Gly Gln Gly Leu Glu Trp Ile 
                  35                  40                  45              
          Gly Tyr Ile Asn Pro Ser Thr Asp Tyr Thr Glu Tyr Asn Gln Lys Phe 
              50                  55                  60                  
          Lys Asp Arg Val Thr Leu Thr Arg Asp Thr Ser Thr Ser Thr Val Tyr 
          65                  70                  75                  80  
          Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys 
                          85                  90                  95      
          Ala Arg Ser Arg Thr Gly Asn Tyr Trp Gly Gln Gly Thr Thr Val Thr 
                      100                 105                 110         
          Val Ser Ser 
                  115 
          <![CDATA[<210> 248]]>
          <![CDATA[<211> 113]]>
          <![CDATA[<212> PRT]]>
          <![CDATA[<213> 智人]]>
          <![CDATA[<400> 248]]>
          Asp Ile Val Met Thr Gln Ser Pro Asp Ser Leu Ala Val Ser Leu Gly 
          1               5                   10                  15      
          Glu Arg Ala Thr Ile Asn Cys Lys Ser Ser Gln Ser Leu Leu Tyr Ser 
                      20                  25                  30          
          Ser Asn Gln Lys Asn Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln 
                  35                  40                  45              
          Ser Pro Lys Leu Leu Ile Tyr Trp Ala Ser Thr Arg Glu Ser Gly Val 
              50                  55                  60                  
          Pro Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr 
          65                  70                  75                  80  
          Ile Ser Ser Leu Gln Ala Glu Asp Val Ala Val Tyr Tyr Cys Gln Gln 
                          85                  90                  95      
          Tyr Tyr Ser Tyr Pro Tyr Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile 
                      100                 105                 110         
          Lys 
          <![CDATA[<210> 249]]>
          <![CDATA[<211> 115]]>
          <![CDATA[<212> PRT]]>
          <![CDATA[<213> 智人]]>
          <![CDATA[<400> 249]]>
          Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala 
          1               5                   10                  15      
          Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Gly Tyr 
                      20                  25                  30          
          Trp Met His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Ile 
                  35                  40                  45              
          Gly Tyr Ile Asn Pro Ser Thr Asp Tyr Thr Glu Tyr Asn Gln Lys Phe 
              50                  55                  60                  
          Lys Asp Arg Val Thr Met Thr Arg Asp Thr Ser Thr Ser Thr Val Tyr 
          65                  70                  75                  80  
          Met Glu Leu Ser Ser Leu Thr Ser Glu Asp Thr Ala Val Tyr Tyr Cys 
                          85                  90                  95      
          Ala Arg Ser Arg Thr Gly Asn Tyr Trp Gly Gln Gly Thr Thr Val Thr 
                      100                 105                 110         
          Val Ser Ser 
                  115 
          <![CDATA[<210> 250]]>
          <![CDATA[<211> 113]]>
          <![CDATA[<212> PRT]]>
          <![CDATA[<213> 智人]]>
          <![CDATA[<400> 250]]>
          Asp Ile Val Met Thr Gln Ser Pro Asp Ser Leu Ala Val Ser Leu Gly 
          1               5                   10                  15      
          Glu Arg Ala Thr Ile Asn Cys Lys Ser Ser Gln Ser Leu Leu Tyr Ser 
                      20                  25                  30          
          Ser Asn Gln Lys Asn Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln 
                  35                  40                  45              
          Pro Pro Lys Leu Leu Ile Tyr Trp Ala Ser Thr Arg Glu Ser Gly Val 
              50                  55                  60                  
          Pro Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr 
          65                  70                  75                  80  
          Ile Ser Ser Leu Gln Ala Glu Asp Val Ala Val Tyr Tyr Cys Gln Gln 
                          85                  90                  95      
          Tyr Tyr Ser Tyr Pro Tyr Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile 
                      100                 105                 110         
          Lys 
          <![CDATA[<210> 251]]>
          <![CDATA[<211> 115]]>
          <![CDATA[<212> PRT]]>
          <![CDATA[<213> 智人]]>
          <![CDATA[<400> 251]]>
          Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala 
          1               5                   10                  15      
          Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Gly Tyr 
                      20                  25                  30          
          Trp Met His Trp Val Arg Gln Arg Pro Gly Gln Gly Leu Glu Trp Ile 
                  35                  40                  45              
          Gly Tyr Ile Asn Pro Ser Thr Asp Tyr Thr Glu Tyr Asn Gln Lys Phe 
              50                  55                  60                  
          Lys Asp Arg Val Thr Met Thr Arg Asp Thr Ser Thr Ser Thr Val Tyr 
          65                  70                  75                  80  
          Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys 
                          85                  90                  95      
          Ala Arg Ser Arg Thr Gly Asn Tyr Trp Gly Gln Gly Thr Thr Val Thr 
                      100                 105                 110         
          Val Ser Ser 
                  115 
          <![CDATA[<210> 252]]>
          <![CDATA[<211> 113]]>
          <![CDATA[<212> PRT]]>
          <![CDATA[<213> 智人]]>
          <![CDATA[<400> 252]]>
          Asp Ile Val Met Thr Gln Ser Pro Asp Ser Leu Ala Val Ser Leu Gly 
          1               5                   10                  15      
          Glu Arg Ala Thr Ile Ser Cys Lys Ser Ser Gln Ser Leu Leu Tyr Ser 
                      20                  25                  30          
          Ser Asn Gln Lys Asn Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln 
                  35                  40                  45              
          Pro Pro Lys Leu Leu Ile Tyr Trp Ala Ser Thr Arg Glu Ser Gly Val 
              50                  55                  60                  
          Pro Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr 
          65                  70                  75                  80  
          Ile Ser Ser Leu Gln Ala Glu Asp Val Ala Val Tyr Tyr Cys Gln Gln 
                          85                  90                  95      
          Tyr Tyr Ser Tyr Pro Tyr Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile 
                      100                 105                 110         
          Lys 
          <![CDATA[<210> 253]]>
          <![CDATA[<211> 115]]>
          <![CDATA[<212> PRT]]>
          <![CDATA[<213> 智人]]>
          <![CDATA[<400> 253]]>
          Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala 
          1               5                   10                  15      
          Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Gly Tyr 
                      20                  25                  30          
          Trp Met His Trp Val Arg Gln Arg Pro Gly Gln Gly Leu Glu Trp Ile 
                  35                  40                  45              
          Gly Tyr Ile Asn Pro Ser Thr Asp Tyr Thr Glu Tyr Asn Gln Lys Phe 
              50                  55                  60                  
          Lys Asp Arg Ala Thr Leu Thr Arg Asp Thr Ser Thr Ser Thr Val Tyr 
          65                  70                  75                  80  
          Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys 
                          85                  90                  95      
          Ala Arg Ser Arg Thr Gly Asn Tyr Trp Gly Gln Gly Thr Thr Val Thr 
                      100                 105                 110         
          Val Ser Ser 
                  115 
          <![CDATA[<210> 254]]>
          <![CDATA[<211> 113]]>
          <![CDATA[<212> PRT]]>
          <![CDATA[<213> 智人]]>
          <![CDATA[<400> 254]]>
          Asp Ile Val Met Thr Gln Ser Pro Asp Ser Leu Ala Val Ser Leu Gly 
          1               5                   10                  15      
          Glu Arg Ala Thr Ile Ser Cys Lys Ser Ser Gln Ser Leu Leu Tyr Ser 
                      20                  25                  30          
          Ser Asn Gln Lys Asn Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln 
                  35                  40                  45              
          Pro Pro Lys Leu Leu Ile Tyr Trp Ala Ser Thr Arg Glu Ser Gly Val 
              50                  55                  60                  
          Pro Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr 
          65                  70                  75                  80  
          Ile Ser Ser Leu Gln Ala Glu Asp Val Ala Val Tyr Tyr Cys Gln Gln 
                          85                  90                  95      
          Tyr Tyr Ser Tyr Pro Tyr Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile 
                      100                 105                 110         
          Lys 
          <![CDATA[<210> 255]]>
          <![CDATA[<211> 115]]>
          <![CDATA[<212> PRT]]>
          <![CDATA[<213> 智人]]>
          <![CDATA[<400> 255]]>
          Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala 
          1               5                   10                  15      
          Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Gly Tyr 
                      20                  25                  30          
          Trp Met His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Ile 
                  35                  40                  45              
          Gly Tyr Ile Asn Pro Ser Thr Asp Tyr Thr Glu Tyr Asn Gln Lys Phe 
              50                  55                  60                  
          Lys Asp Arg Val Thr Met Thr Arg Asp Thr Ser Thr Ser Thr Val Tyr 
          65                  70                  75                  80  
          Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys 
                          85                  90                  95      
          Ala Arg Ser Arg Thr Gly Asn Tyr Trp Gly Gln Gly Thr Thr Val Thr 
                      100                 105                 110         
          Val Ser Ser 
                  115 
          <![CDATA[<210> 256]]>
          <![CDATA[<211> 113]]>
          <![CDATA[<212> PRT]]>
          <![CDATA[<213> 智人]]>
          <![CDATA[<400> 256]]>
          Asp Ile Val Met Thr Gln Ser Pro Asp Ser Leu Ala Val Ser Leu Gly 
          1               5                   10                  15      
          Glu Arg Ala Thr Ile Asn Cys Lys Ser Ser Gln Ser Leu Leu Tyr Ser 
                      20                  25                  30          
          Ser Asn Gln Lys Asn Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln 
                  35                  40                  45              
          Ser Pro Lys Leu Leu Ile Tyr Trp Ala Ser Thr Arg Glu Ser Gly Val 
              50                  55                  60                  
          Pro Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr 
          65                  70                  75                  80  
          Ile Ser Ser Leu Gln Ala Glu Asp Val Ala Val Tyr Tyr Cys Gln Gln 
                          85                  90                  95      
          Tyr Tyr Ser Tyr Pro Tyr Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile 
                      100                 105                 110         
          Lys 
          <![CDATA[<210> 257]]>
          <![CDATA[<211> 115]]>
          <![CDATA[<212> PRT]]>
          <![CDATA[<213> 智人]]>
          <![CDATA[<400> 257]]>
          Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala 
          1               5                   10                  15      
          Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Gly Tyr 
                      20                  25                  30          
          Trp Met His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Ile 
                  35                  40                  45              
          Gly Tyr Ile Asn Pro Ser Thr Asp Tyr Thr Glu Tyr Asn Gln Lys Phe 
              50                  55                  60                  
          Lys Asp Arg Val Thr Met Thr Arg Asp Thr Ser Thr Ser Thr Val Tyr 
          65                  70                  75                  80  
          Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys 
                          85                  90                  95      
          Ala Arg Ser Arg Thr Gly Asn Tyr Trp Gly Gln Gly Thr Thr Val Thr 
                      100                 105                 110         
          Val Ser Ser 
                  115
Figure 12_A0101_SEQ_0001
Figure 12_A0101_SEQ_0002
Figure 12_A0101_SEQ_0003
Figure 12_A0101_SEQ_0004
Figure 12_A0101_SEQ_0005
Figure 12_A0101_SEQ_0006
Figure 12_A0101_SEQ_0007
Figure 12_A0101_SEQ_0008
Figure 12_A0101_SEQ_0009
Figure 12_A0101_SEQ_0010
Figure 12_A0101_SEQ_0011
Figure 12_A0101_SEQ_0012
Figure 12_A0101_SEQ_0013
Figure 12_A0101_SEQ_0014
Figure 12_A0101_SEQ_0015
Figure 12_A0101_SEQ_0016
Figure 12_A0101_SEQ_0017
Figure 12_A0101_SEQ_0018
Figure 12_A0101_SEQ_0019
Figure 12_A0101_SEQ_0020
Figure 12_A0101_SEQ_0021
Figure 12_A0101_SEQ_0022
Figure 12_A0101_SEQ_0023
Figure 12_A0101_SEQ_0024
Figure 12_A0101_SEQ_0025
Figure 12_A0101_SEQ_0026
Figure 12_A0101_SEQ_0027
Figure 12_A0101_SEQ_0028
Figure 12_A0101_SEQ_0029
Figure 12_A0101_SEQ_0030
Figure 12_A0101_SEQ_0031
Figure 12_A0101_SEQ_0032
Figure 12_A0101_SEQ_0033
Figure 12_A0101_SEQ_0034
Figure 12_A0101_SEQ_0035
Figure 12_A0101_SEQ_0036
Figure 12_A0101_SEQ_0037
Figure 12_A0101_SEQ_0038
Figure 12_A0101_SEQ_0039
Figure 12_A0101_SEQ_0040
Figure 12_A0101_SEQ_0041
Figure 12_A0101_SEQ_0042
Figure 12_A0101_SEQ_0043
Figure 12_A0101_SEQ_0044
Figure 12_A0101_SEQ_0045
Figure 12_A0101_SEQ_0046
Figure 12_A0101_SEQ_0047
Figure 12_A0101_SEQ_0048
Figure 12_A0101_SEQ_0049
Figure 12_A0101_SEQ_0050
Figure 12_A0101_SEQ_0051
Figure 12_A0101_SEQ_0052
Figure 12_A0101_SEQ_0053
Figure 12_A0101_SEQ_0054
Figure 12_A0101_SEQ_0055
Figure 12_A0101_SEQ_0056
Figure 12_A0101_SEQ_0057
Figure 12_A0101_SEQ_0058
Figure 12_A0101_SEQ_0059
Figure 12_A0101_SEQ_0060
Figure 12_A0101_SEQ_0061
Figure 12_A0101_SEQ_0062
Figure 12_A0101_SEQ_0063
Figure 12_A0101_SEQ_0064
Figure 12_A0101_SEQ_0065
Figure 12_A0101_SEQ_0066
Figure 12_A0101_SEQ_0067
Figure 12_A0101_SEQ_0068
Figure 12_A0101_SEQ_0069
Figure 12_A0101_SEQ_0070
Figure 12_A0101_SEQ_0071
Figure 12_A0101_SEQ_0072
Figure 12_A0101_SEQ_0073
Figure 12_A0101_SEQ_0074
Figure 12_A0101_SEQ_0075
Figure 12_A0101_SEQ_0076
Figure 12_A0101_SEQ_0077
Figure 12_A0101_SEQ_0078
Figure 12_A0101_SEQ_0079
Figure 12_A0101_SEQ_0080
Figure 12_A0101_SEQ_0081
Figure 12_A0101_SEQ_0082
Figure 12_A0101_SEQ_0083
Figure 12_A0101_SEQ_0084
Figure 12_A0101_SEQ_0085
Figure 12_A0101_SEQ_0086
Figure 12_A0101_SEQ_0087
Figure 12_A0101_SEQ_0088
Figure 12_A0101_SEQ_0089
Figure 12_A0101_SEQ_0090
Figure 12_A0101_SEQ_0091
Figure 12_A0101_SEQ_0092
Figure 12_A0101_SEQ_0093
Figure 12_A0101_SEQ_0094
Figure 12_A0101_SEQ_0095
Figure 12_A0101_SEQ_0096
Figure 12_A0101_SEQ_0097
Figure 12_A0101_SEQ_0098
Figure 12_A0101_SEQ_0099
Figure 12_A0101_SEQ_0100
Figure 12_A0101_SEQ_0101
Figure 12_A0101_SEQ_0102
Figure 12_A0101_SEQ_0103
Figure 12_A0101_SEQ_0104
Figure 12_A0101_SEQ_0105
Figure 12_A0101_SEQ_0106
Figure 12_A0101_SEQ_0107
Figure 12_A0101_SEQ_0108
Figure 12_A0101_SEQ_0109
Figure 12_A0101_SEQ_0110
Figure 12_A0101_SEQ_0111
Figure 12_A0101_SEQ_0112
Figure 12_A0101_SEQ_0113
Figure 12_A0101_SEQ_0114
Figure 12_A0101_SEQ_0115
Figure 12_A0101_SEQ_0116
Figure 12_A0101_SEQ_0117
Figure 12_A0101_SEQ_0118
Figure 12_A0101_SEQ_0119
Figure 12_A0101_SEQ_0120
Figure 12_A0101_SEQ_0121
Figure 12_A0101_SEQ_0122
Figure 12_A0101_SEQ_0123
Figure 12_A0101_SEQ_0124
Figure 12_A0101_SEQ_0125
Figure 12_A0101_SEQ_0126
Figure 12_A0101_SEQ_0127
Figure 12_A0101_SEQ_0128
Figure 12_A0101_SEQ_0129
Figure 12_A0101_SEQ_0130
Figure 12_A0101_SEQ_0131
Figure 12_A0101_SEQ_0132
Figure 12_A0101_SEQ_0133
Figure 12_A0101_SEQ_0134
Figure 12_A0101_SEQ_0135
Figure 12_A0101_SEQ_0136
Figure 12_A0101_SEQ_0137
Figure 12_A0101_SEQ_0138
Figure 12_A0101_SEQ_0139
Figure 12_A0101_SEQ_0140
Figure 12_A0101_SEQ_0141
Figure 12_A0101_SEQ_0142
Figure 12_A0101_SEQ_0143
Figure 12_A0101_SEQ_0144
Figure 12_A0101_SEQ_0145
Figure 12_A0101_SEQ_0146
Figure 12_A0101_SEQ_0147
Figure 12_A0101_SEQ_0148
Figure 12_A0101_SEQ_0149
Figure 12_A0101_SEQ_0150
Figure 12_A0101_SEQ_0151
Figure 12_A0101_SEQ_0152
Figure 12_A0101_SEQ_0153
Figure 12_A0101_SEQ_0154
Figure 12_A0101_SEQ_0155
Figure 12_A0101_SEQ_0156
Figure 12_A0101_SEQ_0157
Figure 12_A0101_SEQ_0158
Figure 12_A0101_SEQ_0159
Figure 12_A0101_SEQ_0160
Figure 12_A0101_SEQ_0161
Figure 12_A0101_SEQ_0162
Figure 12_A0101_SEQ_0163
Figure 12_A0101_SEQ_0164
Figure 12_A0101_SEQ_0165
Figure 12_A0101_SEQ_0166
Figure 12_A0101_SEQ_0167
Figure 12_A0101_SEQ_0168
Figure 12_A0101_SEQ_0169
Figure 12_A0101_SEQ_0170
Figure 12_A0101_SEQ_0171
Figure 12_A0101_SEQ_0172
Figure 12_A0101_SEQ_0173
Figure 12_A0101_SEQ_0174
Figure 12_A0101_SEQ_0175
Figure 12_A0101_SEQ_0176
Figure 12_A0101_SEQ_0177
Figure 12_A0101_SEQ_0178
Figure 12_A0101_SEQ_0179
Figure 12_A0101_SEQ_0180
Figure 12_A0101_SEQ_0181
Figure 12_A0101_SEQ_0182
Figure 12_A0101_SEQ_0183
Figure 12_A0101_SEQ_0184
Figure 12_A0101_SEQ_0185
Figure 12_A0101_SEQ_0186
Figure 12_A0101_SEQ_0187
Figure 12_A0101_SEQ_0188
Figure 12_A0101_SEQ_0189
Figure 12_A0101_SEQ_0190
Figure 12_A0101_SEQ_0191
Figure 12_A0101_SEQ_0192
Figure 12_A0101_SEQ_0193
Figure 12_A0101_SEQ_0194
Figure 12_A0101_SEQ_0195
Figure 12_A0101_SEQ_0196
Figure 12_A0101_SEQ_0197
Figure 12_A0101_SEQ_0198
Figure 12_A0101_SEQ_0199
Figure 12_A0101_SEQ_0200
Figure 12_A0101_SEQ_0201
Figure 12_A0101_SEQ_0202
Figure 12_A0101_SEQ_0203
Figure 12_A0101_SEQ_0204
Figure 12_A0101_SEQ_0205
Figure 12_A0101_SEQ_0206
Figure 12_A0101_SEQ_0207
Figure 12_A0101_SEQ_0208
Figure 12_A0101_SEQ_0209
Figure 12_A0101_SEQ_0210
Figure 12_A0101_SEQ_0211
Figure 12_A0101_SEQ_0212
Figure 12_A0101_SEQ_0213
Figure 12_A0101_SEQ_0214
Figure 12_A0101_SEQ_0215
Figure 12_A0101_SEQ_0216
Figure 12_A0101_SEQ_0217
Figure 12_A0101_SEQ_0218
Figure 12_A0101_SEQ_0219
Figure 12_A0101_SEQ_0220
Figure 12_A0101_SEQ_0221
Figure 12_A0101_SEQ_0222
Figure 12_A0101_SEQ_0223
Figure 12_A0101_SEQ_0224
Figure 12_A0101_SEQ_0225
Figure 12_A0101_SEQ_0226
Figure 12_A0101_SEQ_0227
Figure 12_A0101_SEQ_0228
Figure 12_A0101_SEQ_0229
Figure 12_A0101_SEQ_0230
Figure 12_A0101_SEQ_0231
Figure 12_A0101_SEQ_0232
Figure 12_A0101_SEQ_0233
Figure 12_A0101_SEQ_0234
Figure 12_A0101_SEQ_0235
Figure 12_A0101_SEQ_0236
Figure 12_A0101_SEQ_0237
Figure 12_A0101_SEQ_0238
Figure 12_A0101_SEQ_0239

Claims (46)

  1. 一種結合分子，其包含至少一個與血管內皮生長因子(Vascular Endothelial Growth Factor；VEGF)特異性結合之抗原結合位點及至少一個與肌旋蛋白受體激酶B (Tropomyosin receptor kinase B；TrkB)特異性結合之抗原結合位點。
  2. 如請求項1之結合分子，其中該分子為雙特異性且四價的。
  3. 如請求項1或2之結合分子，其中該至少一個與VEGF特異性結合之抗原結合位點為免疫球蛋白(Ig)分子。
  4. 如請求項3之結合分子，其中該至少一個與TrkB特異性結合之抗原結合位點與該Ig分子之重鏈的C端融合。
  5. 如請求項1或2之結合分子，其中該至少一個與TrkB特異性結合之抗原結合位點包含一或多個scFv。
  6. 如請求項1或2之結合分子，其中該至少一個與VEGF特異性結合之抗原結合位點為免疫球蛋白(Ig)分子，且該至少一個與TrkB特異性結合之抗原結合位點包含一或多個scFv。
  7. 如請求項5之結合分子，其中該一或多個scFv自N端至C端具有VL-VH定向。
  8. 如請求項5之結合分子，其中該一或多個scFv與該Ig分子之重鏈的C端融合。
  9. 如請求項3之結合分子，其中該Ig分子為單株抗體、人類單株抗體、人源化單株抗體、嵌合抗體、(scFv) 2或抗體之片段，諸如F(ab')2片段。
  10. 如請求項3之結合分子，其中該Ig分子為IgG或F(ab')2。
  11. 如請求項5之結合分子，其中該一或多個scFv藉由肽連接子，較佳地長度為約4至20個胺基酸之肽連接子與該Ig分子融合。
  12. 如請求項1或2之結合分子，其中與TrkB特異性結合之該抗原結合位點選自： a)  包含輕鏈CDR之抗原結合位點，該輕鏈CDR包含SEQ ID NO:201 (CDR1)、SEQ ID NO:202 (CDR2)及SEQ ID NO:203 (CDR3)之胺基酸序列，及 包含重鏈CDR之抗原結合位點，該重鏈CDR包含SEQ ID NO:204 (CDR1)、SEQ ID NO:205 (CDR2)及SEQ ID NO:206 (CDR3)之胺基酸序列；或 包含重鏈CDR之抗原結合位點，該重鏈CDR包含SEQ ID NO:207 (CDR1)、SEQ ID NO:208 (CDR2)及SEQ ID NO:209 (CDR3)之胺基酸序列；或 包含重鏈CDR之抗原結合位點，該重鏈CDR包含SEQ ID NO:210 (CDR1)、SEQ ID NO:211 (CDR2)及SEQ ID NO:212 (CDR3)之胺基酸序列。
  13. 如請求項1或2之結合分子，其中與TrkB特異性結合之該抗原結合位點選自： a)  包含輕鏈可變域及重鏈可變域之抗原結合位點，該輕鏈可變域包含與SEQ ID NO:213或215之胺基酸序列至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或至少99%一致的胺基酸序列，該重鏈可變域包含與SEQ ID NO:214或216之胺基酸序列至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或至少99%一致的胺基酸序列。
  14. 如請求項1或2之結合分子，其包含SEQ ID NO:222之胺基酸序列、或SEQ ID NO:223之胺基酸序列、或SEQ ID NO:224之胺基酸序列或SEQ ID NO:225之胺基酸序列。
  15. 如請求項1或2之結合分子，其中與VEGF特異性結合之該抗原結合位點選自由抗原結合位點a)至c)組成之群： a)  包含輕鏈CDR之抗原結合位點，該輕鏈CDR包含SEQ ID NO:145 (CDR1)、SEQ ID NO:146 (CDR2)及SEQ ID NO:147 (CDR3)之胺基酸序列，及 包含重鏈CDR之抗原結合位點，該重鏈CDR包含SEQ ID NO:148 (CDR1)、SEQ ID NO:149 (CDR2)及SEQ ID NO:150 (CDR3)之胺基酸序列；或 包含重鏈CDR之抗原結合位點，該重鏈CDR包含SEQ ID NO:151 (CDR1)、SEQ ID NO:152 (CDR2)及SEQ ID NO:153 (CDR3)之胺基酸序列；或 包含重鏈CDR之抗原結合位點，該重鏈CDR包含SEQ ID NO:154 (CDR1)、SEQ ID NO:155 (CDR2)及SEQ ID NO:156 (CDR3)之胺基酸序列； b)  包含輕鏈CDR之抗原結合位點，該輕鏈CDR包含SEQ ID NO:157 (CDR1)、SEQ ID NO:158 (CDR2)及SEQ ID NO:159 (CDR3)之胺基酸序列，及 包含重鏈CDR之抗原結合位點，該重鏈CDR包含SEQ ID NO:160 (CDR1)、SEQ ID NO:161 (CDR2)及SEQ ID NO:162 (CDR3)之胺基酸序列；或 包含重鏈CDR之抗原結合位點，該重鏈CDR包含SEQ ID NO:163 (CDR1)、SEQ ID NO:164 (CDR2)及SEQ ID NO:165 (CDR3)之胺基酸序列；或 包含重鏈CDR之抗原結合位點，該重鏈CDR包含SEQ ID NO:166 (CDR1)、SEQ ID NO:167 (CDR2)及SEQ ID NO:168 (CDR3)之胺基酸序列； c)  包含輕鏈CDR之抗原結合位點，該輕鏈CDR包含SEQ ID NO:169 (CDR1)、SEQ ID NO:170 (CDR2)及SEQ ID NO:171 (CDR3)之胺基酸序列，及 包含重鏈CDR之抗原結合位點，該重鏈CDR包含SEQ ID NO:172 (CDR1)、SEQ ID NO:173 (CDR2)及SEQ ID NO:174 (CDR3)之胺基酸序列；或 包含重鏈CDR之抗原結合位點，該重鏈CDR包含SEQ ID NO:175 (CDR1)、SEQ ID NO:176 (CDR2)及SEQ ID NO:177 (CDR3)之胺基酸序列；或 包含重鏈CDR之抗原結合位點，該重鏈CDR包含SEQ ID NO:178 (CDR1)、SEQ ID NO:179 (CDR2)及SEQ ID NO:180 (CDR3)之胺基酸序列。
  16. 如請求項1或2之結合分子，其中與VEGF特異性結合之該抗原結合位點選自由抗原結合位點a)至d)組成之群： a)  包含輕鏈可變域及重鏈可變域之抗原結合位點，該輕鏈可變域包含與SEQ ID NO:181之胺基酸序列至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或至少99%一致的胺基酸序列，該重鏈可變域包含與SEQ ID NO:182之胺基酸序列至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或至少99%一致的胺基酸序列； b)  包含輕鏈可變域及重鏈可變域之抗原結合位點，該輕鏈可變域包含與SEQ ID NO:183之胺基酸序列至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或至少99%一致的胺基酸序列，該重鏈可變域包含與SEQ ID NO:184之胺基酸序列至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或至少99%一致的胺基酸序列； c)  包含輕鏈可變域及重鏈可變域之抗原結合位點，該輕鏈可變域包含與SEQ ID NO:189之胺基酸序列至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或至少99%一致的胺基酸序列，該重鏈可變域包含與SEQ ID NO:190、191、192或194之胺基酸序列至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或至少99%一致的胺基酸序列； d)  包含輕鏈可變域及重鏈可變域之抗原結合位點，該輕鏈可變域包含與SEQ ID NO:193之胺基酸序列至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或至少99%一致的胺基酸序列，該重鏈可變域包含與SEQ ID NO:190、191、192或194之胺基酸序列至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或至少99%一致的胺基酸序列。
  17. 如請求項1或2之結合分子，其中與VEGF特異性結合之該抗原結合位點選自由抗原結合位點a)至d)組成之群： a)  包含輕鏈及重鏈之抗原結合位點，該輕鏈包含與SEQ ID NO:185之胺基酸序列至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或至少99%一致的胺基酸序列，該重鏈包含與SEQ ID NO:186之胺基酸序列至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或至少99%一致的胺基酸序列； b)  包含輕鏈及重鏈之抗原結合位點，該輕鏈包含與SEQ ID NO:187之胺基酸序列至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或至少99%一致的胺基酸序列，該重鏈包含與SEQ ID NO:188之胺基酸序列至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或至少99%一致的胺基酸序列； c)  包含輕鏈及重鏈之抗原結合位點，該輕鏈包含與SEQ ID NO:195之胺基酸序列至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或至少99%一致的胺基酸序列，該重鏈包含與SEQ ID NO:196、197、198或200之胺基酸序列至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或至少99%一致的胺基酸序列； d)  包含輕鏈及重鏈之抗原結合位點，該輕鏈包含與SEQ ID NO:199之胺基酸序列至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或至少99%一致的胺基酸序列，該重鏈包含與SEQ ID NO:196、197、198或200之胺基酸序列至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或至少99%一致的胺基酸序列。
  18. 一種結合分子，其包含輕鏈及重鏈，該輕鏈包含與SEQ ID NO:1、3、5、7、9、11、13、15、17、19、21、23、25、27、29、31、33、35、37、39、41、43、45、47、49、51、53、55、57、59、61、63、65、67、69、71、73、75、77、79、81、83、85、87、89、91、93、95、97、99、101、103、105、107、109、111、113、115、117、119、121、123、125、127、129、131、133、135、137、139、141或143之胺基酸序列至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或至少99%一致的胺基酸序列；該重鏈包含與SEQ ID NO:2、4、6、8、10、12、14、16、18、20、22、24、26、28、30、32、34、36、38、40、42、44、46、48、50、52、54、56、58、60、62、64、66、68、70、72、74、76、78、80、82、84、86、88、90、92、94、96、98、100、102、104、106、108、110、112、114、116、118、120、122、124、126、128、130、132、134、136、138、140、142或144之胺基酸序列至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或至少99%一致的胺基酸序列。
  19. 一種結合分子，其包含：(i)包含SEQ ID NO:41之胺基酸序列的輕鏈及包含SEQ ID NO:42之胺基酸序列的重鏈；或(ii)包含SEQ ID NO:43之胺基酸序列的輕鏈及包含SEQ ID NO:44之胺基酸序列的重鏈；或(iii)包含SEQ ID NO:45之胺基酸序列的輕鏈及包含SEQ ID NO:46之胺基酸序列的重鏈；或(iv)包含SEQ ID NO:47之胺基酸序列的輕鏈及包含SEQ ID NO:48之胺基酸序列的重鏈；或(v)包含SEQ ID NO:49之胺基酸序列的輕鏈及包含SEQ ID NO:50之胺基酸序列的重鏈；或(vi)包含SEQ ID NO:51之胺基酸序列的輕鏈及包含SEQ ID NO:52之胺基酸序列的重鏈；或(vii)包含SEQ ID NO:53之胺基酸序列的輕鏈及包含SEQ ID NO:54之胺基酸序列的重鏈；或(viii)包含SEQ ID NO:55之胺基酸序列的輕鏈及包含SEQ ID NO:56之胺基酸序列的重鏈；或(ix)包含SEQ ID NO:57之胺基酸序列的輕鏈及包含SEQ ID NO:58之胺基酸序列的重鏈；或(x)包含SEQ ID NO:59之胺基酸序列的輕鏈及包含SEQ ID NO:60之胺基酸序列的重鏈；或(xi)包含SEQ ID NO:61之胺基酸序列的輕鏈及包含SEQ ID NO:62之胺基酸序列的重鏈；或(xii)包含SEQ ID NO:63之胺基酸序列的輕鏈及包含SEQ ID NO:64之胺基酸序列的重鏈；或(xiii)包含SEQ ID NO:65之胺基酸序列的輕鏈及包含SEQ ID NO:66之胺基酸序列的重鏈；或(xiv)包含SEQ ID NO:67之胺基酸序列的輕鏈及包含SEQ ID NO:68之胺基酸序列的重鏈；或(xv)包含SEQ ID NO:69之胺基酸序列的輕鏈及包含SEQ ID NO:70之胺基酸序列的重鏈；或(xvi)包含SEQ ID NO:71之胺基酸序列的輕鏈及包含SEQ ID NO:72之胺基酸序列的重鏈；或(xvii)包含SEQ ID NO:73之胺基酸序列的輕鏈及包含SEQ ID NO:74之胺基酸序列的重鏈；或(xviii)包含SEQ ID NO:75之胺基酸序列的輕鏈及包含SEQ ID NO:76之胺基酸序列的重鏈；或(xix)包含SEQ ID NO:77之胺基酸序列的輕鏈及包含SEQ ID NO:78之胺基酸序列的重鏈；或(xx)包含SEQ ID NO:79之胺基酸序列的輕鏈及包含SEQ ID NO:80之胺基酸序列的重鏈；或(xxi)包含SEQ ID NO:81之胺基酸序列的輕鏈及包含SEQ ID NO:82之胺基酸序列的重鏈；或(xxii)包含SEQ ID NO:83之胺基酸序列的輕鏈及包含SEQ ID NO:84之胺基酸序列的重鏈；或(xxiii)包含SEQ ID NO:85之胺基酸序列的輕鏈及包含SEQ ID NO:86之胺基酸序列的重鏈；或(xxiv)包含SEQ ID NO:87之胺基酸序列的輕鏈及包含SEQ ID NO:88之胺基酸序列的重鏈；或(xxv)包含SEQ ID NO:89之胺基酸序列的輕鏈及包含SEQ ID NO:90之胺基酸序列的重鏈；或(xxvi)包含SEQ ID NO:91之胺基酸序列的輕鏈及包含SEQ ID NO:92之胺基酸序列的重鏈；或(xxvii)包含SEQ ID NO:93之胺基酸序列的輕鏈及包含SEQ ID NO:94之胺基酸序列的重鏈；或(xxviii)包含SEQ ID NO:95之胺基酸序列的輕鏈及包含SEQ ID NO:96之胺基酸序列的重鏈；或(xxix)包含SEQ ID NO:97之胺基酸序列的輕鏈及包含SEQ ID NO:98之胺基酸序列的重鏈；或(xxx)包含SEQ ID NO:99之胺基酸序列的輕鏈及包含SEQ ID NO:100之胺基酸序列的重鏈；或(xxxi)包含SEQ ID NO:101之胺基酸序列的輕鏈及包含SEQ ID NO:102之胺基酸序列的重鏈；或(xxxii)包含SEQ ID NO:103之胺基酸序列的輕鏈及包含SEQ ID NO:104之胺基酸序列的重鏈；或(xxxiii)包含SEQ ID NO:105之胺基酸序列的輕鏈及包含SEQ ID NO:106之胺基酸序列的重鏈；或(xxxiv)包含SEQ ID NO:107之胺基酸序列的輕鏈及包含SEQ ID NO:108之胺基酸序列的重鏈；或(xxxv)包含SEQ ID NO:109之胺基酸序列的輕鏈及包含SEQ ID NO:110之胺基酸序列的重鏈；或(xxxvi)包含SEQ ID NO:111之胺基酸序列的輕鏈及包含SEQ ID NO:112之胺基酸序列的重鏈；或(xxxvii)包含SEQ ID NO:113之胺基酸序列的輕鏈及包含SEQ ID NO:114之胺基酸序列的重鏈；或(xxxviii)包含SEQ ID NO:115之胺基酸序列的輕鏈及包含SEQ ID NO:116之胺基酸序列的重鏈；或(xxxix)包含SEQ ID NO:117之胺基酸序列的輕鏈及包含SEQ ID NO:118之胺基酸序列的重鏈；或(xl)包含SEQ ID NO:119之胺基酸序列的輕鏈及包含SEQ ID NO:120之胺基酸序列的重鏈；或(xli)包含SEQ ID NO:121之胺基酸序列的輕鏈及包含SEQ ID NO:122之胺基酸序列的重鏈；或(xlii)包含SEQ ID NO:123之胺基酸序列的輕鏈及包含SEQ ID NO:124之胺基酸序列的重鏈；或(xliii)包含SEQ ID NO:125之胺基酸序列的輕鏈及包含SEQ ID NO:126之胺基酸序列的重鏈；或(xliv)包含SEQ ID NO:127之胺基酸序列的輕鏈及包含SEQ ID NO:128之胺基酸序列的重鏈；或(xlv)包含SEQ ID NO:129之胺基酸序列的輕鏈及包含SEQ ID NO:130之胺基酸序列的重鏈；或(xlvi)包含SEQ ID NO:131之胺基酸序列的輕鏈及包含SEQ ID NO:132之胺基酸序列的重鏈；或(xlvii)包含SEQ ID NO:133之胺基酸序列的輕鏈及包含SEQ ID NO:134之胺基酸序列的重鏈；或(xlviii)包含SEQ ID NO:135之胺基酸序列的輕鏈及包含SEQ ID NO:136之胺基酸序列的重鏈；或(xlix)包含SEQ ID NO:137之胺基酸序列的輕鏈及包含SEQ ID NO:138之胺基酸序列的重鏈；或(l)包含SEQ ID NO:139之胺基酸序列的輕鏈及包含SEQ ID NO:140之胺基酸序列的重鏈；或(li)包含SEQ ID NO:141之胺基酸序列的輕鏈及包含SEQ ID NO:142之胺基酸序列的重鏈；或(lii)包含SEQ ID NO:143之胺基酸序列的輕鏈及包含SEQ ID NO:144的重鏈。
  20. 一種TrkB結合分子，其包含兩個scFv或由其組成，其中各scFv與TrkB特異性結合。
  21. 如請求項20之TrkB結合分子，其進一步包含Ig分子。
  22. 如請求項21之TrkB結合分子，其中該Ig分子為單株抗體；人類單株抗體；人源化單株抗體；嵌合抗體；抗體之片段，諸如Fv、Fab、Fab'或F(ab')2片段；單鏈抗體，諸如單鏈可變片段(single chain variable fragment；scFv)；小模組免疫藥物(Small Modular Immunopharmaceutical；SMIP)；域抗體；奈米抗體；或雙功能抗體。
  23. 如請求項22之TrkB結合分子，其中各scFv與該Ig分子之重鏈的C端融合。
  24. 如請求項21至23中任一項之TrkB結合分子，其中該Ig分子為IgG、F(ab)或F(ab')2。
  25. 如請求項21或23之TrkB結合分子，其中該Ig分子包含Fc區或由其組成。
  26. 如請求項21至23中任一項之TrkB結合分子，其中該TrkB結合分子為雙特異性且四價的。
  27. 如請求項21至23中任一項之TrkB結合分子，其中各scFv藉由肽連接子，較佳地長度為約4至20個胺基酸之肽連接子與該Ig分子融合。
  28. 一種與TrkB特異性結合之scFv，其包含(i)包含SEQ ID NO:213之胺基酸序列的輕鏈可變域及包含SEQ ID NO:214之胺基酸序列的重鏈可變域；或(ii)包含SEQ ID NO:215之胺基酸序列的輕鏈可變域及包含SEQ ID NO:216之胺基酸序列的重鏈可變域。
  29. 如請求項28之scFv，其包含SEQ ID NO:222之胺基酸序列、或SEQ ID NO:223之胺基酸序列、或SEQ ID NO:224之胺基酸序列或SEQ ID NO:225之胺基酸序列。
  30. 一種與VEGF特異性結合之抗體分子，其包含： (i)輕鏈可變域，其包含SEQ ID NO:189之胺基酸序列，及 重鏈可變域，其包含SEQ ID NO:191之胺基酸序列；或 重鏈可變域，其包含SEQ ID NO:192之胺基酸序列；或 重鏈可變域，其包含SEQ ID NO:194之胺基酸序列； (ii)重鏈可變域，其包含SEQ ID NO:190之胺基酸序列，及 輕鏈可變域，其包含SEQ ID NO:192之胺基酸序列；或 輕鏈可變域，其包含SEQ ID NO:193之胺基酸序列。
  31. 如請求項30之抗體分子，其包含： 輕鏈，其包含SEQ ID NO:195或199之胺基酸序列，及 重鏈，其包含SEQ ID NO:196、197、198或200之胺基酸序列。
  32. 一種經分離之核酸分子，其編碼如請求項1至19中任一項之結合分子的(i)重鏈或重鏈可變域及/或(ii)輕鏈或輕鏈可變域。
  33. 一種經分離之核酸分子，其編碼如請求項20至27中任一項之TrkB結合分子的(i)重鏈或重鏈可變域及/或(ii)輕鏈或輕鏈可變域。
  34. 一種經分離之核酸分子，其編碼如請求項28至29中任一項之scFv的(i)重鏈可變域及/或(ii)輕鏈可變域。
  35. 一種經分離之核酸分子，其編碼如請求項30至31中任一項之抗體分子的(i)重鏈或重鏈可變域及/或(ii)輕鏈或輕鏈可變域。
  36. 一種病毒載體，其包含如請求項32至35中任一項之經分離之核酸分子。
  37. 一種表現載體，其包含如請求項32至35中任一項之經分離之核酸分子。
  38. 一種宿主細胞，其用如請求項37之表現載體轉染。
  39. 一種製造如請求項1至19中任一項之結合分子、如請求項20至27中任一項之TrkB結合分子、如請求項28至29中任一項之scFv或如請求項30至31中任一項之抗體分子之方法，其包含 (a)    在允許該分子表現之條件下培養如請求項38之宿主細胞；及 (b)    回收該分子；及視情況 (c) 進一步純化及/或修飾及/或調配該分子。
  40. 一種醫藥組合物，其包含醫藥學上可接受之載劑及如請求項1至19中任一項之結合分子、如請求項20至27中任一項之TrkB結合分子、如請求項28至29中任一項之scFv或如請求項30至31中任一項之抗體分子。
  41. 一種如請求項1至19中任一項之結合分子、或如請求項20至27中任一項之TrkB結合分子、或如請求項28至29中任一項之scFv、或如請求項30至31中任一項之抗體分子之用途，其用於製備用於治療或預防眼部疾病或視網膜疾病或神經退化性疾病的醫藥組合物。
  42. 如請求項41之用途，其中該醫藥組合物係用於治療神經/神經元眼部或視網膜疾病。
  43. 如請求項41之用途，其中該醫藥組合物係用於治療黃斑變性、老年性黃斑變性、糖尿病性視網膜病變、糖尿病性黃斑水腫、色素性視網膜炎、遺傳性視網膜營養性萎縮、遺傳性黃斑營養不良、近視變性、地圖狀萎縮、視網膜動脈阻塞、眼內炎、葡萄膜炎、囊樣黃斑水腫、繼發於任何視網膜疾病之脈絡膜新生血管性膜、視神經病、青光眼、視網膜脫落、毒性視網膜病、輻射性視網膜病、及創傷性視網膜病、前驅性及輕度至中度阿茲海默氏症(Alzheimer´s disease)，延遲患有阿茲海默氏病、杭丁頓氏症(Huntington´s disease)、帕金森氏症(Parkinson´s disease)、嚴重抑鬱症、精神分裂症、與精神分裂症相關之認知障礙之患者的疾病進展，預防患有減弱精神病症候群之個體的第一次精神病發作，預防患有精神分裂症、難治性抑鬱、暴食、肥胖症或代謝症候群之患者復發。
  44. 如請求項41之用途，其中該醫藥組合物係用於治療濕性年齡相關之黃斑變性(wet age-related macular degeneration；wAMD)。
  45. 如請求項41之用途，其中該醫藥組合物係用於治療視網膜靜脈阻塞(retinal vein occlusion；RVO)。
  46. 如請求項41之用途，其中該醫藥組合物係用於治療及/或預防地圖狀萎縮。
TW110138827A 2020-10-21 2021-10-20 用於治療眼部疾病之雙特異性抗-VEGF及抗-TrkB結合分子 TW202233668A (zh)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
EP20203030 2020-10-21
EP20203030.0 2020-10-21

Publications (1)

Publication Number Publication Date
TW202233668A true TW202233668A (zh) 2022-09-01

Family

ID=73005392

Family Applications (1)

Application Number Title Priority Date Filing Date
TW110138827A TW202233668A (zh) 2020-10-21 2021-10-20 用於治療眼部疾病之雙特異性抗-VEGF及抗-TrkB結合分子

Country Status (7)

Country Link
US (2) US20220119536A1 (zh)
EP (2) EP4232476A2 (zh)
JP (2) JP2023546229A (zh)
CN (2) CN116829586A (zh)
AR (1) AR123862A1 (zh)
TW (1) TW202233668A (zh)
WO (2) WO2022084355A2 (zh)

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
AR123862A1 (es) * 2020-10-21 2023-01-18 Boehringer Ingelheim Int Moléculas de unión biespecíficas anti-vegf y anti-trkb para el tratamiento de enfermedades oculares

Family Cites Families (30)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5731A (en) 1848-08-22 Elisha k
US168A (en) 1837-04-17 Improvement in fire-arms
US4676980A (en) 1985-09-23 1987-06-30 The United States Of America As Represented By The Secretary Of The Department Of Health And Human Services Target specific cross-linked heteroantibodies
DE3785186T2 (de) 1986-09-02 1993-07-15 Enzon Lab Inc Bindungsmolekuele mit einzelpolypeptidkette.
DE3883899T3 (de) 1987-03-18 1999-04-22 Sb2 Inc Geänderte antikörper.
EP0368684B2 (en) 1988-11-11 2004-09-29 Medical Research Council Cloning immunoglobulin variable domain sequences.
US5427908A (en) 1990-05-01 1995-06-27 Affymax Technologies N.V. Recombinant library screening methods
WO1993008829A1 (en) 1991-11-04 1993-05-13 The Regents Of The University Of California Compositions that mediate killing of hiv-infected cells
ES2162823T5 (es) 1992-08-21 2010-08-09 Vrije Universiteit Brussel Inmunoglobulinas desprovistas de cadenas ligeras.
JP3720353B2 (ja) 1992-12-04 2005-11-24 メディカル リサーチ カウンシル 多価および多重特異性の結合タンパク質、それらの製造および使用
ES2138662T3 (es) 1993-06-03 2000-01-16 Therapeutic Antibodies Inc Produccion de fragmentos de anticuerpos.
GB9625640D0 (en) 1996-12-10 1997-01-29 Celltech Therapeutics Ltd Biological products
CA2288994C (en) 1997-04-30 2011-07-05 Enzon, Inc. Polyalkylene oxide-modified single chain polypeptides
WO2001079442A2 (en) 2000-04-12 2001-10-25 Human Genome Sciences, Inc. Albumin fusion proteins
IL156955A0 (en) 2001-01-17 2004-02-08 Genecraft Inc Binding domain-immunoglobulin fusion proteins
EP1456410A2 (en) 2001-12-11 2004-09-15 AlgoNomics N.V. Method for displaying loops from immunoglobulin domains in different contexts
DK1517921T3 (da) 2002-06-28 2006-10-09 Domantis Ltd Immunglobulin-enkeltvariable antigen-bindende domæner og dobbeltspecifikke konstruktioner deraf
EP2316852B1 (en) 2002-11-08 2014-03-05 Ablynx N.V. Stabilized single domain antibodies
AU2004220325B2 (en) 2003-06-30 2011-05-12 Domantis Limited Polypeptides
HUE035250T2 (hu) 2005-10-12 2018-05-02 Morphosys Ag Humán CD38-ra specifikus teljesen humán HuCAL GOLD-eredetû terápiás ellenanyagok létrehozása és profilozása
KR101516823B1 (ko) * 2006-03-17 2015-05-07 바이오겐 아이덱 엠에이 인코포레이티드 안정화된 폴리펩티드 조성물
AU2007316418A1 (en) 2006-11-09 2008-05-15 Irm Llc Agonist TrkB antibodies and uses thereof
MX350962B (es) 2008-01-07 2017-09-27 Amgen Inc Metodo para fabricar moleculas heterodimericas de fragmentos cristalizables de anticuerpo, utilizando efectos electrostaticos de direccion.
US8268314B2 (en) * 2008-10-08 2012-09-18 Hoffmann-La Roche Inc. Bispecific anti-VEGF/anti-ANG-2 antibodies
WO2010086828A2 (en) 2009-02-02 2010-08-05 Rinat Neuroscience Corporation Agonist anti-trkb monoclonal antibodies
WO2012061558A2 (en) * 2010-11-04 2012-05-10 Abbott Laboratories Dual variable domain immunoglobulins and uses thereof
US10975152B2 (en) * 2016-05-03 2021-04-13 The Scripps Research Institute TrkB agonist antibodies and methods for treating an ocular degenerative disorder characterized by degeneration of retinal ganglion cells (RGCs)
WO2018166495A1 (en) * 2017-03-15 2018-09-20 Tsinghua University Novel anti-trkb antibodies
US10793634B2 (en) * 2017-06-09 2020-10-06 Boehringer Ingelheim International Gmbh Anti-TrkB antibodies
AR123862A1 (es) * 2020-10-21 2023-01-18 Boehringer Ingelheim Int Moléculas de unión biespecíficas anti-vegf y anti-trkb para el tratamiento de enfermedades oculares

Also Published As

Publication number Publication date
WO2022084355A3 (en) 2022-06-02
WO2022084354A1 (en) 2022-04-28
CN116829586A (zh) 2023-09-29
US20220119535A1 (en) 2022-04-21
AR123862A1 (es) 2023-01-18
JP2023546228A (ja) 2023-11-01
EP4232476A2 (en) 2023-08-30
US20220119536A1 (en) 2022-04-21
JP2023546229A (ja) 2023-11-01
WO2022084355A2 (en) 2022-04-28
EP4232474A1 (en) 2023-08-30
CN117043186A (zh) 2023-11-10

Similar Documents

Publication Publication Date Title
KR101644717B1 (ko) 항-ｖｅｇｆ 항체
JP7107914B2 (ja) ＶＥ－ＰＴＰ（ＨＰＴＰ－β）を標的化するヒト化モノクローナル抗体
CN109517063B (zh) 靶向epo的抗体的组合物和方法
JP2021061854A (ja) ＦｃＲｎ抗体およびその使用方法
US11873334B2 (en) Method of treating ocular conditions by administering an antibody that activates Tie2 and binds VEGF
TWI384998B (zh) 抗-ＴＧＦ-β受體II抗體
US9840554B2 (en) Antibodies against platelet-derived growth factor (PDGF)
RU2702553C2 (ru) Новое антитело против tie-2 человека
CA2700481A1 (en) Antigen binding proteins
JP2023517345A (ja) 抗インターロイキン－３３抗体及びその使用
TW201641515A (zh) Ｖｅｇｆａ／ａｎｇ２化合物
CN113795509A (zh) 抗-sema3a抗体及其用于治疗眼或眼部疾病的用途
US20220119535A1 (en) Bispecific anti-vegf and anti-trkb binding molecules for the treatment of eye diseases
US20220356236A1 (en) Anti-betacellulin antibodies, fragments thereof, and multi-specific binding molecules
JP2022538374A (ja) Ｐｄｇｆ－ｂおよびｐｄｇｆ－ｄに結合する抗原結合分子ならびにその使用
KR20240004694A (ko) 항체
CN114423788A (zh) 抗nrp1a抗体及其用于治疗眼或眼部疾病的用途