TW202216745A - 包含經修飾ｉｌ－２多肽之多肽及其用途 - Google Patents

包含經修飾ｉｌ－２多肽之多肽及其用途 Download PDF

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TW202216745A
TW202216745A TW110124255A TW110124255A TW202216745A TW 202216745 A TW202216745 A TW 202216745A TW 110124255 A TW110124255 A TW 110124255A TW 110124255 A TW110124255 A TW 110124255A TW 202216745 A TW202216745 A TW 202216745A
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約翰 Ｃ 湯門
佛羅里安 薩梅爾
凱特琳 Ｍ 威爾斯
布萊恩 貝克倫
伯瑞登 Ｐ 艾克曼
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美商英伊布里克斯公司
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Abstract

本發明提供包含經修飾IL-2之多肽，其中相對於野生型IL-2，該經修飾IL-2對IL-2受體之親和力降低。在一些實施例中，提供會結合且促效已活化之T細胞的包含經修飾IL-2之多肽。亦提供該等包含經修飾IL-2之多肽的用途。

Description

包含經修飾IL-2多肽之多肽及其用途
本發明係關於對CD25及CD122之親和力降低的經修飾IL-2以及與靶向部分融合之此類經修飾IL-2。本發明亦係關於使用經修飾IL-2及包含經修飾IL-2之多肽的方法，包括(但不限於)治療癌症之方法。
IL-2為經由由CD25、CD122及CD132構成之雜三聚體IL-2受體(IL-2R)或僅由CD122及CD132構成之雜二聚體IL-2受體刺激T細胞及NK細胞增殖的有效細胞介素。IL-2R之兩種形式均為T細胞存活、增殖及總體活化狀態之有效介體。IL-2一般係藉由T細胞及NK細胞在活化時產生且在局部微環境中順式及反式地介導信號傳導。IL-2R信號傳導可誘導原生T細胞分化成效應子及記憶T細胞，且亦可刺激抑制調節性T細胞。儘管IL-2R之三聚體形式對IL-2之親和力比二聚體形式高，但兩者皆具有合理的高親和力且引起受體介導之迅速內化及降解，從而導致半衰期極短。重組人類IL-2 (rhIL-2，普留淨(Proleukin))在臨床上用於治療腎細胞癌及惡性黑色素瘤；然而，其與嚴重毒性相關。歸因於IL-2信號傳導對表現高親和力IL-2R之內皮細胞的作用，血管滲漏症候群為用普留淨治療之癌症患者的主要毒性問題。
T細胞經由使其TCR與呈遞結合互補肽之MHC的相鄰細胞接合來活化，從而引起TCR複合物之聚集及經由NFAT之信號傳導。經由CD28共刺激T細胞係由增強T細胞活化之CD80及CD86驅動。在初始活化之後，T細胞上調各種蛋白質，包括細胞介素受體以及用以調節T細胞反應之許多共刺激及檢查點受體。
近期已報導針對檢查點受體之拮抗劑抗體(諸如CTLA-4、PD-1及PD-L1)具有持久抗腫瘤臨床反應。然而，即使在大部分反應性適應症中，反應率仍限於約30%之患者。因此，需要改良之T細胞調節治療劑。
本文提供包含經修飾IL-2之多肽，該經修飾IL-2包含至少一個在至少一個胺基酸位置處之取代。在一些實施例中，經修飾IL-2相對於野生型IL-2對CD25、CD122及/或IL-2R之結合親和力降低。在一些實施例中，經修飾IL-2相對於野生型IL-2對靜息或活化T細胞之活性降低。
本文提供以下實施例： 實施例1. 一種包含經修飾IL-2之多肽，其中該經修飾IL-2包含D84Y取代。 實施例2. 如實施例1之多肽，其中相較於野生型IL-2，該經修飾IL-2對CD122之親和力降低。 實施例3. 如實施例1至2中任一項之多肽，其中該經修飾IL-2包含至少一個在選自以下之至少一個胺基酸位置處的取代：H16、L19、M23、N88及E95。 實施例4. 如實施例3之多肽，其中該經修飾IL-2包含胺基酸位置H16處之取代。 實施例5. 如實施例4之多肽，其中該取代係選自H16A、H16N、H16V及H16T。 實施例6. 如實施例1至5中任一項之多肽，其中該經修飾IL-2包含胺基酸位置L19處之取代。 實施例7. 如實施例6之多肽，其中該取代係選自L19A、L19P、L19Q、L19Y、L19N、L19S、L19T、L19V。 實施例8. 如實施例1至7中任一項之多肽，其中該經修飾IL-2包含胺基酸位置M23處之取代。 實施例9. 如實施例8之多肽，其中該取代係選自M23A、M23G、M23S、M23T、M23V、M23D、M23E、M23I、M23K、M23L、M23N、M23Q、M23R及M23Y。 實施例10. 如實施例1至9中任一項之多肽，其中該經修飾IL-2包含胺基酸位置N88處之取代。 實施例11. 如實施例10之多肽，其中該取代係選自N88T、N88A及N88S。 實施例12. 如實施例1至11中任一項之多肽，其中該經修飾IL-2包含胺基酸位置E95處之取代。 實施例13. 如實施例12之多肽，其中該取代係選自E95Q、E95G、E95T、E95V、E95P、E95H、E95N及E95Y。 實施例14. 如實施例1至13中任一項之多肽，其中相較於野生型IL-2，該經修飾IL-2包含至少一個降低對CD132之親和力之取代。 實施例15. 如實施例1至14中任一項之多肽，其中該經修飾IL-2包含至少一個在選自以下之至少一個胺基酸位置處的取代：Q22、R120、T123、Q126、S127、I129及S130。 實施例16. 如實施例15之多肽，其中該經修飾IL-2包含胺基酸位置Q22處之取代。 實施例17. 如實施例16之多肽，其中該取代係選自Q22A、Q22D、Q22G、Q22H、Q22K、Q22N、Q22R、Q22S、Q22T、Q22V及Q22Y。 實施例18. 如實施例15至17中任一項之多肽，其中該經修飾IL-2包含在胺基酸位置R120處之取代。 實施例19. 如實施例18之多肽，其中該取代係選自R120A、R120D、R120E、R120F、R120G、R120H、R120K、R120N、R120Q、R120S、R120V及R120Y。 實施例20. 如實施例15至19中任一項之多肽，其中該經修飾IL-2包含胺基酸位置T123處之取代。 實施例21. 如實施例20之多肽，其中該取代係選自T123D、T123E、T123H、T123K、T123N、T123Q及T123R。 實施例22. 如實施例15至21中任一項之多肽，其中該經修飾IL-2包含胺基酸位置Q126處之取代。 實施例23. 如實施例22之多肽，其中該取代係選自Q126N、Q126A及Q126Y。 實施例24. 如實施例15至23中任一項之多肽，其中該經修飾IL-2包含胺基酸位置S127處之取代。 實施例25. 如實施例24之多肽，其中該取代係選自S127D、S127E、S127H、S127K、S127N、S127P及S127R。 實施例26. 如實施例15至25中任一項之多肽，其中該經修飾IL-2包含胺基酸位置I129處之取代。 實施例27. 如實施例26之多肽，其中該取代係選自I129A、I129H、I129R及I129S。 實施例28. 如實施例15至27中任一項之多肽，其中該經修飾IL-2包含胺基酸位置S130處之取代。 實施例29. 如實施例28之多肽，其中該取代係選自S130E、S130K、S130N、S130P、S130Q及S130R。 實施例30. 一種包含經修飾IL-2之多肽，其中該經修飾IL-2包含至少一個在選自以下之至少一個胺基酸位置處的取代：Q22、R120、T123、S127及S130。 實施例31. 如實施例30之多肽，其中相較於野生型IL-2，該經修飾IL-2對CD132之親和力降低。 實施例32. 如實施例30至31中任一項之多肽，其中該經修飾IL-2包含胺基酸位置Q22處之取代。 實施例33. 如實施例32之多肽，其中該取代係選自Q22A、Q22D、Q22E、Q22G、Q22H、Q22K、Q22N、Q22P、Q22R、Q22S、Q22T、Q22V及Q22Y。 實施例34. 如實施例30至33中任一項之多肽，其中該經修飾IL-2包含胺基酸位置R120處之取代。 實施例35. 如實施例34之多肽，其中該取代係選自R120A、R120D、R120E、R120F、R120G、R120H、R120K、R120N、R120P、R120Q、R120S、R120V及R120Y。 實施例36. 如實施例30至35之多肽，其中該經修飾IL-2包含胺基酸位置T123處之取代。 實施例37. 如實施例36之多肽，其中該取代係選自T123D、T123E、T123H、T123K、T123N、T123Q及T123R。 實施例38. 如實施例30至37中任一項之多肽，其中該經修飾IL-2包含胺基酸位置S127處之取代。 實施例39. 如實施例38之多肽，其中該取代係選自S127D、S127E、S127H、S127K、S127N、S127P、S127Q及S127R。 實施例40. 如實施例30至39中任一項之多肽，其中該經修飾IL-2包含胺基酸位置S130處之取代。 實施例41. 如實施例40之多肽，其中該取代係選自S130D、S130E、S130H、S130K、S130N、S130P、S130Q及S130R。 實施例42. 如實施例30至41中任一項之多肽，其中相較於野生型IL-2，該經修飾IL-2包含至少一個降低對CD122之親和力之取代。 實施例43. 如實施例42之多肽，其中該經修飾IL-2包含至少一個在選自以下之至少一個胺基酸位置處的取代：H16、L19、M23、D84、N88及E95。 實施例44. 如實施例43之多肽，其中該經修飾IL-2包含胺基酸位置H16處之取代。 實施例45. 如實施例44之多肽，其中該取代係選自H16A、H16T、H16V及H16N。 實施例46. 如實施例43至45中任一項之多肽，其中該經修飾IL-2包含胺基酸位置L19處之取代。 實施例47. 如實施例46之多肽，其中該取代係選自L19A、L19P、L19Q、L19Y、L19N、L19S、L19T、L19V。 實施例48. 如實施例43至47中任一項之多肽，其中該經修飾IL-2包含胺基酸位置M23處之取代。 實施例49. 如實施例48之多肽，其中該取代係選自M23A、M23G、M23S、M23T、M23V、M23D、M23E、M23I、M23K、M23L、M23N、M23Q、M23R及M23Y。 實施例50. 如實施例43至49中任一項之多肽，其中該經修飾IL-2包含胺基酸位置D84處之取代。 實施例51. 如實施例50之多肽，其中該取代係選自D84S、D84G、D84A、D84T、D84V、D84Y及D84N。 實施例52. 如實施例43至51中任一項之多肽，其中該經修飾IL-2包含胺基酸位置N88處之取代。 實施例53. 如實施例52之多肽，其中該取代係選自N88T、N88A及N88S。 實施例54. 如實施例43至53中任一項之多肽，其中該經修飾IL-2包含胺基酸位置E95處之取代。 實施例55. 如實施例54之多肽，其中該取代係選自E95Q、E95G、E95T、E95V、E95P、E95H、E95N及E95Y。 實施例56. 如實施例1至55中任一項之多肽，其中相較於野生型IL-2，該經修飾IL-2包含至少一個降低對CD25之親和力之取代。 實施例57. 如實施例1至56中任一項之多肽，其中該經修飾IL-2包含至少一個在選自以下之至少一個胺基酸位置處的取代：K43、Y45、E61、I114、P65、F42、R38及L72，及/或其中該經修飾IL-2包含胺基酸F42之缺失。 實施例58. 如實施例57之多肽，其中該經修飾IL-2包含胺基酸F42處之取代或包含胺基酸F42之缺失。 實施例59. 如實施例58之多肽，其中該經修飾IL-2包含選自以下之胺基酸位置F42處之取代：F42K、F42A、F42R、F42G、F42S及F42T。 實施例60. 如實施例58之多肽，其中該經修飾IL-2包含胺基酸F42之缺失。 實施例61. 如實施例57至60中任一項之多肽，其中該經修飾IL-2包含胺基酸位置K43處之取代。 實施例62. 如實施例61之多肽，其中該取代係選自K43E及K43D。 實施例63. 如實施例57至62中任一項之多肽，其中該經修飾IL-2包含胺基酸位置Y45處之取代。 實施例64. 如實施例63之多肽，其中該取代係選自Y45R及Y45K。 實施例65. 如實施例57至64中任一項之多肽，其中該經修飾IL-2包含胺基酸位置E61處之取代。 實施例66. 如實施例65之多肽，其中該取代係選自E61R、E61G、E61H、E61N、E61P、E61S、E61T、E61Y、E61A、E61Q及E61K。 實施例67. 如實施例57至66中任一項之多肽，其中該經修飾IL-2包含胺基酸位置I114處之取代。 實施例68. 如實施例67之多肽，其中該取代為I114F、I114Y或I114W。 實施例69. 如實施例57至68中任一項之多肽，其中該經修飾IL-2包含胺基酸位置P65處之取代。 實施例70. 如實施例69之多肽，其中該取代係選自P65R、P65E、P65K、P65H、P65Y、P65Q、P65D及P65N。 實施例71. 如實施例57至70中任一項之多肽，其中該經修飾IL-2包含胺基酸位置R38處之取代。 實施例72. 如實施例71之多肽，其中該R38處之取代係選自R38A及R38G。 實施例73. 如實施例57至72中任一項之多肽，其中該經修飾IL-2包含胺基酸位置L72處之取代。 實施例74. 如實施例73之多肽，其中該L72處之取代為L72G。 實施例75. 如實施例1至74中任一項之多肽，其中該經修飾IL-2包含取代Q22A或取代R120A或取代Q22A及R120A。 實施例76. 如實施例1至75中任一項之多肽，其中該經修飾IL-2包含取代P65R及R38A或取代P65R及E61R。 實施例77. 如實施例1至76中任一項之多肽，其中該經修飾IL-2包含至少一個選自以下之取代：H16A、L19A、L19N、M23A、D84S或D84Y、N88S及E95Q。 實施例78. 如實施例1至77中任一項之多肽，其中該經修飾IL-2包含胺基酸位置P65、H16及D84處之取代。 實施例79. 如實施例78之多肽，其中該經修飾IL-2包含取代P65R、H16A及D84S；或取代P65R、H16A及D84Y。 實施例80. 如實施例1至79中任一項之多肽，其中該經修飾IL-2包含至少一個在選自T3及C125之至少一個胺基酸位置處的取代，及/或包含IL-2之前五個胺基酸之缺失。 實施例81. 如實施例80之多肽，其中該經修飾IL-2包含至少一個選自以下之取代：T3A、C125A、C125V及C125S。 實施例82. 如實施例81之多肽，其中該經修飾IL-2包含T3A及C125S取代，或T3A及C125V取代。 實施例83. 如實施例81之多肽，其中該經修飾IL-2包含IL-2之前五個胺基酸之缺失及C125S取代或C125V取代。 實施例84. 如前述實施例中任一項之多肽，其中該經修飾IL-2包含一組選自以下之取代：[T3A、H16A、E61R、P65R、D84Y、C125S]、[T3A、H16A、M23T、E61R、P65R、D84Y、E95Q、C125S]、[T3A、H16A、L19N、E61R、P65R、D84Y、C125S]、[T3A、H16A、L19N、M23T、E61R、P65R、D84Y、E95Q、C125S]、[T3A、H16A、E61R、P65R、D84Y、C125S、S127D]、[T3A、H16A、M23T、E61R、P65R、D84Y、E95Q、C125S、S127D]、[T3A、H16A、L19N、E61R、P65R、D84Y、C125S、S127D]及[T3A、H16A、L19N、M23T、E61R、P65R、D84Y、E95Q、C125S、S127D]。 實施例85. 一種包含經修飾IL-2之經修飾多肽，其中該經修飾IL-2包含一組選自以下之取代：[T3A、H16A、E61R、P65R、D84Y、C125S]、[T3A、H16A、M23T、E61R、P65R、D84Y、E95Q、C125S]、[T3A、H16A、L19N、E61R、P65R、D84Y、C125S]、[T3A、H16A、L19N、M23T、E61R、P65R、D84Y、E95Q、C125S]、[T3A、H16A、E61R、P65R、D84Y、C125S、S127D]、[T3A、H16A、M23T、E61R、P65R、D84Y、E95Q、C125S、S127D]、[T3A、H16A、L19N、E61R、P65R、D84Y、C125S、S127D]及[T3A、H16A、L19N、M23T、E61R、P65R、D84Y、E95Q、C125S、S127D]。 實施例86. 如前述實施例中任一項之多肽，其中該經修飾IL-2包含指定取代，且不包含任何額外取代。 實施例87. 如前述實施例中任一項之多肽，其中該經修飾IL-2為經修飾之人類IL-2。 實施例88. 如前述實施例中任一項之多肽，其中該等胺基酸位置對應於SEQ ID NO: 1中之胺基酸位置。 實施例89. 如前述實施例中任一項之多肽，其中該經修飾IL-2包含與SEQ ID NO: 84至少90%、91%、92%、93%、94%、95%、96%、97%、98%或99%一致且包含選自SEQ ID NO: 105至290之胺基酸序列之對應取代的胺基酸序列。 實施例90. 如前述實施例中任一項之多肽，其中該經修飾IL-2包含與選自SEQ ID NO: 270至277之胺基酸序列至少90%、91%、92%、93%、94%、95%、96%、97%、98%、99%或100%一致的胺基酸序列且包含取代D84Y。 實施例91. 如前述實施例中任一項之多肽，其中該經修飾IL-2包含選自SEQ ID NO: 105至290之胺基酸序列。 實施例92. 如前述實施例中任一項之多肽，其中該經修飾IL-2包含選自SEQ ID NO: 270至277之胺基酸序列。 實施例93. 如前述實施例中任一項之多肽，其中該多肽包含Fc區。 實施例94. 如實施例93之多肽，其中該經修飾IL-2與該Fc區之N端或C端融合。 實施例95. 如實施例93或實施例94之多肽，其中該Fc區包含Kabat胺基酸位置T366處之取代。 實施例96. 如實施例95之多肽，其中該Fc區包含T366W取代。 實施例97. 如實施例93或實施例94之多肽，其中該Fc區包含至少一個在選自T366、L368及Y407之至少一個Kabat胺基酸位置處的取代。 實施例98. 如實施例108之多肽，其中該Fc區包含T366S、L368A及Y407V突變。 實施例99. 如實施例93至98中任一項之多肽，其中該Fc區包含選自S354及Y349之Kabat位置處的取代。 實施例100. 如實施例99之多肽，其中該Fc區包含S354C或Y349C取代。 實施例101. 如實施例93至100中任一項之多肽，其中該Fc區包含Kabat胺基酸位置H435處之取代。 實施例102. 如實施例101之多肽，其中該Fc區包含選自H435R及H435K之取代。 實施例103. 如實施例93至102中任一項之多肽，其中該Fc區包含至少一個在選自M252及M428之至少一個Kabat胺基酸位置處的取代。 實施例104. 如實施例103之多肽，其中該Fc區包含M252Y及M428V取代。 實施例105. 如實施例93至104中任一項之多肽，其中該Fc區包含Kabat胺基酸E233、L234及L235之缺失。 實施例106. 如實施例93至104中任一項之多肽，其中該Fc區包含至少一個在選自L234、L235及P329之至少一個胺基酸位置處的取代。 實施例107. 如實施例106之多肽，其中該Fc區包含L234A、L235A及P329G取代。 實施例108. 如實施例93至107中任一項之多肽，其中該Fc區包含與選自SEQ ID NO: 47至83、292及293之胺基酸序列至少90%、91%、92%、93%、94%、95%、96%、97%、98%、99%或100%一致的胺基酸序列。 實施例109. 如實施例93至108中任一項之多肽，其中該Fc區為重鏈恆定區之一部分。 實施例110. 如實施例109之多肽，其中該重鏈恆定區為IgG恆定區。 實施例111. 如實施例110之多肽，其中該重鏈恆定區為IgG1、IgG2、IgG3或IgG4恆定區。 實施例112. 如實施例93至111中任一項之多肽，其中該經修飾IL-2與該Fc區或重鏈恆定區之C端融合。 實施例113. 如實施例112之多肽，其中該經修飾IL-2經由包含1至20個胺基酸之連接子而與該Fc區或重鏈恆定區之C端融合。 實施例114. 如實施例113之多肽，其中該連接子包含甘胺酸胺基酸。 實施例115. 如實施例114之多肽，其中該連接子包含甘胺酸及絲胺酸胺基酸。 實施例116. 如實施例113至115中任一項之多肽，其中該連接子中之大部分或所有該等胺基酸為甘胺酸及絲胺酸。 實施例117. 如實施例93至116中任一項之多肽，其中該多肽包含選自SEQ ID NO: 105至290之胺基酸序列及選自SEQ ID NO: 48、64、292及293之胺基酸序列。 實施例118. 如前述實施例中任一項之多肽，其中該多肽包含至少一個抗原結合域。 實施例119. 如實施例118之多肽，其中該多肽包含兩個、三個或四個抗原結合域。 實施例120. 如實施例118或實施例119之多肽，其中至少一個抗原結合域特異性結合於T細胞抗原或自然殺手細胞抗原。 實施例121. 如實施例118至120中任一項之多肽，其中至少一個抗原結合域特異性結合於CD4 +T細胞抗原或CD8 +T細胞抗原。 實施例122. 如實施例121之多肽，其中該至少一個抗原結合域特異性結合於經活化CD4 +T細胞或經活化CD8 +T細胞上之抗原。 實施例123. 如實施例118至122中任一項之多肽，其中至少一個抗原結合域為促效劑。 實施例124. 如實施例118至122中任一項之多肽，其中該抗原結合域為拮抗劑。 實施例125. 如實施例118至124中任一項之多肽，其中至少一個抗原結合域特異性結合於PD-1、CTLA-4、LAG3、TIM3、4-1BB、OX40、GITR、CD8a、CD8b、CD4、NKp30、NKG2A、TIGIT、TGFβR1、TGFβR2、Fas、NKG2D、NKp46、PD-L1、CD107a、ICOS、TNFR2、CD16a或γδTCR。 實施例126. 如實施例118至124中任一項之多肽，其中至少一個抗原結合域特異性結合於PD-1。 實施例127. 如實施例118至126中任一項之多肽，其中至少一個抗原結合域為人類或人類化抗原結合域。 實施例128. 如實施例127之多肽，其中各抗原結合域獨立地為人類或人類化抗原結合域。 實施例129. 如實施例118至128中任一項之多肽，其中至少一個抗原結合域包含VHH域。 實施例130. 如實施例129之多肽，其中各抗原結合域包含VHH域。 實施例131. 如實施例118至128中任一項之多肽，其中至少一個抗原結合域包含VH域及VL域。 實施例132. 如實施例131之多肽，其中至少一個抗原結合域包含選自以下之抗體之VH域及VL域：派立珠單抗(pembrolizumab)、納武單抗(nivolumab)、AMP-514、TSR-042、STI-A1110、伊匹單抗(ipilimumab)、曲美單抗(tremelimumab)、烏瑞魯單抗(urelumab)、烏圖木單抗(utomilumab)、阿特珠單抗(atezolizumab)及德瓦魯單抗(durvalumab)。 實施例133. 如實施例131或132之多肽，其中該至少一個抗原結合域包含單鏈Fv (scFv)。 實施例134. 如實施例131或132之多肽，其中該多肽包含重鏈恆定區，其中該VH域與該重鏈恆定區融合，且其中該VL域與該VH域締合。 實施例135. 如實施例134之多肽，其中該VL域與輕鏈恆定區融合。 實施例136. 如實施例135之多肽，其中該輕鏈恆定區係選自κ及λ。 實施例137. 如實施例118至136中任一項之多肽，其中該等抗原結合域中之每一者係相同的。 實施例138. 如實施例118至137之多肽，其中該等抗原結合域中之每一者特異性結合於相同抗原。 實施例139. 如實施例118至136之多肽，其中該等抗原結合域中之至少一者特異性結合於與其他抗原結合域中之至少一者不同的抗原。 實施例140. 如實施例139之多肽，其中至少一個抗原結合域特異性結合於PD-1，且至少一個其他抗原結合域特異性結合於除PD-1以外之T細胞抗原或自然殺手細胞抗原。 實施例141. 如實施例118至140中任一項之多肽，其中至少一個抗原結合域結合於PD-1、CTLA-4、LAG3、TIM3、4-1BB、OX40、GITR、CD8a、CD8b、CD4、NKp30、NKG2A、TIGIT、TGFβR1、TGFβR2、Fas、NKG2D、NKp46、PD-L1、CD107a、ICOS、TNFR2、CD16a、DNAM1或γδTCR (Vγ9、Vγ2、Vδ1)。 實施例142. 如實施例93至141中任一項之多肽，其中該多肽在生理條件下形成均二聚體。 實施例143. 如前述實施例中任一項之多肽，其中該經修飾IL-2以比人類野生型IL-2對該IL-2R之親和力低至少2倍、3倍、4倍、5倍、6倍、7倍、8倍、9倍、至少10倍、至少20倍、至少30倍、至少50倍或至少100倍的親和力結合人類IL-2R。 實施例144. 一種複合物，其包含第一多肽及第二多肽，其中該第一多肽為如前述實施例中任一項之多肽。 實施例145. 如實施例144之複合物，其中該第一多肽包含第一Fc區，且該第二多肽包含第二Fc區。 實施例146. 如實施例144或實施例145之複合物，其中各Fc區為選自人類IgG1、IgG2、IgG3及IgG4之同型。 實施例147. 如實施例146之複合物，其中各Fc區為人類IgG1。 實施例148. 如實施例144至147中任一項之複合物，其中各Fc區包含胺基酸E233、L234及L235之缺失。 實施例149. 如實施例144至148中任一項之複合物，其中各Fc區包含H435R或H435K突變。 實施例150. 如實施例155至160中任一項之複合物，其中該Fc區包含突變M252Y及M428L或突變M252Y及M428V。 實施例151. 如實施例144至150中任一項之複合物，其中該第一Fc區或該第二Fc區包含T366W突變，且其他Fc區包含突變T366S、L368A及Y407V。 實施例152. 如實施例151之複合物，其中該第一Fc區或該第二Fc區包含S354C突變。 實施例153. 如實施例144至152中任一項之複合物，其中各Fc區獨立地包含與選自SEQ ID NO: 47至83、292及293之胺基酸序列至少90%、91%、92%、93%、94%、95%、96%、97%、98%、99%或100%一致的胺基酸序列。 實施例154. 如實施例144至153中任一項之複合物，其中該第二多肽不包含經修飾IL-2。 實施例155. 如實施例144至154中任一項之複合物，其中該第一多肽包含至少一個抗原結合域。 實施例156. 如實施例144至155中任一項之複合物，其中該第二多肽包含至少一個抗原結合域。 實施例157. 如實施例144至156中任一項之複合物，其中該第一多肽包含第一抗原結合域、Fc區及經修飾IL-2。 實施例158. 如實施例157之複合物，其中該第一抗原結合域與該Fc區之N端融合，且該經修飾IL-2與該Fc區之C端融合。 實施例159. 如實施例157或實施例158之複合物，其中該第二多肽包含第二抗原結合域及Fc區。 實施例160. 如實施例159之複合物，其中該第一抗原結合域及該第二抗原結合域相同或不同。 實施例161. 如實施例160之複合物，其中： a. 該第一抗原結合域及該第二抗原結合域兩者均結合PD-1； b. 該第一抗原結合域結合PD-1，且該第二抗原結合域結合LAG3； c. 該第一抗原結合域結合PD-1，且該第二抗原結合域結合CTLA-4； d. 該第一抗原結合域結合PD-1，且該第二抗原結合域結合4-1BB； e. 該第一抗原結合域結合PD-1，且該第二抗原結合域結合OX40； f. 該第一抗原結合域結合PD-1，且該第二抗原結合域結合GITR； g. 該第一抗原結合域結合PD-1，且該第二抗原結合域結合CD8a； h. 該第一抗原結合域結合PD-1，且該第二抗原結合域結合CD8b； i. 該第一抗原結合域結合PD-1，且該第二抗原結合域結合CD4； j. 該第一抗原結合域結合PD-1，且該第二抗原結合域結合NKp30； k. 該第一抗原結合域結合PD-1，且該第二抗原結合域結合NKG2A； l. 該第一抗原結合域結合PD-1，且該第二抗原結合域結合TIGIT； m. 該第一抗原結合域結合PD-1，且該第二抗原結合域結合NKG2D； n. 該第一抗原結合域結合PD-1，且該第二抗原結合域結合TGFBR2； o. 該第一抗原結合域結合PD-1，且該第二抗原結合域結合Fas； p. 該第一抗原結合域結合PD-1，且該第二抗原結合域結合CD107a； q. 該第一抗原結合域結合PD-1，且該第二抗原結合域結合NKp46； r. 該第一抗原結合域結合CD8a，且該第二抗原結合域結合TGFRβR2； s. 該第一抗原結合域結合CD8a，且該第二抗原結合域結合Fas； t. 該第一抗原結合域結合NKG2D，且該第二抗原結合域結合TGFRβR2； u. 該第一抗原結合域結合NKG2D，且該第二抗原結合域結合Fas； v. 該第一抗原結合域結合NKG2A，且該第二抗原結合域結合TGFRβR2； w. 該第一抗原結合域結合NKG2A，且該第二抗原結合域結合Fas； x. 該第一抗原結合域結合NKp46，且該第二抗原結合域結合TGFRβR2； y. 該第一抗原結合域結合NKp46，且該第二抗原結合域結合Fas； z. 該第一抗原結合域結合CTLA-4，且該第二抗原結合域結合LAG3； aa. 該第一抗原結合域結合CTLA-4，且該第二抗原結合域結合Tim3； bb. 該第一抗原結合域結合CTLA-4，且該第二抗原結合域結合OX40； cc. 該第一抗原結合域結合CTLA-4，且該第二抗原結合域結合GITR； dd. 該第一抗原結合域結合CTLA-4，且該第二抗原結合域結合CD107a； ee. 該第一抗原結合域結合CTLA-4，且該第二抗原結合域結合NKp46； ff. 該第一抗原結合域結合ICOS，且該第二抗原結合域結合TNFR2； gg. 該第一抗原結合域結合γδTCR，且該第二抗原結合域結合NKG2D； hh. 該第一抗原結合域結合γδTCR，且該第二抗原結合域結合DNAM1； ii. 該第一抗原結合域結合γδTCR，且該第二抗原結合域結合TIGIT； jj. 該第一抗原結合域結合γδTCR，且該第二抗原結合域結合4-1BB； kk. 該第一抗原結合域結合γδTCR，且該第二抗原結合域結合Fas； ll. 該第一抗原結合域結合γδTCR，且該第二抗原結合域結合NKG2A；或 mm. 該第一抗原結合域結合γδTCR，且該第二抗原結合域結合CD16a。 實施例162. 如實施例144至161中任一項之複合物，其中該經修飾IL-2以比人類野生型IL-2對該IL-2R之親和力低至少2倍、3倍、4倍、5倍、6倍、7倍、8倍、9倍、至少10倍、至少20倍、至少30倍、至少50倍或至少100倍的親和力結合人類IL-2R。 實施例163. 一種醫藥組合物，其包含如實施例1至154中任一項之多肽或如實施例144至162中任一項之複合物及醫藥學上可接受之載劑。 實施例164. 一種經分離核酸，其編碼如實施例1至143中任一項之多肽或如實施例144至162中任一項之複合物。 實施例165. 一種表現載體，其包含如實施例164之核酸。 實施例166. 一種經分離宿主細胞，其包含如實施例164之核酸或如實施例165之表現載體。 實施例167. 一種經分離宿主細胞，其表現如實施例1至143中任一項之多肽或如實施例144至162中任一項之複合物。 實施例168. 一種產生如實施例1至143中任一項之多肽或如實施例144至162中任一項之複合物的方法，其包含在適合表現該多肽或複合物之條件下培育如實施例166或實施例167之宿主細胞。 實施例169. 如實施例168之方法，其進一步包含分離該多肽或複合物。 實施例170. 一種增加CD4+及/或CD8+ T細胞增殖之方法，其包含使T細胞與如實施例1至154中任一項之多肽或如實施例144至162中任一項之複合物接觸。 實施例171. 如實施例170之方法，其中該等CD4+及/或CD8+ T細胞係在活體外。 實施例172. 如實施例170之方法，其中該等CD4+及/或CD8+ T細胞係在活體內。 實施例173. 如實施例170至172中任一項之方法，其中該增加為至少1.5倍、至少2倍、至少3倍或至少5倍。 實施例174. 一種增加NK細胞增殖之方法，其包含使NK細胞與如實施例1至143中任一項之多肽或如實施例144至162中任一項之複合物接觸。 實施例175. 如實施例174之方法，其中該增加為至少1.5倍、至少2倍、至少3倍或至少5倍。 實施例176. 一種治療癌症之方法，其包含向患有癌症之受試者投與醫藥學上有效量的如實施例1至143中任一項之多肽或如實施例144至162中任一項之複合物或如實施例163之醫藥組合物。 實施例177. 如實施例176之方法，其中該癌症係選自基底細胞癌；膽道癌；膀胱癌；骨癌；大腦及中樞神經系統癌症；乳癌；腹膜癌；子宮頸癌；絨毛膜癌；結腸及直腸癌症；結締組織癌；消化系統癌症；子宮內膜癌；食道癌；眼癌；頭頸癌；胃癌(gastric cancer)；胃腸癌；神經膠母細胞瘤；肝癌瘤；肝腫瘤；上皮細胞內贅瘤；腎臟癌或腎癌；喉癌；肝癌；肺癌；小細胞肺癌；非小細胞肺癌；肺腺癌；肺鱗狀癌(squamous carcinoma of the lung)；黑色素瘤；骨髓瘤；神經母細胞瘤；口腔癌；卵巢癌；胰臟癌；前列腺癌；視網膜母細胞瘤；橫紋肌肉瘤；直腸癌；呼吸系統癌症；唾液腺癌；肉瘤；皮膚癌；鱗狀細胞癌；胃癌(stomach cancer)；睾丸癌；甲狀腺癌；子宮或子宮內膜癌；泌尿系統癌症；外陰癌；淋巴瘤；霍奇金氏淋巴瘤(Hodgkin's lymphoma)；非霍奇金氏淋巴瘤(non-Hodgkin's lymphoma)；B細胞淋巴瘤；低級/濾泡性非霍奇金氏淋巴瘤(NHL)；小淋巴球性(SL) NHL；中級/濾泡性NHL；中級瀰漫性NHL；高級免疫母細胞性NHL；高級淋巴母細胞性NHL；高級小無裂細胞NHL；腫塊性病變NHL；套細胞淋巴瘤；AIDS相關淋巴瘤；瓦爾登斯特倫氏巨球蛋白血症(Waldenstrom's macroglobulinemia)；慢性淋巴球性白血病(CLL)；急性淋巴母細胞性白血病(ALL)；毛細胞白血病；及慢性骨髓母細胞性白血病。 實施例178. 如實施例176或177之方法，其進一步包含投與額外治療劑。 實施例179. 如實施例178之方法，其中該額外治療劑為抗癌劑。 實施例180. 如實施例179之方法，其中該抗癌劑係選自化學治療劑、抗癌生物製劑、放射療法、CAR-T療法及溶瘤病毒。 實施例181. 如實施例179或實施例180之方法，其中該額外治療劑為抗癌生物製劑。 實施例182. 如實施例181之方法，其中該抗癌生物製劑為抑制PD-1及/或PD-L1之藥劑。 實施例183. 如實施例181之方法，其中該抗癌生物製劑為抑制VISTA、gpNMB、B7H3、B7H4、HHLA2、CTLA4或TIGIT之藥劑。 實施例184. 如實施例179至183中任一項之方法，其中該抗癌劑為抗體。 實施例185. 如實施例181之方法，其中該抗癌生物製劑為細胞介素。 實施例186. 如實施例179之方法，其中該抗癌劑為CAR-T療法。 實施例187. 如實施例179之方法，其中該抗癌劑為溶瘤病毒。 實施例188. 如實施例176至187中任一項之方法，其進一步包含腫瘤切除及/或放射療法。
相關申請案之交叉參考
本申請案主張2020年7月2日申請之美國臨時申請案第63/047,681號之優先權，其出於任何目的以全文引用之方式併入本文中。
本文所提供之實施例係關於包含調節T細胞之活性之經修飾IL-2的多肽及其在治療癌症之各種方法中的用途。 定義及各種實施例
本文所使用之章節標題僅出於組織目的而不應被視為限制所描述之主題。
本文所引用之所有參考文獻(包括專利申請案、專利公開案及Genbank寄存編號)均以引用方式併入本文中，如同各個別參考文獻具體地且單獨地指出以全文引用的方式併入本文中一般。
本文所描述或提及之技術及程序一般為熟習此項技術者充分理解且通常使用習知方法而採用，諸如以下中所描述之廣泛利用之方法：Sambrook等人，Molecular Cloning: A Laboratory Manual第3版(2001) Cold Spring Harbor Laboratory Press, Cold Spring Harbor, N.Y. CURRENT PROTOCOLS IN MOLECULAR BIOLOGY (F. M. Ausubel等人編, (2003))；METHODS IN ENZYMOLOGY系列(Academic Press, Inc.): PCR 2: A PRACTICAL APPROACH (M. J. MacPherson、B. D. Hames及G. R. Taylor編(1995))、Harlow及Lane編(1988) ANTIBODIES、A LABORATORY MANUAL及ANIMAL CELL CULTURE (R. I. Freshney編(1987))；Oligonucleotide Synthesis (M. J. Gait編, 1984)；Methods in Molecular Biology, Humana Press；Cell Biology: A Laboratory Notebook (J. E. Cellis編, 1998) Academic Press；Animal Cell Culture (R. I. Freshney)編, 1987)；Introduction to Cell and Tissue Culture (J. P. Mather及P. E. Roberts, 1998) Plenum Press；Cell and Tissue Culture Laboratory Procedures (A. Doyle、J. B. Griffiths及D. G. Newell編, 1993-8) J. Wiley and Sons；Handbook of Experimental Immunology (D. M. Weir及C. C. Blackwell編)；Gene Transfer Vectors for Mammalian Cells (J. M. Miller及M. P. Calos編, 1987)；PCR: The Polymerase Chain Reaction, (Mullis等人編, 1994)；Current Protocols in Immunology (J. E. Coligan等人編, 1991)；Short Protocols in Molecular Biology (Wiley and Sons, 1999)；Immunobiology (C. A. Janeway及P. Travers, 1997)；Antibodies (P. Finch, 1997)；Antibodies: A Practical Approach (D. Catty.編, IRL Press, 1988-1989)；Monoclonal Antibodies: A Practical Approach (P. Shepherd及C. Dean編, Oxford University Press, 2000)；Using Antibodies: A Laboratory Manual (E. Harlow及D. Lane (Cold Spring Harbor Laboratory Press, 1999)；The Antibodies (M. Zanetti及J. D. Capra編, Harwood Academic Publishers, 1995)；及Cancer: Principles and Practice of Oncology (V. T. DeVita等人編, J.B. Lippincott Company, 1993)；以及其更新版本。
除非另外定義，否則結合本發明使用之科學及技術術語應具有一般熟習此項技術者通常理解之含義。此外，除非上下文另外需要或明確地指示，否則單數術語應包括複數且複數術語應包括單數。關於各種來源或參考文獻之間在定義方面之任何衝突，將以本文所提供之定義為準。
一般而言，免疫球蛋白重鏈中之殘基編號係如Kabat等人, Sequences of Proteins of Immunological Interest, 第5版Public Health Service, National Institutes of Health, Bethesda, Md.(1991)中之EU索引之編號。「如Kabat中之EU索引」係指人類IgG1 EU抗體之殘基編號。
應瞭解，本文所描述之本發明實施例包括「由實施例組成」及/或「基本上由實施例組成」。除非另外指示，否則如本文所使用，單數形式「一(a/an)」及「該(the)」包括複數個參考物。術語「或」在本文中之使用不意謂暗示替代方案係互相排斥的。
在本申請案中，除非明確地陳述或熟習此項技術者所理解，否則「或」之使用意謂「及/或」。在多重附屬項之情況下，「或」之使用重新提及超過一個前述獨立項或附屬項。
片語「參考樣本」、「參考細胞」或「參考組織」表示可用作與具有至少一種未知特徵之樣本進行比較的具有至少一種已知特徵之樣本。在一些實施例中，參考樣本可用作陽性或陰性指示物。參考樣本可用於確定例如在健康組織中存在之蛋白質及/或mRNA之含量，與在具有未知特徵之樣本中存在之蛋白質及/或mRNA之含量形成對比。在一些實施例中，參考樣本來自同一受試者，但來自所測試受試者之不同部位。在一些實施例中，參考樣本來自癌周圍或鄰近癌之組織區域。在一些實施例中，參考樣本不來自所測試之受試者，而是為來自已知患有或未患有所討論之病症(例如，特定癌症或T細胞相關病症)的受試者之樣本。在一些實施例中，參考樣本係來自同一受試者，但來自在受試者罹患癌症前之時間點。在一些實施例中，參考樣本係來自相同或不同受試者之良性癌樣本。當使用陰性參考樣本進行比較時，陰性參考樣本中所討論的分子之表現量或量將指示出熟習此項技術者將瞭解之含量，假定本發明中無分子及/或存在具有低含量之分子。當使用陽性參考樣本進行比較時，陽性參考樣本中所討論的分子之表現量或量將指示出熟習此項技術者將瞭解之含量，假定本發明中存在一定含量之分子。
如本文在受益於治療劑投與或對治療劑投與有反應之上下文中所使用的術語「益處」、「臨床益處」、「反應」及「治療反應」可藉由評定各種指標來量測，例如在一定程度上抑制疾病進展，包括減緩及完全遏止；減少疾病發作及/或症狀之數目；減小病變大小；抑制(亦即，減少、減緩或完全停止)疾病細胞浸潤至鄰近外周器官及/或組織；抑制(亦即，減少、減緩或完全停止)疾病擴散；在一定程度上減輕與該病症相關之一或多種症狀；增加在治療後呈現無病(例如，無進展存活期)之時長；增加總體存活率；反應率更高；及/或減小在治療後給定時間點之死亡率。「無反應」或「無法反應」之受試者或癌症係無法滿足關於「反應」之上述限制條件之受試者或癌症。
術語「核酸分子」、「核酸」及「聚核苷酸」可互換使用，且係指核苷酸之聚合物。此類核苷酸之聚合物可含有天然及/或非天然核苷酸，且包括(但不限於) DNA、RNA及PNA。「核酸序列」係指包含於核酸分子或聚核苷酸中之核苷酸的線性序列。
術語「多肽」及「蛋白質」可互換使用以指代胺基酸殘基之聚合物，且不限於最小長度。此類胺基酸殘基之聚合物可含有天然或非天然胺基酸殘基，且包括(但不限於)肽、寡肽、胺基酸殘基之二聚體、三聚體及多聚體。全長蛋白質及其片段皆涵蓋於該定義中。術語亦包括多肽之表現後修飾，例如糖基化、唾液酸化、乙醯化、磷酸化及其類似者。此外，出於本發明之目的，「多肽」係指蛋白質，其包括對原生序列之修飾，諸如缺失、添加及取代(實際上通常係保守的)，只要該蛋白質保持所需活性即可。此等修飾可為有意的，如經由定點突變誘發進行；或可為偶然的，諸如經由產生蛋白質之宿主的突變或由於PCR擴增所引起的錯誤引起。「胺基酸序列」係指包含於多肽或蛋白質中之胺基酸的線性序列。
如本文所使用之「IL-2」或「介白素-2」係指由在細胞中加工IL-2前驅體產生之任何原生成熟IL-2。除非另外指示，否則該術語包括來自任何脊椎動物來源之IL-2，該等脊椎動物來源包括哺乳動物，諸如靈長類動物(例如，人類及食蟹獼猴或恆河猴)及嚙齒動物(例如，小鼠及大鼠)。該術語亦包括IL-2之天然產生之變異體，諸如剪接變異體或對偶基因變異體。非限制性例示性人類IL-2胺基酸序列示於例如GenBank寄存編號NP_000577.2中。參見SEQ ID NO. 1 (成熟形式)。
如本文所使用之「經修飾IL-2」係指因至少一個胺基酸位置處之取代而不同於野生型IL-2胺基酸序列的多肽。
術語「特異性結合」於抗原或抗原決定基係此項技術中充分瞭解之術語，且用於測定此特異性結合之方法亦為此項技術中熟知的。若分子與特定細胞或物質之反應或締合比其與替代性細胞或物質更頻繁、更快速、持續時間更長及/或親和力更大，則稱其展現「特異性結合」或「優先結合」。若抗原結合域與抗原之結合相比其與其他物質之結合的親和力更大、親合力更大、更容易及/或持續時間更長，則該抗原結合域「特異性結合」或「優先結合」於該抗原。舉例而言，特異性或優先結合於抗原決定基之sdAb或含VHH多肽為與此抗原決定基之結合相比其與同一目標抗原上之其他抗原決定基或其他目標抗原上之抗原決定基之結合的親和力更大、親合力更大、更容易及/或持續時間更長的sdAb或含VHH多肽。藉由閱讀此定義亦應理解，例如特異性或優先結合於第一抗原的抗原結合域可或可不特異性或優先結合於第二抗原。因此，「特異性結合」或「優先結合」未必需要(儘管其可包括)排他性結合。一般而言，但不一定，提及結合意謂優先結合。「特異性」係指結合蛋白選擇性結合抗原之能力。
如本文中所使用，關於IL-2之活性的術語「調節」係指IL-2之活性的改變。在一些實施例中，「調節」係指IL-2活性之增加。
如本文中所使用，術語「抗原決定基」係指抗原結合分子(例如，含抗原結合域之多肽)在目標分子(例如抗原，諸如蛋白質、核酸、碳水化合物或脂質)上結合之位點。抗原決定基常常包括一組表面具有化學活性之分子，諸如胺基酸、多肽或糖側鏈，且具有特定三維結構特徵以及荷質比特徵。抗原決定基可由目標分子之相鄰及/或併接非相鄰殘基(例如，胺基酸、核苷酸、糖、脂質部分)形成。由相鄰殘基(例如，胺基酸、核苷酸、糖、脂質部分)形成之抗原決定基通常在暴露於變性溶劑時得以保留，而藉由三級摺疊形成之抗原決定基通常在經變性溶劑處理時丟失。抗原決定基可包括(但不限於)至少3個、至少5個或8至10個殘基(例如，胺基酸或核苷酸)。在一些實施例中，抗原決定基之長度小於20個殘基(例如，胺基酸或核苷酸)、小於15個殘基或小於12個殘基。若兩個抗體對一抗原展現競爭性結合，則其可結合該抗原內之同一抗原決定基。在一些實施例中，可藉由距抗原結合分子上之CDR殘基之某一最小距離鑑別抗原決定基。在一些實施例中，抗原決定基可藉由上述距離鑑別，且進一步受限於抗原結合分子之殘基與抗原殘基之間的一鍵(例如，氫鍵)所涉及之彼等殘基。抗原決定基亦可藉由各種掃描來鑑別，例如丙胺酸或精胺酸掃描可指示抗原結合分子可相互作用之一或多個殘基。除非明確表示，否則作為抗原決定基之一組殘基不排除其他殘基作為特定抗原結合域或分子之抗原決定基的一部分。實際上，該組之存在表示最小的抗原決定基系列(或一組物質)。因此，在一些實施例中，鑑別為抗原決定基之一組殘基表示該抗原之最小相關抗原決定基，而非抗原上之抗原決定基的排他性殘基清單。
「非線性抗原決定基」或「構形抗原決定基」包含抗原蛋白質內之非相鄰多肽、胺基酸及/或糖，其與對該抗原決定基具有特異性之抗原結合分子(例如，含抗原結合域之多肽)結合。在一些實施例中，至少一個殘基將與抗原決定基之其他所指出之殘基不相鄰；然而，一或多個殘基亦可與其他殘基相鄰。
「線性抗原決定基」包含抗原蛋白質內之相鄰多肽、胺基酸及/或糖，其與對該抗原決定基具有特異性之抗原結合分子(例如，含抗原結合域之多肽)結合。應注意，在一些實施例中，並非線性抗原決定基內之每一個殘基均需要與抗原結合分子直接結合(或與鍵相關)。在一些實施例中，線性抗原決定基可來自用有效地由線性抗原決定基之序列組成的肽免疫，或來自與蛋白質之其餘部分相對分離的蛋白質之結構部分(使得抗原結合分子可至少首先僅與該序列部分相互作用)。
術語「抗體」及「抗原結合分子」就最廣義而言可互換使用，且涵蓋包含抗原結合域之各種多肽，包括(但不限於)習知抗體(通常包含至少一個重鏈及至少一個輕鏈)、單域抗體(sdAb，其僅包含一條通常類似於重鏈之鏈)、含VHH多肽(包含至少一個重鏈、僅包含抗體可變域或VHH之多肽)及前述任一者之片段，只要其展現所需抗原結合活性即可。在一些實施例中，抗體包含二聚域。此等二聚域包括(但不限於)重鏈恆定域(包含CH1、鉸鏈、CH2及CH3，其中CH1通常與輕鏈恆定域CL配對，而鉸鏈介導二聚化)及Fc區(包含鉸鏈、CH2及CH3，其中鉸鏈介導二聚化)。術語抗體亦包括(但不限於)嵌合抗體、人類化抗體及諸如駱駝(包括駱馬)、鯊魚、小鼠、人類、食蟹獼猴等各種物種之抗體。
術語「單域抗體」及「sdAb」在本文中可互換使用以指代具有單一單體域(通常為重鏈(或VHH))而無輕鏈的抗體。
如本文所使用之術語「VHH」或「VHH域」或「VHH抗原結合域」係指單域抗體，諸如駱駝抗體或鯊魚抗體之抗原結合部分。在一些實施例中，VHH包含三個CDR及四個構架區，稱為FR1、CDR1、FR2、CDR2、FR3、CDR3及FR4。在一些實施例中，VHH可在N端或C端處截短以使得其僅包含部分FR1及/或FR4，或缺少彼等構架區中之一或兩者，只要VHH實質上維持抗原結合及特異性即可。
術語「含VHH多肽」係指包含至少一個VHH域之多肽。在一些實施例中，VHH多肽包含兩個、三個或四個或更多個VHH域，其中各VHH域可相同或不同。在一些實施例中，含VHH多肽包含Fc區。在一些此類實施例中，VHH多肽可形成二聚體。含VHH多肽之非限制性結構包括VHH 1-Fc、VHH 1-VHH 2-Fc及VHH 1-VHH 2-VHH 3-Fc，其中VHH 1、VHH 2及VHH 3可相同或不同。在此類結構之一些實施例中，一個VHH可藉由連接子連接至另一VHH，或一個VHH可藉由連接子連接至Fc。在一些此類實施例中，連接子包含1-20個胺基酸，較佳為1-20個主要由甘胺酸及視情況存在之絲胺酸構成的胺基酸。在一些實施例中，當含VHH多肽包含Fc時，其形成二聚體。因此，若結構VHH 1-VHH 2-Fc形成二聚體，則認為其為四價的(亦即，二聚體具有四個VHH域)。類似地，若結構VHH 1-VHH 2-VHH 3-Fc形成二聚體，則認為其為六價的(亦即，二聚體具有六個VHH域)。
術語「單株抗體」係指實質上同質之抗體群的抗體(包括sdAb或含VHH多肽)，亦即，包含該群體之個別抗體除可能存在少量天然產生之突變以外均相同。單株抗體為高度特異性的，其針對單一抗原位點。此外，與通常包括針對不同決定子(抗原決定基)之不同抗體的多株抗體製劑相反，各單株抗體針對抗原上之單個決定子。因此，單株抗體之樣本可結合於抗原上之同一抗原決定基。修飾語「單株」指示抗體之特徵為自實質上同質之抗體群獲得，且不應理解為需要藉由任何特定方法產生該抗體。舉例而言，單株抗體可藉由Kohler及Milstein, 1975, Nature 256:495首次描述之融合瘤方法製造，或可藉由諸如美國專利第4,816,567號中所描述之重組DNA方法製造。舉例而言，單株抗體亦可自使用McCafferty等人, 1990, Nature 348:552-554中所描述之技術生成的噬菌體庫中分離。
術語「CDR」表示互補決定區，如由熟習此項技術者藉由至少一種鑑別方式所定義。在一些實施例中，可根據Chothia編號方案、Kabat編號方案、Kabat與Chothia之組合、AbM定義及/或接觸定義中之任一者來定義CDR。VHH包含三個CDR，稱為CDR1、CDR2及CDR3。
如本文所使用之術語「重鏈恆定區」係指包含至少三個重鏈恆定域C H1、鉸鏈、C H2及C H3之區域。當然，除非另外指定，否則該等結構域中不改變功能之缺失及更改涵蓋於術語「重鏈恆定區」之範疇內。非限制性例示性重鏈恆定區包括γ、δ及α。非限制性例示性重鏈恆定區亦包括ε及μ。各重鏈恆定區對應於一種抗體同型。舉例而言，包含γ恆定區之抗體為IgG抗體，包含δ恆定區之抗體為IgD抗體，且包含α恆定區之抗體為IgA抗體。此外，包含μ恆定區之抗體為IgM抗體，且包含ε恆定區之抗體為IgE抗體。某些同型可進一步細分為子類。舉例而言，IgG抗體包括(但不限於) IgG1 (包含γ 1恆定區)、IgG2 (包含γ 2恆定區)、IgG3 (包含γ 3恆定區)及IgG4 (包含γ 4恆定區)抗體；IgA抗體包括(但不限於) IgA1 (包含α 1恆定區)及IgA2 (包含α 2恆定區)抗體；且IgM抗體包括(但不限於) IgM1及IgM2。
如本文所使用之「Fc區」係指包含CH2及CH3之重鏈恆定區之部分。在一些實施例中，Fc區包含鉸鏈、CH2及CH3。在各種實施例中，當Fc區包含鉸鏈時，鉸鏈介導兩個含Fc之多肽之間的二聚化。Fc區可為本文所論述之任何抗體重鏈恆定區同型。在一些實施例中，Fc區為IgG1、IgG2、IgG3或IgG4。
如本文所論述，如本文所使用之「受體人類構架」為包含源自人類免疫球蛋白構架或人類共同構架之重鏈可變域(V H)構架之胺基酸序列的構架。源自人類免疫球蛋白構架或人類共同構架之受體人類構架可包含與其相同之胺基酸序列，或其可含有胺基酸序列改變。在一些實施例中，跨單一抗原結合域(諸如VHH)中之所有人類構架，胺基酸改變之數目少於10、或少於9、或少於8、或少於7、或少於6、或少於5、或少於4或少於3。
「親和力」係指分子(例如，抗體或含VHH多肽)之單一結合位點與其結合搭配物(例如，抗原)之間的非共價相互作用之總和的強度。分子X對其搭配物Y之親和力或表觀親和力通常可分別由解離常數(K D)或K D- 表觀來表示。可藉由此項技術中已知之常用方法(諸如ELISA K D、KinExA、流式細胞測量術及/或表面電漿子共振裝置)，包括本文所描述之彼等方法來量測親和力。此等方法包括(但不限於)涉及BIAcore®、Octet®或流式細胞測量術之方法。
如本文中所使用，術語「K D」係指抗原結合分子/抗原相互作用之平衡解離常數。當本文使用術語「K D」時，其包括K D及K D- 表觀。
在一些實施例中，抗原結合分子之K D係使用表現抗原之細胞株且將在各抗體濃度下量測之平均螢光與非線性單點結合方程式擬合(Prism Software graphpad)藉由流式細胞測量術來量測。在一些此類實施例中，K D為K D- 表觀。
術語「生物活性」係指分子之任何一或多種生物特性(無論係在活體內發現為天然存在的，或藉由重組方式提供或實現的)。生物特性包括(但不限於)結合配位體、誘導或增加細胞增殖(諸如T細胞增殖)及誘導或增加細胞介素之表現。
如本文中所使用，術語「IL-2活性」或IL-2之「生物活性」包括任何生物作用或IL-2之生物學相關功能中之至少一者。在一些實施例中，IL-2活性包括IL-2誘導T細胞增殖及/或活化自然殺手(NK)細胞之能力。非限制性例示性IL-2活性包括增加pSTAT5表現、增加CD4 +及/或CD8 +T細胞之增殖、增加CD71在T細胞上之表現，及減少Treg細胞對CD4 +及CD8 +T細胞活化及增殖之抑制活性。
「促效劑」或「活化」抗體(諸如sdAb或含VHH多肽)為增加及/或活化目標抗原之生物活性的抗體。在一些實施例中，促效劑抗體係結合於抗原，且使其生物學活性增加至少約20%、40%、60%、80%、85%或更多。
「拮抗劑」、「阻斷」或「中和」抗體為使目標抗原之生物活性降低及/或失活的抗體。在一些實施例中，中和抗體係結合於抗原，且使其生物學活性降低至少約20%、40%、60%、80%、85%、90%、95%、99%或更多。
「親和力成熟」之含VHH多肽係指相較於沒有改變之親本含VHH多肽，該含VHH多肽在一或多個CDR中具有一或多個改變，此等改變造成改良該含VHH多肽對抗原之親和力。
如本文所使用之「人類化VHH」係指其中一或多個構架區已實質上經人類構架區置換之VHH。在一些情況下，人類免疫球蛋白之某些構架區(FR)殘基經對應之非人類殘基置換。此外，人類化VHH可包含不存在於原始VHH或人類構架序列中，但包括在其中以進一步改進及最佳化VHH或含VHH多肽之效能的殘基。在一些實施例中，人類化含VHH多肽包含人類Fc區。如應瞭解，人類化序列可藉由其一級序列鑑別，且不一定代表產生抗體之過程。
「功能性Fc區」具有原生序列Fc區之「效應功能」。例示性「效應功能」包括Fc受體結合；Clq結合及補體依賴性細胞毒性(CDC)；Fc受體結合；抗體依賴性細胞介導之細胞毒性(ADCC)；吞噬作用；細胞表面受體(例如B細胞受體)之下調；以及B細胞活化等。此類效應功能一般需要Fc區與結合域(例如抗體可變域)組合且可使用各種分析評定。
「原生序列Fc區」包含與自然界中存在之Fc區之胺基酸序列一致的胺基酸序列。原生序列人類Fc區包括原生序列人類IgG1 Fc區(非A及A同種異型)；原生序列人類IgG2 Fc區；原生序列人類IgG3 Fc區；及原生序列人類IgG4 Fc區以及其天然存在之變異體。
「變異Fc區」包含與原生序列Fc區之胺基酸序列相差至少一個胺基酸修飾的胺基酸序列。在一些實施例中，「變異Fc區」包含與原生序列Fc區之胺基酸序列相差至少一個胺基酸修飾，但保留原生序列Fc區之至少一種效應功能的胺基酸序列。在一些實施例中，變異Fc區相較於原生序列Fc區或相較於親本多肽之Fc區具有至少一個胺基酸取代，例如在原生序列Fc區中或在親本多肽之Fc區中約一個至約十個胺基酸取代，且較佳約一個至約五個胺基酸取代。在一些實施例中，本文中之變異Fc區與原生序列Fc區及/或與親本多肽之Fc區具有至少約80%序列一致性、至少約90%序列一致性、至少約95%、至少約96%、至少約97%、至少約98%或至少約99%序列一致性。
「Fc受體」或「FcR」描述與抗體之Fc區結合之受體。在一些實施例中，FcγR為原生人類FcR。在一些實施例中，FcR為結合IgG抗體之FcR (γ受體)且包括FcγRI、FcγRII及FcγRIII子類之受體，包括彼等受體之對偶基因變異體及交替剪接形式。FcγRII受體包括FcγRIIA (「活化受體」)及FcγRIIB (「抑制受體」)，兩者均具有主要在其細胞質域方面不同的類似胺基酸序列。活化受體FcγRIIA在其細胞質域中含有基於免疫受體酪胺酸之活化模體(ITAM)。抑制受體FcγRIIB在其細胞質域中含有基於免疫受體酪胺酸之抑制模體(ITIM)。(參見例如Daeron, Annu. Rev. Immunol. 15:203-234 (1997))。FcR綜述於例如Ravetch及Kinet, Annu. Rev. Immunol9:457-92 (1991)；Capel等人, Immunomethods4:25-34 (1994)；及de Haas等人, J. Lab. Clin. Med.126:330-41 (1995)中。包括將來鑑別之彼等FcR的其他FcR由本文中之術語「FcR」涵蓋。舉例而言，術語「Fc受體」或「FcR」亦包括新生兒受體FcRn，其負責將母體IgG轉移至胎兒(Guyer等人, J. Immunol.117:587 (1976)及Kim等人, J. Immunol.24:249 (1994))且調節免疫球蛋白之體內平衡。與FcRn之結合之量測方法為已知的(參見例如Ghetie及Ward, Immunol.Today 18(12):592-598 (1997)；Ghetie等人, Nature Biotechnology, 15(7):637-640 (1997)；Hinton等人, J. Biol. Chem.279(8):6213-6216 (2004)；WO 2004/92219 (Hinton等人))。
如本文中所使用，術語「實質上類似」或「實質上相同」表示兩個或更多個數值之間的相似度足夠高，使得在藉由該值量測生物特徵之情況下，熟習此項技術者將認為該兩個或更多個值之間的差異具有極小或不具有生物及/或統計顯著性。在一些實施例中，兩個或更多個實質上類似的值相差大約不超過以下中之任一者：5%、10%、15%、20%、25%或50%。
多肽「變異體」意謂在比對序列且必要時引入間隙以達成最大序列一致性百分比，且不考慮任何保守取代為序列一致性之一部分之後，與原生序列多肽具有至少約80%胺基酸序列一致性的生物活性多肽。此類變異體包括例如在多肽之N端或C端添加或缺失一或多個胺基酸殘基的多肽。在一些實施例中，變異體將具有至少約80%胺基酸序列一致性。在一些實施例中，變異體將具有至少約90%胺基酸序列一致性。在一些實施例中，變異體與原生序列多肽將具有至少約95%胺基酸序列一致性。
如本文中所使用，關於肽、多肽或抗體序列之「胺基酸序列一致性百分比(%)」及「同源性」定義為在比對序列且必要時引入間隙以達成最大序列一致性百分比，且不考慮任何保守取代為序列一致性之一部分之後，候選序列中與特定肽或多肽序列中之胺基酸殘基一致的胺基酸殘基之百分比。出於確定胺基酸序列一致性百分比之目的之比對可以在此項技術之技能範圍內之各種方式達成，例如使用公開可用之電腦軟體，諸如BLAST、BLAST-2、ALIGN或MEGALIGNTM (DNASTAR)軟體。熟習此項技術者可判定用於量測比對之適當參數，包括用於達成所比較之序列之全長內之最大比對所需的任何演算法。
胺基酸取代可包括(但不限於)將多肽中之一個胺基酸置換為另一個胺基酸。例示性取代示於表1中。胺基酸取代可引入至所關注之抗體中，且針對例如抗原或受體結合保留/改良、抗原或受體結合降低、免疫原性降低或ADCC或CDC改良之所需活性來篩選產物。 表1
原始殘基 例示性取代
Ala (A) Val; Leu; Ile
Arg (R) Lys; Gln; Asn
Asn (N) Gln; His; Asp, Lys; Arg
Asp (D) Glu; Asn
Cys (C) Ser; Ala
Gln (Q) Asn; Glu
Glu (E) Asp; Gln
Gly (G) Ala
His (H) Asn; Gln; Lys; Arg
Ile (I) Leu; Val; Met; Ala; Phe；正白胺酸
Leu (L) 正白胺酸; Ile; Val; Met; Ala; Phe
Lys (K) Arg; Gln; Asn
Met (M) Leu; Phe; Ile
Phe (F) Trp; Leu; Val; Ile; Ala; Tyr
Pro (P) Ala
Ser (S) Thr
Thr (T) Val; Ser
Trp (W) Tyr; Phe
Tyr (Y) Trp; Phe; Thr; Ser
Val (V) Ile; Leu; Met; Phe; Ala；正白胺酸
胺基酸可根據共同的側鏈特性來進行分組： (1)疏水性：正白胺酸、Met、Ala、Val、Leu、Ile； (2)中性親水性：Cys、Ser、Thr、Asn、Gln； (3)酸性：Asp、Glu； (4)鹼性：His、Lys、Arg； (5)影響鏈定向之殘基：Gly、Pro； (6)芳族：Trp、Tyr、Phe。
非保守取代將引起此等類別中之一者之成員與另一類別交換。
術語「載體」用於描述可經工程改造以含有可在宿主細胞中繁殖之一或多個經選殖之聚核苷酸的聚核苷酸。載體可包括以下一或多種元件：複製起點、一或多個調節所關注多肽之表現的調節序列(諸如啟動子及/或強化子)、及/或一或多個可選擇標記物基因(諸如抗生素抗性基因及可用於比色分析中之基因，例如β-半乳糖苷酶)。術語「表現載體」係指用於宿主細胞中表現所關注多肽之載體。
「宿主細胞」係指可為或已為載體或經分離聚核苷酸之接受者的細胞。宿主細胞可為原核細胞或真核細胞。例示性真核細胞包括哺乳動物細胞，諸如靈長類動物或非靈長類動物細胞；真菌細胞，諸如酵母；植物細胞；以及昆蟲細胞。非限制性例示性哺乳動物細胞包括(但不限於) NSO細胞、PER.C6 ®細胞(Crucell)以及293F及CHO細胞，以及其衍生物，諸如293-6E、CHO-DG44、CHO-K1、CHO-S及CHO-DS細胞。宿主細胞包括單個宿主細胞之後代，且後代可能由於自然、偶然或故意突變而不一定與原始親本細胞完全一致(在形態或基因體DNA補體方面)。宿主細胞包括在活體內經本文所提供之聚核苷酸轉染之細胞。
如本文所使用之術語「經分離」係指已與自然界中通常一起發現或產生之至少一些組分分離之分子。舉例而言，當多肽與產生多肽之細胞的至少一些組分分離時，該多肽稱為「經分離」。若多肽在表現後由細胞分泌，則含有該多肽之上清液與產生其之細胞之物理性分離即視為「分離」多肽。類似地，當聚核苷酸不為自然界中通常存在之較大聚核苷酸(諸如以DNA聚核苷酸為例係指基因體DNA或粒線體DNA)之一部分，或與產生該聚核苷酸之細胞之至少一些組分分離(例如以RNA聚核苷酸為例)時，該聚核苷酸稱為「經分離」。因此，宿主細胞內部之載體中所含的DNA聚核苷酸可稱為「經分離」。
術語「個體(individual)」與「受試者(subject)」在本文中可互換使用以指代動物；例如哺乳動物。在一些實施例中，提供治療哺乳動物之方法，該等哺乳動物包括(但不限於)人類、嚙齒動物、猿猴、貓科動物、犬科動物、馬科動物、牛科動物、豬科動物、綿羊、山羊、哺乳類實驗室動物、哺乳類農畜、哺乳類運動動物及哺乳類寵物。在一些實例中，「個體」或「受試者」係指需要治療疾病或病症之個體或受試者。在一些實施例中，接受治療之受試者可為患者，表明以下事實：該受試者已鑑別為患有與該治療有關聯之病症，或有極大的風險感染該病症。
如本文所使用之「疾病」或「病症」係指需要及/或期望治療之病狀。
除非另外指定，否則術語「腫瘤細胞」、「癌細胞」、「癌症」、「腫瘤」及/或「贅瘤」在本文中可互換使用，且係指展現生長不受控及/或細胞存活率異常增加及/或抑制細胞凋亡之細胞，其干擾身體器官及系統之正常功能。此定義中包括良性及惡性癌症、息肉、增生以及潛伏性腫瘤或微小轉移灶。
術語「癌症」及「腫瘤」涵蓋實體癌症及血液/淋巴癌，且亦涵蓋惡性、癌前及良性生長，諸如發育異常。此定義中亦包括具有免疫系統無法阻止(例如免疫逃避及免疫逃脫機制)之異常增殖的細胞(例如病毒感染細胞)。例示性癌症包括(但不限於)：基底細胞癌；膽道癌；膀胱癌；骨癌；大腦及中樞神經系統癌症；乳癌；腹膜癌；子宮頸癌；絨毛膜癌；結腸及直腸癌症；結締組織癌；消化系統癌症；子宮內膜癌；食道癌；眼癌；頭頸癌；胃癌(包括胃腸癌)；神經膠母細胞瘤；肝癌瘤；肝腫瘤；上皮細胞內贅瘤；腎臟癌或腎癌；喉癌；白血病；肝癌；肺癌(例如，小細胞肺癌、非小細胞肺癌、肺腺癌及肺鱗狀癌)；黑色素瘤；骨髓瘤；神經母細胞瘤；口腔癌(唇癌、舌癌、口癌及咽癌)；卵巢癌；胰臟癌；前列腺癌；視網膜母細胞瘤；橫紋肌肉瘤；直腸癌；呼吸系統癌症；唾液腺癌；肉瘤；皮膚癌；鱗狀細胞癌；胃癌；睾丸癌；甲狀腺癌；子宮或子宮內膜癌；泌尿系統癌症；外陰癌；淋巴瘤，包括霍奇金氏淋巴瘤及非霍奇金氏淋巴瘤以及B細胞淋巴瘤(包括低級/濾泡性非霍奇金氏淋巴瘤(NHL)；小淋巴球性(SL) NHL；中級/濾泡性NHL；中級瀰漫性NHL；高級免疫母細胞性NHL；高級淋巴母細胞性NHL；高級小無裂細胞NHL；腫塊性病變NHL；套細胞淋巴瘤；AIDS相關淋巴瘤；及瓦爾登斯特倫氏巨球蛋白血症；慢性淋巴球性白血病(CLL)；急性淋巴母細胞性白血病(ALL)；毛細胞白血病；慢性骨髓母細胞性白血病；以及其他癌瘤及肉瘤；及移植後淋巴增生性病症(PTLD)，以及與母斑病、水腫(諸如與腦瘤相關)及梅格斯氏症候群(Meigs' syndrome)相關之異常血管增生。
如本文所使用之術語「非腫瘤細胞」係指正常細胞或組織。例示性非腫瘤細胞包括(但不限於)：T細胞、B細胞、自然殺手(NK)細胞、自然殺手T (NKT)細胞、樹突狀細胞、單核球、巨噬細胞、上皮細胞、纖維母細胞、肝細胞、間質性腎細胞、纖維母細胞樣滑膜細胞、骨母細胞以及位於乳房、骨骼肌、胰臟、胃、卵巢、小腸、胎盤、子宮、睾丸、腎臟、肺、心臟、大腦、肝、前列腺、結腸、淋巴器官、骨及骨衍生之間葉幹細胞中之細胞。如本文所使用之術語「位於外周之細胞或組織」係指並非位於腫瘤細胞附近及/或腫瘤微環境內之非腫瘤細胞。
如本文所使用之術語「腫瘤微環境內之細胞或組織」係指圍繞及/或喂飼腫瘤細胞之細胞、分子、胞外基質及/或血管。腫瘤微環境內之例示性細胞或組織包括(但不限於)：腫瘤脈管；腫瘤浸潤淋巴球；纖維母細胞網狀細胞；內皮先驅細胞(EPC)；癌症相關纖維母細胞；外被細胞；其他基質細胞；胞外基質(ECM)之組分；樹突狀細胞；抗原呈遞細胞；T細胞；調節性T細胞(Treg細胞)；巨噬細胞；嗜中性球；骨髓衍生之抑制細胞(MDSC)及位於靠近腫瘤處之其他免疫細胞。如下文中所描述，用於鑑別腫瘤細胞及/或位於腫瘤微環境內之細胞/組織的方法為此項技術中熟知的。
在一些實施例中，「增加」或「減少」分別係指統計學上顯著之增加或減少。如熟習此項技術者將顯而易見，「調節」亦可涉及相較於相同條件但不存在測試劑之情形，目標或抗原對其配位體、結合搭配物、搭配物中之一或多者締合為均多聚體或雜多聚體形式，或受質之親和力、親合力、特異性及/或選擇性實現改變(其可為增加或減少)；目標或抗原對該目標或抗原所存在之介質或環境中之一或多種條件(諸如pH、離子強度、輔因子之存在等)的敏感度實現改變(其可為增加或減少)；及/或細胞增殖或細胞介素產生。視所涉及之目標而定，此可藉由任何適合方式及/或使用本身已知或本文所描述之任何適合分析來判定。
如本文中所使用，「免疫反應」意謂涵蓋足以抑制或阻止疾病發作或改善疾病症狀(例如癌症或癌轉移)之細胞及/或體液免疫反應。「免疫反應」可涵蓋先天性及後天性免疫系統兩者之態樣。
如本文中所使用，「治療」為用於獲得有益或所需臨床結果之途徑。如本文所使用之「治療」涵蓋治療劑對哺乳動物(包括人類)之疾病進行之任何投藥或施用。出於本發明之目的，有益或所需臨床結果包括(但不限於)以下中之任何一或多者：緩解一或多種症狀、減弱疾病程度、預防或延遲疾病擴散(例如轉移，例如轉移至肺或淋巴結)、預防或延遲疾病復發、延遲或減緩疾病進展、改善疾病狀態、抑制疾病或疾病進展、抑制或減緩疾病或其進展、遏制其發展，及緩解(無論部分或完全)。「治療」亦涵蓋增生性疾病之病理結果減輕。本文所提供之方法涵蓋此等治療態樣中之任何一或多者。根據上述內容，術語治療不需要百分之一百移除病症之所有態樣。
「改善」意謂與未投與治療劑相比，一或多種症狀得以減輕或改良。「改善」亦包括縮短或減少症狀之持續時間。
術語「抗癌劑」在本文中就其最廣含義而言用於指用於治療一或多種癌症之藥劑。例示性種類之此等藥劑包括(但不限於)化學治療劑、抗癌生物製劑(諸如細胞介素、受體胞外域-Fc融合體及抗體)、放射療法、CAR-T療法、治療性寡核苷酸(諸如反義寡核苷酸及siRNA)及溶瘤病毒。
術語「生物樣本」意謂一定量的來自活物或先前為活物之物質。此類物質包括(但不限於)血液(例如全血)、血漿、血清、尿液、羊水、滑液、內皮細胞、白血球、單核球、其他細胞、器官、組織、骨髓、淋巴結及脾臟。
術語「對照」或「參考」係指已知不含分析物之組合物(「陰性對照」)或已知含有分析物之組合物(「陽性對照」)。陽性對照可包含已知濃度之分析物。
術語「抑制(inhibition/inhibit)」係指任何表型特徵減少或停止，或該特徵之發生率、程度或可能性降低或停止。「降低」或「抑制」係使活性、功能及/或量相較於參考物減小、降低或停滯。在一些實施例中，「降低」或「抑制」意謂總體減少10%或更多之能力。在一些實施例中，「降低」或「抑制」意謂總體減少50%或更多之能力。在一些實施例中，「降低」或「抑制」意謂總體減少75%、85%、90%、95%或更多之能力。在一些實施例中，一段時間內上文所提及之量相對於同一段時間內之對照而言受到抑制或減少。
如本文中所使用，「延遲疾病發展」意謂推遲、阻礙、減緩、扼止、穩定、抑制及/或延緩疾病(諸如癌症)之發展。視所治療之疾病及/或個體之病史而定，此延遲可具有不同的時間長度。如熟習此項技術者顯而易見，充分或顯著延遲可實際上涵蓋預防，使得該個體不罹患該疾病。舉例而言，可延遲晚期癌症，諸如轉移發展。
如本文中所使用，「預防」包括在受試者之疾病出現或復發方面提供預防作用，該受試者可能易患該疾病但尚未診斷患有該疾病。除非另外規定，否則術語「降低」、「抑制」或「預防」不表示或不要求一直完全預防，而僅在所量測之時間段內預防。
物質/分子(促效劑或拮抗劑)之「治療有效量」可根據以下因素改變：諸如個體之疾病狀態、年齡、性別及體重，以及物質/分子(促效劑或拮抗劑)在個體內引發所要反應之能力。治療有效量亦為治療有益作用超過該物質/分子(促效劑或拮抗劑)之任何有毒或有害作用的量。治療有效量可經一或多次投藥來遞送。治療有效量係指在所必需之劑量下及時段內有效達成所需治療及/或防治性結果的量。
術語「醫藥調配物」及「醫藥組合物」係指所呈形式允許活性成分之生物活性有效，且不含對調配物將投與之受試者具有不可接受毒性之額外組分的製劑。此類調配物可為無菌的。
「醫藥學上可接受之載劑」係指此項技術中習知之無毒固體、半固體或液體填充劑、稀釋劑、囊封材料、調配助劑或載劑，其與治療劑一起使用，一起構成向受試者投與之「醫藥組合物」。醫藥學上可接受之載劑在所採用之劑量及濃度下對接受者無毒且與調配物之其他成分相容。醫藥學上可接受之載劑適於所採用之調配物。
與一或多種其他治療劑「組合」投與包括同時(並行)及以任何次序依序投與。
術語「並行」在本文中用於指投與兩種或更多種治療劑，其中投與之至少部分在時間上重疊，或其中一種治療劑之投與落入針對另一治療劑之投與的較短時段內，或其中兩種藥劑之治療效果重疊至少一個時段。
術語「依序」在本文中用於指兩種或更多種治療劑之投與在時間上不重疊，或其中該等藥劑之治療作用不重疊。
如本文中所使用，「結合」係指除一種治療模態以外亦投與另一種治療模態。因此，「結合」係指在向個體投與一種治療模態之前、期間或之後投與另一種治療模態。
術語「藥品說明書」用於指通常包括於治療產品之商業包裝中的說明，其含有關於與使用此類治療產品有關之適應症、用法、劑量、投與、組合療法、禁忌及/或警告的資訊。
「製品」係包含至少一種試劑，例如用於治療疾病或病症(例如，癌症)之藥劑或用於特異性偵測本文所描述之生物標記物之探針的任何製品(例如，包裝或容器)或套組。在一些實施例中，製品或套組係以用於執行本文所描述之方法之單元形式推銷、分銷或出售。
術語「標記」及「可偵測標記」意謂例如附著至抗體或抗原以使得特異性結合對之成員之間的反應(例如，結合)可偵測之部分。特異性結合對之經標記成員稱為「可偵測標記」。因此，術語「經標記之結合蛋白」係指併入有標記以便鑑別結合蛋白之蛋白質。在一些實施例中，標記為可產生可藉由目視或儀器方式偵測的信號之可偵測標記物，例如併入經放射性標記之胺基酸或連接至可藉由經標記之抗生物素蛋白(例如含有可藉由光學或比色方法偵測之螢光標記物或酶促活性的抗生蛋白鏈菌素)偵測之生物素基部分的多肽。用於多肽之標記的實例包括(但不限於)以下：放射性同位素或放射性核素(例如， 3H、 14C、 35S、 90Y、 99Tc、 111In、 125I、 131I、 177Lu、 166Ho或 153Sm)；色素原、螢光標記(例如，FITC、若丹明(rhodamine)、鑭系磷光體(lanthanide phosphor))、酶標記(例如，辣根過氧化酶、螢光素酶、鹼性磷酸酶)；化學發光標記物；生物素基；由二級報導子識別之預定多肽抗原決定基(例如，白胺酸拉鏈對序列、二級抗體之結合位點、金屬結合域、抗原決定基標籤)；及磁化劑，諸如釓螯合物。常用於免疫分析之標記之代表性實例包括產生光之部分，例如吖啶化合物；及產生螢光之部分，例如螢光素。就此而言，該部分自身可能未經可偵測標記，但可在與又一部分反應之後變為可偵測的。 例示性含經修飾 IL-2 之多肽
本文提供包含經修飾IL-2之多肽。在一些實施例中，相較於野生型IL-2，經修飾IL-2包含至少一個降低經修飾IL-2對IL-2受體之親和力的胺基酸取代。在各種實施例中，本文所提供之包含經修飾IL-2之多肽為IL-2R之促效劑。在一些實施例中，經修飾IL-2為經修飾人類IL-2，且IL-2R為人類IL-2R。在一些實施例中，經修飾IL-2以比人類野生型IL-2對IL-2R之親和力低至少2倍、3倍、4倍、5倍、6倍、7倍、8倍、9倍、至少10倍、至少20倍、至少30倍、至少50倍或至少100倍的親和力結合人類IL-2R。
在各種實施例中，包含經修飾IL-2之多肽包含至少一個結合T細胞或自然殺手(NK)細胞抗原的抗原結合域。在一些實施例中，本文所提供之包含經修飾IL-2之多肽包含一個、兩個、三個、四個、五個、六個、七個或八個抗原結合域，其中之至少一者或全部結合T細胞或自然殺手細胞抗原。在一些實施例中，本文所提供之包含經修飾IL-2之多肽包含一個、兩個、三個或四個抗原結合域，其中之至少一者或全部結合T細胞或自然殺手細胞抗原。在一些實施例中，含經修飾IL-2之多肽在不存在抗原結合域之情況下不結合或活化IL-2R。在一些實施例中，含經修飾IL-2之多肽僅在該多肽包含結合至與IL-2R相同之細胞上的抗原之抗原結合域時結合及/或活化細胞上之IL-2R。
在各種實施例中，經修飾IL-2包含至少一個在選自以下之至少一個胺基酸位置處的取代：L19、Q22、R38、E61、N88、R120、T123、Q126、S127、I129及S130。在一些實施例中，經修飾IL-2包含至少一個在選自以下之至少一個胺基酸位置處的取代：T3、P65、H16、D84、M23、E95及C125。在一些實施例中，經修飾IL-2包含在選自L19、Q22、R38、E61、N88、R120、T123、Q126、S127、I129及S130之至少一個胺基酸位置處及在胺基酸位置T3、P65、H16、D84及C125處的取代。在一些此等實施例中，經修飾IL-2進一步包含胺基酸位置M23及/或E95處之取代。
在一些實施例中，胺基酸位置L19處之取代係選自L19A、L19N、L19P、L19Q、L19Y、L19S、L19T及L19V。在一些實施例中，胺基酸位置Q22處之取代係選自Q22A、Q22D、Q22G、Q22H、Q22K、Q22N、Q22R、Q22S、Q22T、Q22V及Q22Y。在一些實施例中，胺基酸位置R38處之取代為R38A或R38G。在一些實施例中，胺基酸位置E61處之取代係選自E61A、E61P、E61G、E61H、E61Q、E61N、E61R、E61S、E61T、E61K及E61Y。在一些實施例中，胺基酸位置N88處之取代係選自N88A、N88S及N88T。在一些實施例中，胺基酸位置R120處之取代係選自R120A、R120D、R120G、R120H、R120E、R120F、R120K、R120N、R120P、R120Q、R120S、R120V及R120Y。在一些實施例中，胺基酸位置T123處之取代基係選自T123D、T123E、T123H、T123K、T123N、T123R及T123Q。在一些實施例中，胺基酸位置Q126處之取代係選自Q126A、Q126N及Q126Y。在一些實施例中，胺基酸位置S127處之取代係選自S127E、S127D、S127N、S127H、S127P、S127Q及S127R。在一些實施例中，胺基酸位置I129處之取代係選自I129A、I129H、I129R及I129S。在一些實施例中，胺基酸位置S130處之取代係選自S130D、S130P、S130E、S130K、S130N、S130R、S130H及S130Q。
在一些實施例中，胺基酸位置P65處之取代係選自P65R、P65E、P65K、P65H、P65Y、P65Q、P65D及P65N。在一些實施例中，胺基酸位置H16處之取代係選自H16A、H16N、H16T及H16V。在一些實施例中，胺基酸位置D84之取代係選自D84S、D84N、D84G、D84A、D84T、D84V及D84Y。在一些實施例中，胺基酸位置M23處之取代係選自M23A、M23R、M23Q、M23N、M23L、M23K、M23G、M23E、M23D、M23S、M23T及M23V。在一些實施例中，胺基酸位置E95處之取代係選自E95Q、E95Y、E95G、E95T、E95V、E95P、E95H及E95N。
在一些實施例中，胺基酸位置T3處之取代係選自T3A及T3G。在一些實施例中，胺基酸位置C125處之取代係選自C125A及C125S。
在一些實施例中，經修飾IL-2進一步包含胺基酸位置F42處之取代。在一些此類實施例中，F42處之取代係選自F42K、F42A、F42R、F42G、F42S及F42T。
在一些實施例中，經修飾IL-2進一步包含至少一個在選自Y45及L72之至少一個胺基酸位置處的取代。在一些此類實施例中，經修飾IL-2包含至少一個選自Y45R、Y45K及L72G之取代。
在一些實施例中，經修飾IL-2包含取代T3A、P65R、H16A、D84Y及C125S。在一些實施例中，經修飾IL-2包含取代T3A、P65R、H16A、D84Y及C125S，且包含一或多個在選自以下之至少一個位置處的取代：L19、Q22、R38、E61、N88、R120、T123、Q126、S127、I129及S130。在一些實施例中，經修飾IL-2包含取代T3A、P65R、H16A、D84S及C125S，且包含一或多個在選自以下之至少一個位置處的取代：L19、Q22、R38、E61、N88、R120、T123、Q126、S127、I129及S130。在一些實施例中，經修飾IL-2包含取代T3A、P65R、H16A、D84Y、C125S及E61R。在一些實施例中，經修飾IL-2包含取代T3A、P65R、H16A、D84Y、C125S及E61R，且包含至少一個選自以下之取代：L19N、M23T、E95Q及S127D。在一些實施例中，經修飾IL-2包含以下取代 a) T3A、H16A、E61R、P65R、D84Y及C125S， b) T3A、H16A、M23T、E61R、P65R、D84Y、E95Q及C125S， c) T3A、H16A、L19N、E61R、P65R、D84Y及C125S， d) T3A、H16A、L19N、M23T、E61R、P65R、D84Y、E95Q及C125S, e) T3A、H16A、E61R、P65R、D84Y、C125S及S127D， f)  T3A、H16A、M23T、E61R、P65R、D84Y、E95Q、C125S及S127D， g) T3A、H16A、L19N、E61R、P65R、D84Y、C125S及S127D，或 h) T3A、H16A、L19N、M23T、E61R、P65R、D84Y、E95Q、C125S及S127D。
在本文所描述之任一實施例中，經修飾IL-2可為經修飾人類IL-2。在各種實施例中，該等取代之胺基酸位置對應於SEQ ID NO: 1中之該等胺基酸位置。
在一些實施例中，經修飾IL-2包含與SEQ ID NO: 84至少90%、91%、92%、93%、94%、95%、96%、97%、98%或99%一致且包括胺基酸取代之胺基酸序列，該等胺基酸取代對應於選自某些序列表之描述欄中所列之SEQ ID NO: 105至277的胺基酸序列中之取代。對應取代意謂在比對兩個序列時之相同胺基酸。舉例而言，SEQ ID NO: 106包含取代T3A、E61R、P65R及C125S。若比對SEQ ID NO: 84及SEQ ID NO: 106，則SEQ ID NO: 106中之位置E61對應於SEQ ID NO: 84中之依序位置E51。SEQ ID NO: 106之T3在SEQ ID NO: 84中無對應位置，此係因為不存在對應胺基酸。因此，在對應於SEQ ID NO: 106之彼等位置的位置處包含SEQ ID NO: 106之取代的SEQ ID NO: 84包含對應於E61R、P65R及C125S之突變，其在SEQ ID NO: 84中將分別為E51R、P55R及C115S。在一些實施例中，經修飾IL-2包含與SEQ ID NO: 84至少90%、91%、92%、93%、94%、95%、96%、97%、98%或99%一致且包括至少一個位置處之取代的胺基酸序列，該位置對應於選自SEQ ID NO: 1之L19、Q22、R38、E61、N88、R120、T123、Q126、S127、I129及S130的位置。
在一些實施例中，經修飾IL-2包含與選自SEQ ID NO: 105至290之胺基酸序列至少90%、91%、92%、93%、94%、95%、96%、97%、98%、99%或100%一致且包括在某些序列表中之描述中針對各別胺基酸序列所指示之取代的胺基酸序列。在一些實施例中，經修飾IL-2包含與選自SEQ ID NO: 105至290之胺基酸序列至少90%、91%、92%、93%、94%、95%、96%、97%、98%、99%或100%一致且包括至少一個位置處之取代的胺基酸序列，該位置選自L19、Q22、R38、E61、N88、R120、T123、Q126、S127、I129及S130。在一些實施例中，經修飾IL-2包含選自SEQ ID NO: 105至290之胺基酸序列。在一些實施例中，經修飾IL-2包含選自SEQ ID NO: 270至277之胺基酸序列。
在一些實施例中，含經修飾IL-2之多肽包含至少一個結合T細胞或自然殺手細胞抗原之抗原結合域及一Fc區。在一些實施例中，本文所提供之含經修飾IL-2之多肽包含一個、兩個、三個或四個抗原結合域及一Fc區。在一些實施例中，Fc區介導含經修飾IL-2之多肽在生理學條件下之二聚化以使得形成抗原結合位點之數目加倍之二聚體。舉例而言，包含三個抗原結合域及一Fc區的含經修飾IL-2之多肽作為單體係三價的，但在生理學條件下，Fc區可介導二聚化，使得含經修飾IL-2之多肽在此類條件下以六價二聚體形式存在。
在各種實施例中，包含經修飾IL-2之多肽包含選自SEQ ID NO: 105至290之序列。在各種實施例中，包含經修飾IL-2之多肽包含選自SEQ ID NO: 270至277之序列。在一些實施例中，多肽進一步包含抗原結合域。在一些實施例中，抗原結合域經人類化。
在一些實施例中，至少一個抗原結合域為天然或原生同源結合搭配物、抗運載蛋白(Anticalin) (經工程改造之脂質運載蛋白)、錨蛋白重複蛋白(Darpin)、菲諾體(Fynomer)、生替林(Centyrin) (經工程改造之纖維結合蛋白III域)、胱胺酸結域(cystine-knot domain)、阿菲林(Affilin)、親和抗體(Affibody)或經工程改造之CH3域。在一些實施例中，天然同源結合搭配物包含腫瘤相關抗原(TAA)之原生同源結合搭配物之配位體或胞外域或其結合片段，或其展現與TAA之結合活性的變異體。
在一些實施例中，包含經修飾IL-2及至少一個抗原結合域之多肽增強抗腫瘤T細胞反應或自然殺手細胞反應，同時避開Treg、外周T細胞及內皮細胞。在一些此等實施例中，至少一個抗原結合域使經修飾IL-2靶向活化T細胞。在一些實施例中，經修飾IL-2僅在IL-2R處於與結合至少一個抗原結合域之抗原相同的細胞上時結合且調節IL-2R。在一些實施例中，當IL-2R處於與表現結合至少一個抗原結合域之抗原的細胞不同之細胞上時，經修飾IL-2不結合或活化IL-2R。
在各種實施例中，抗原結合域結合於選自以下之蛋白質：PD-1、CTLA-4、LAG3、TIM3、4-1BB、OX40、GITR、CD8a、CD8b、CD4、NKp30、NKG2A、TIGIT、TGFβR1、TGFβR2、Fas、NKG2D、NKp46、PD-L1、CD107a、ICOS、TNFR2、CD16a及γδTCR。在一些實施例中，包含經修飾IL-2之多肽包含以下之抗原結合域：納武單抗(BMS；PD-1)；派立珠單抗(Merck；PD-1)；AMP-514 (Amplimmune；PD-1)；TSR-042 (Tesaro/AnaptysBio，ANB-011；PD-1)；STI-A1110 (Sorrento Therapeutics；PD-1)、伊匹單抗(BMS；CTLA-4)；曲美單抗(AstraZeneca，CTLA-4)；烏瑞魯單抗(BMS，4-1BB)；烏圖木單抗(Pfizer，4-1BB)；阿特珠單抗(Roche，PD-L1)、德瓦魯單抗(AstraZeneca，PD-L1)；莫納珠單抗(monalizumab) (NKG2A，Innate Pharma and AstraZeneca)；BMS-986016 (Bristo-Meyers Squibb，LAG-3)。
在一些實施例中，多肽包含至少一個特異性結合於PD-1之抗原結合域。在一些實施例中，多肽包含至少一個特異性結合於LAG3之抗原結合域。在一些實施例中，多肽包含至少一個特異性結合於NKp46之抗原結合域。在一些實施例中，多肽包含至少一個特異性結合於NKG2D之抗原結合域。在一些實施例中，多肽包含至少一個特異性結合於CD8a之抗原結合域。
在一些實施例中，抗原結合域可經人類化。包含人類化抗原結合域之多肽(諸如含VHH多肽)適用作治療性分子，因為人類化抗原結合域及人類化抗體降低或消除對非人類抗體之人類免疫反應，該人類免疫反應會導致對抗體治療劑之免疫反應且降低治療劑之有效性。一般而言，人類化抗原結合域或人類化抗體包含一或多個可變域，其中CDR (或其部分)來源於非人類抗體，且FR (或其部分)來源於人類抗體序列。人類化抗原結合域或人類化抗體視情況亦將包含人類恆定區之至少一部分。在一些實施例中，人類化抗原結合域或人類化抗體中之一些FR殘基經來自非人類抗體(例如，CDR殘基所來源之抗體)的對應殘基取代，例如以恢復或改良抗體特異性或親和力。
人類化抗體及其製備方法綜述於例如Almagro及Fransson, (2008) Front. Biosci.13: 1619-1633中，且進一步描述於例如Riechmann等人, (1988) Nature332:323-329；Queen等人, (1989) Proc. Natl Acad. Sci. USA86: 10029-10033；美國專利第5,821,337號、第7,527,791號、第6,982,321號及第7,087,409號；Kashmiri等人, (2005) Methods36:25-34；Padlan, (1991) Mol. Immunol.28:489-498 (描述「表面重塑」)；Dall'Acqua等人, (2005) Methods36:43-60 (描述「FR改組」)；及Osbourn等人, (2005) Methods36:61-68及Klimka等人, (2000) Br. J. Cancer, 83:252-260 (描述FR改組之「導引選擇」方法)中。
可用於人類化之人類構架區包括(但不限於)：使用「最佳擬合(best-fit)」方法選擇之構架區(參見例如Sims等人(1993) J. Immunol.151 :2296)；來源於重鏈可變區之特定子群之人類抗體的共有序列之構架區(參見例如Carter等人(1992) Proc. Natl. Acad. Sci. USA, 89:4285；及Presta等人(1993) J. Immunol, 151:2623)；人類成熟(體細胞突變)構架區或人類生殖系構架區(參見例如Almagro及Fransson, (2008) Front. Biosci. 13:1619-1633)；及來源於篩選FR庫之構架區(參見例如Baca等人, (1997) J. Biol. Chem.272: 10678-10684及Rosok等人, (1996) J. Biol. Chem.271 :22611-22618)。通常，VHH之FR區經人類FR區置換以製備人類化VHH。在一些實施例中，人類FR之某些FR殘基經置換以便改良人類化VHH之一或多個特性。具有此等經置換殘基之VHH域在本文中仍稱為「人類化」。
在各種實施例中，包括於含經修飾IL-2之多肽中的Fc區為人類Fc區，或來源於人類Fc區。
在一些實施例中，包括於含經修飾IL-2之多肽中的Fc區來源於人類Fc區，且包含在低級鉸鏈中對應於IgG1 E233、L234及L235之三個胺基酸缺失，本文中稱為「Fc xELL」。Fc xELL多肽不接合FcγR，且因此稱為「效應子靜默」或「效應子空缺」，然而在一些實施例中，xELL Fc區結合FcRn且因此具有延長之半衰期及與FcRn介導之再循環相關的胞吞轉送。
在一些實施例中，包括於含經修飾IL-2之多肽中的Fc區來源於人類Fc區且包含突變M252Y及M428V，本文中稱作「Fc-YV」。在一些實施例中，包括於含經修飾IL-2之多肽中的Fc區來源於人類Fc區且包含突變M252Y及M428L，本文中稱作「Fc-YL」。在一些實施例中，此等突變在核內體之酸性pH (接近6.5)下增強與FcRn之結合，而在中性pH (約7.2)下失去可偵測之結合，使得FcRn介導之再循環增強且半衰期延長。
在一些實施例中，包括於本文中之含經修飾IL-2之多肽中的Fc區來源於人類Fc區且包含經設計以用於雜二聚化之突變，本文中稱作「杵」及「臼」。在一些實施例中，「杵」Fc區包含突變T366W。在一些實施例中，「臼」Fc區包含突變T366S、L368A及Y407V。在一些實施例中，用於雜二聚化之Fc區包含額外突變，諸如位於形成不對稱二硫鍵之雜二聚體Fc對之第一成員上的突變S354C及位於雜二聚體Fc對之第二成員上的對應突變Y349C。在一些實施例，雜二聚體Fc對之一個成員包含修飾H435R或H435K以阻止蛋白質A結合，同時維持FcRn結合。在一些實施例中，雜二聚體Fc對之一個成員包含修飾H435R或H435K，而雜二聚體Fc對之第二成員在H435處不經修飾。在各種實施例中，臼Fc區包含修飾H435R或H435K (在一些情況下當修飾為H435R時稱作「臼-R」)，而杵Fc區不包含該修飾。在一些情況下，相對於可能存在之均二聚體臼Fc區，臼-R突變改良雜二聚體之純化。
可用於含經修飾IL-2之多肽中的非限制性例示性Fc區包括包含SEQ ID NO: 47至83、292及293之胺基酸序列的Fc區。
在一些實施例中，包含至少一個抗原結合域及一Fc區的含經修飾IL-2之多肽包含選自SEQ ID NO: 105至290之胺基酸序列及與彼胺基酸序列之C端融合的Fc區。在一些實施例中，包含至少一個抗原結合域及一Fc區的含經修飾IL-2之多肽包含選自SEQ ID NO: 270至277之胺基酸序列及與彼胺基酸序列之C端融合的Fc區。在一些實施例中，包含至少一個抗原結合域及一Fc區的含經修飾IL-2之多肽包含選自SEQ ID NO: 105至290之胺基酸序列及與彼胺基酸序列之N端融合的Fc區。在一些實施例中，包含至少一個抗原結合域及一Fc區的含經修飾IL-2之多肽包含選自SEQ ID NO: 270至277之胺基酸序列及與彼胺基酸序列之N端融合的Fc區。在一些實施例中，包含至少一個抗原結合域及一Fc區的含經修飾IL-2之多肽包含選自SEQ ID NO: 105至290之胺基酸序列及選自SEQ ID NO: 47至83、292及293之胺基酸序列。在一些實施例中，包含至少一個抗原結合域及一Fc區的含經修飾IL-2之多肽包含選自SEQ ID NO: 105至290之胺基酸序列及選自SEQ ID NO: 48、64、292及293之胺基酸序列。在一些實施例中，包含至少一個抗原結合域及一Fc區的含經修飾IL-2之多肽包含選自SEQ ID NO: 270至277之胺基酸序列及選自SEQ ID NO: 48、64、292及293之胺基酸序列。在一些實施例中多肽包含選自SEQ ID NO: 105至290之胺基酸序列及結合表現於T細胞或自然殺手細胞上之抗原的抗原結合域。在一些實施例中，多肽包含選自SEQ ID NO: 270至277之胺基酸序列及結合表現於T細胞或自然殺手細胞上之抗原的抗原結合域。 含經修飾 IL-2 之多肽之例示性活性
在各種實施例中，本文所提供之含經修飾IL-2之多肽為IL-2R活性之促效劑。在一些實施例中，可使用本文實例中所提供之方法，諸如使用293F細胞或類似細胞測定促效劑活性。在一些實施例中，本文所提供之含經修飾IL-2之多肽在靶向T細胞時為IL-2R活性之促效劑，但在不存在靶向之情況下顯示極少或不顯示促效劑活性。在一些實施例中，本文所提供之含經修飾IL-2之多肽在靶向NK細胞及/或T細胞時為IL-2R活性之促效劑，但在不存在靶向之情況下顯示極少或不顯示促效劑活性。在一些實施例中，靶向T細胞或NK細胞的含經修飾IL-2之多肽包含至少一個特異性結合於表現在T細胞或NK細胞上之抗原的抗原結合域。
在一些實施例中，本文所提供之含經修飾IL-2之多肽在活體外及/或活體內增加CD4 +及/或CD8 +T細胞之增殖。在一些實施例中，多肽在Treg細胞之存在下增加CD4 +及/或CD8 +T細胞增殖。在一些此等實施例中，CD4 +及/或CD8 +T細胞為活化CD4 +及/或CD8 +T細胞。在一些實施例中，本文所提供之含經修飾IL-2之多肽在活體外增加活化CD4 +及/或CD8 +T細胞增殖。在一些實施例中，含經修飾IL-2之多肽使活化CD4 +及/或CD8 +T細胞增殖相對於在不存在多肽之情況下的CD4 +及/或CD8 +T細胞增殖增加至少1.5倍、至少2倍、至少3倍或至少5倍。在一些實施例中，多肽使活化CD4 +及/或CD8 +T細胞之增殖相對於在不存在多肽之情況下觀測到的增殖增加至少1.5倍、至少2倍、至少3倍或至少5倍，且實質上不增加靜息CD4 +及/或CD8 +T細胞之增殖。
在一些實施例中，本文所提供之含經修飾IL-2之多肽在活體外及/或活體內增加NK細胞之增殖。在一些此等實施例中，NK細胞為活化NK細胞。在一些實施例中，本文所提供之含經修飾IL-2之多肽在活體外增加活化NK細胞增殖。在一些實施例中，含經修飾IL-2之多肽使活化NK細胞增殖相對於在不存在多肽之情況下的NK細胞增殖增加至少1.5倍、至少2倍、至少3倍或至少5倍。在一些實施例中，多肽使活化NK細胞之增殖相對於在不存在多肽之情況下觀測到的增殖增加至少1.5倍、至少2倍、至少3倍或至少5倍，且實質上不增加靜息NK細胞之增殖。
活化CD4 +及/或CD8 +T細胞之增殖的增加可藉由此項技術中之任何方法，諸如本文實例中所提供之方法測定。一種非限制性例示性分析如下。可自一或多個健康人類供體分離CD4 +及/或CD8 +T細胞。將T細胞用CellTrace Violet (CTV)染色且用抗CD3抗體活化，與包含經修飾IL-2之多肽接觸，且隨後藉由FACS分析。CTV染色損失指示增殖。在一些實施例中，CD4 +及/或CD8 +T細胞增殖之增加係諸如藉由量測自不同健康人類供體分離之CD4 +及/或CD8 +T細胞之增殖，以一組實驗或合併T細胞之平均值形式測定。在一些實施例中，CD4 +及/或CD8 +T細胞增殖之增加係以使用來自至少五個或至少十個不同健康供體之T細胞進行的實驗的平均值，或來自至少五個或至少十個不同健康供體之T細胞池的平均值形式測定。在一些實施例中，本文所提供之含經修飾IL-2之多肽即使在Treg細胞的存在下仍增加CD4 +及/或CD8 +T細胞之增殖。
在一些實施例中，本文所提供之含經修飾IL-2之多肽在活體外及/或活體內增加CD4 +及/或CD8 +T細胞上之CD71表現。CD71表現指示T細胞活化。在一些實施例中，本文所提供之含經修飾IL-2之多肽活體外增加CD4 +及/或CD8 +T細胞上之CD71表現。在一些實施例中，含經修飾IL-2之多肽使CD4 +及/或CD8 +T細胞上之CD71表現相對於在不存在多肽之情況下的CD71表現增加至少1.5倍、至少2倍、至少3倍或至少5倍。在一些實施例中，多肽使活化CD4 +及/或CD8 +T細胞上之CD71表現相對於在不存在多肽之情況下觀測到的CD71表現增加至少1.5倍、至少2倍、至少3倍或至少5倍，且實質上不增加靜息CD4 +及/或CD8 +T細胞上之CD71表現。在一些實施例中，多肽在Treg細胞之存在下增加CD4 +及/或CD8 +T細胞上之CD71表現。
CD4 +及/或CD8 +T細胞上之CD71表現的增加可藉由此項技術中之任何方法，諸如本文實例中所提供之方法測定。一種非限制性例示性分析如下。可將CD4 +及/或CD8 +T細胞自一或多個健康人類供體分離且用抗CD3抗體刺激，與含經修飾IL-2之多肽接觸，且隨後藉由FACS分析CD71表現。在一些實施例中，CD4 +及/或CD8 +T細胞上之CD71表現的增加係諸如藉由量測自不同健康人類供體分離之CD4 +及/或CD8 +T細胞上的CD71表現，以一組實驗或合併T細胞之平均值形式測定。在一些實施例中，CD4 +及/或CD8 +T細胞上之CD71表現的增加係以使用來自至少五個或至少十個不同健康供體之T細胞進行的實驗的平均值，或來自至少五個或至少十個不同健康供體之T細胞池的平均值形式測定。在一些實施例中，本文所提供之含經修飾IL-2之多肽即使在Treg細胞的存在下仍增加CD4 +及/或CD8 +T細胞上之CD71表現。
在一些實施例中，本文所提供之含經修飾IL-2之多肽在活體外及/或活體內增加CD4 +及/或CD8 +T細胞中之pSTAT5表現。pSTAT5表現指示T細胞活化。在一些實施例中，本文所提供之含經修飾IL-2之多肽活體外增加CD4 +及/或CD8 +T細胞中之pSTAT5表現。在一些實施例中，含經修飾IL-2之多肽使CD4 +及/或CD8 +T細胞上之pSTAT5表現相對於在不存在多肽之情況下的pSTAT5表現增加至少1.5倍、至少2倍、至少3倍或至少5倍。在一些實施例中，多肽在Treg細胞之存在下增加CD4 +及/或CD8 +T細胞上之pSTAT5表現。CD4 +及/或CD8 +T細胞中之pSTAT5表現的增加可藉由此項技術中之任何方法，諸如本文實例中所提供之方法測定。在一些實施例中，本文所提供之含經修飾IL-2之多肽即使在Treg細胞的存在下仍增加CD4 +及/或CD8 +T細胞中之pSTAT5表現。
在一些實施例中，本文所提供之含經修飾IL-2之多肽在活體外及/或活體內增加NK細胞中之pSTAT5表現。pSTAT5表現指示NK細胞活化。在一些實施例中，本文所提供之含經修飾IL-2之多肽活體外增加NK細胞中之pSTAT5表現。在一些實施例中，含經修飾IL-2之多肽使NK細胞上之pSTAT5表現相對於在不存在多肽之情況下的pSTAT5表現增加至少1.5倍、至少2倍、至少3倍或至少5倍。在一些實施例中，多肽在Treg細胞之存在下增加NK細胞中之pSTAT5表現。NK細胞中之pSTAT5表現的增加可藉由此項技術中之任何方法，諸如本文實例中所提供之方法測定。
在一些實施例中，本文所提供之含經修飾IL-2之多肽降低或減弱調節性T細胞(Treg)之抑制活性。在一些實施例中，含經修飾IL-2之多肽將CD4 +及/或CD8 +T細胞上之Treg抑制活性降低至少10%、至少20%、至少30%或至少50%。習知CD4 +及/或CD8 +T細胞上之Treg抑制活性的降低可藉由此項技術中之任何方法，諸如本文實例中所提供之方法測定。一種非限制性例示性分析如下。在將Treg及CD4 +T細胞自健康人類供體PBMC分離後，用螢光增殖性細胞染料進行差異性標記。將CD4 +T細胞用抗CD3抗體刺激，同時在本文所提供之含經修飾IL-2之多肽的存在下培育Treg細胞。將兩個T細胞群體共培養3天，且藉由流式細胞測量術監測CD4 +T細胞之增殖及活化。在一些實施例中，例如相較於在Treg細胞之存在下而在不存在本文所提供之含經修飾IL-2之多肽的情況下之CD4 +及/或CD8 +T細胞活化及增殖，本文所提供之含經修飾IL-2之多肽增加在Treg細胞的存在下之CD4 +及/或CD8 +T細胞活化及增殖。 多肽表現及產生
提供包含編碼含經修飾IL-2之結合多肽之聚核苷酸的核酸分子。因此，在各種實施例中，提供編碼包含經修飾IL-2之多肽的核酸分子。在一些實施例中，核酸分子編碼經修飾IL-2及至少一個抗原結合域。在各種實施例中，核酸分子編碼經修飾IL-2及Fc區以及視情況存在之至少一個抗原結合域。在一些實施例中，Fc區包含經設計用於雜二聚化之突變，諸如「杵」或「臼」突變。在一些實施例中，提供一種編碼含經修飾IL-2之多肽的核酸分子，該含經修飾IL-2之多肽包含經修飾IL-2、至少一個抗原結合域及Fc區，其中Fc區與至少一個抗原結合域之C端融合，且經修飾IL-2與Fc區之C端融合。在前述實施例中之任一者中，核酸分子亦可編碼前導序列，其導引含經修飾IL-2之多肽之分泌，該前導序列通常經裂解以使得其不存在於所分泌多肽中。前導序列可為原生重鏈(或VHH)前導序列，或可為另一異源前導序列。
可使用此項技術中習知之重組DNA技術來構築核酸分子。在一些實施例中，核酸分子為適合於在所選宿主細胞中表現之表現載體。
提供包含編碼本文所描述之含經修飾IL-2之多肽之核酸的載體。此類載體包括(但不限於) DNA載體、噬菌體載體、病毒載體、逆轉錄病毒載體等。在一些實施例中，選擇經最佳化以在所需細胞類型(諸如293F、CHO或CHO衍生之細胞)中或在NSO細胞中表現多肽之載體。例示性此類載體描述於例如Running Deer等人, Biotechnol. Prog. 20:880-889 (2004)中。
在一些實施例中，含經修飾IL-2之多肽可表現於原核細胞，諸如細菌細胞中；或真核細胞，諸如真菌細胞(諸如酵母)、植物細胞、昆蟲細胞及哺乳動物細胞中。此類表現可例如根據此項技術中已知之程序進行。可用於表現多肽之例示性真核細胞包括(但不限於) COS細胞，包括COS 7細胞；293細胞，包括293F細胞；CHO細胞，包括CHO-S、DG44、Lec13 CHO細胞及FUT8 CHO細胞；PER.C6 ®細胞(Crucell)；及NSO細胞。在一些實施例中，含經修飾IL-2之多肽可表現於酵母中。參見例如美國公開案第US 2006/0270045 A1號。在一些實施例中，特定真核宿主細胞係基於其對多肽產生所需轉譯後修飾的能力來選擇。舉例而言，在一些實施例中，CHO細胞產生多肽，該等多肽之唾液酸化水準高於293F細胞中所產生之相同多肽。
將一或多種核酸(諸如載體)引入至所需宿主細胞中可藉由任何方法完成，包括(但不限於)磷酸鈣轉染、DEAE-聚葡萄糖介導之轉染、陽離子脂質介導之轉染、電穿孔、轉導、感染等。非限制性例示性方法描述於例如Sambrook等人, Molecular Cloning, A Laboratory Manual, 第3版Cold Spring Harbor Laboratory Press (2001)中。核酸可根據任何適合方法短暫或穩定轉染於所需宿主細胞中。
亦提供包含本文所描述之核酸或載體中之任一者的宿主細胞。在一些實施例中，提供一種表現本文所描述之含經修飾IL-2之多肽的宿主細胞。可藉由任何適合方法純化表現於宿主細胞中之含經修飾IL-2之多肽。此類方法包括(但不限於)使用親和基質或疏水性相互作用層析。適合之親和配位體包括ROR1 ECD及結合Fc區之藥劑。舉例而言，蛋白質A、蛋白質G、蛋白質A/G或抗體親和管柱可用於結合Fc區及純化包含Fc區的含經修飾IL-2之多肽。疏水相互作用層析，例如丁基或苯基管柱亦可適用於純化一些多肽，諸如抗體。離子交換層析(例如，陰離子交換層析及/或陽離子交換層析)亦可適用於純化一些多肽，諸如抗體。混合模式層析(例如，逆相/陰離子交換、逆相/陽離子交換、親水相互作用/陰離子交換、親水相互作用/陽離子交換等)亦可適用於純化一些多肽，諸如抗體。純化多肽之許多方法為此項技術中已知的。
在一些實施例中，含經修飾IL-2之多肽係在無細胞系統中產生。非限制性例示性無細胞系統描述於例如Sitaraman等人, Methods Mol. Biol.498: 229-44 (2009)；Spirin, Trends Biotechnol.22: 538-45 (2004)；Endo等人, Biotechnol. Adv. 21: 695-713 (2003)中。
在一些實施例中，提供藉由上文所描述之方法製備的含經修飾IL-2之多肽。在一些實施例中，含經修飾IL-2之多肽係在宿主細胞中製備。在一些實施例中，含經修飾IL-2之多肽係在無細胞系統中製備。在一些實施例中，含經修飾IL-2之多肽經純化。在一些實施例中，提供一種包含含經修飾IL-2之多肽之細胞培養基。
在一些實施例中，提供包含藉由上文所描述之方法製備之抗體的組合物。在一些實施例中，該組合物包含在宿主細胞中製備之含經修飾IL-2之多肽。在一些實施例中，該組合物包含在無細胞系統中製備之含經修飾IL-2之多肽。在一些實施例中，該組合物包含經純化之含經修飾IL-2之多肽。 使用含經修飾IL-2之多肽治療疾病之例示性方法
在一些實施例中，提供治療個體之疾病之方法，其包含投與含經修飾IL-2之多肽。此類疾病包括將受益於增加CD4 +及/或CD8 +T細胞之增殖及活化之任何疾病。在一些實施例中，提供用於治療個體之癌症的方法。該方法包含向個體投與有效量的本文所提供之含經修飾IL-2之多肽。此類治療方法可係針對人類或動物。在一些實施例中，提供治療人類之方法。可用本文所提供之含經修飾IL-2之多肽治療的非限制性例示性癌症包括基底細胞癌；膽道癌；膀胱癌；骨癌；大腦及中樞神經系統癌症；乳癌；腹膜癌；子宮頸癌；絨毛膜癌；結腸及直腸癌症；結締組織癌；消化系統癌症；子宮內膜癌；食道癌；眼癌；頭頸癌；胃癌；胃腸癌；神經膠母細胞瘤；肝癌瘤；肝腫瘤；上皮細胞內贅瘤；腎臟癌或腎癌；喉癌；肝癌；肺癌；小細胞肺癌；非小細胞肺癌；肺腺癌；肺鱗狀癌；黑色素瘤；骨髓瘤；神經母細胞瘤；口腔癌；卵巢癌；胰臟癌；前列腺癌；視網膜母細胞瘤；橫紋肌肉瘤；直腸癌；呼吸系統癌症；唾液腺癌；肉瘤；皮膚癌；鱗狀細胞癌；胃癌；睾丸癌；甲狀腺癌；子宮或子宮內膜癌；泌尿系統癌症；及外陰癌；淋巴瘤；霍奇金氏淋巴瘤；非霍奇金氏淋巴瘤；B細胞淋巴瘤；低級/濾泡性非霍奇金氏淋巴瘤(NHL)；小淋巴球性(SL) NHL；中級/濾泡性NHL；中級瀰漫性NHL；高級免疫母細胞性NHL；高級淋巴母細胞性NHL；高級小無裂細胞NHL；腫塊性病變NHL；套細胞淋巴瘤；AIDS相關淋巴瘤；瓦爾登斯特倫氏巨球蛋白血症；慢性淋巴球性白血病(CLL)；急性淋巴母細胞性白血病(ALL)；毛細胞白血病；及慢性骨髓母細胞性白血病。
含經修飾IL-2之多肽可按需要投與至受試者。可由熟習此項技術者，諸如主治醫師，基於考慮所治療之病狀、所治療之受試者之年齡、所治療之病狀之嚴重程度、所治療之受試者的一般健康狀況及其類似者來決定投與頻率。在一些實施例中，一次或多次向受試者投與有效劑量的含經修飾IL-2之多肽。在一些實施例中，每天、每半週、每週、每兩週、每月一次等向受試者投與有效劑量的含經修飾IL-2之多肽。至少一次向受試者投與有效劑量的含經修飾IL-2之多肽。在一些實施例中，可多次投與有效劑量的含經修飾IL-2之多肽，包括在至少一個月、至少六個月或至少一年之時程內投與多次。
在一些實施例中，包含含經修飾IL-2之多肽的醫藥組合物係以對治療(包括預防)癌症及/或增加T細胞增殖有效之量投與。治療有效量通常取決於所治療之受試者之體重、其生理或健康狀況、所治療之病狀的延伸性或所治療之受試者的年齡。一般而言，可按每劑約0.05毫克/公斤體重至約100毫克/公斤體重之範圍內的量投與多肽。在一些實施例中，可按每劑約10微克/公斤體重至約100毫克/公斤體重之範圍內的量投與多肽。在一些實施例中，可按每劑約50微克/公斤體重至約5毫克/公斤體重之範圍內的量投與多肽。在一些實施例中，可按每劑約100微克/公斤體重至約10毫克/公斤體重之範圍內的量投與多肽。在一些實施例中，可按每劑約100微克/公斤體重至約20毫克/公斤體重之範圍內的量投與多肽。在一些實施例中，可按每劑約0.5毫克/公斤體重至約20毫克/公斤體重之範圍內的量投與多肽。在一些實施例中，可按每劑約0.5毫克/公斤體重至約10毫克/公斤體重之範圍內的量投與多肽。在一些實施例中，可按每劑約0.05毫克/公斤體重至約20毫克/公斤體重之範圍內的量投與多肽。在一些實施例中，可按每劑約0.05毫克/公斤體重至約10毫克/公斤體重之範圍內的量投與多肽。在一些實施例中，可按約5毫克/公斤體重或更低，例如低於4、低於3、低於2或低於1毫克/公斤之抗體範圍內的量投與多肽。
在一些實施例中，含經修飾IL-2之多肽可在活體內藉由各種途徑投與，該等途徑包括(但不限於)靜脈內、動脈內、非經腸、腹膜內或皮下。可根據預期應用選擇適當調配物及投藥途徑。
在一些實施例中，使用含經修飾IL-2之多肽之治療性治療係藉由增加T細胞增殖及/或活化來達成。在一些實施例中，增加T細胞增殖及/或活化抑制癌症之生長。 醫藥組合物
在一些實施例中，包含含經修飾IL-2之多肽之組合物係以具有各種醫藥學上可接受之載劑的調配物形式提供(參見例如Gennaro, Remington: The Science and Practice of Pharmacy with Facts and Comparisons: Drugfacts Plus, 第20版(2003)；Ansel等人, Pharmaceutical Dosage Forms and Drug Delivery Systems, 第7版, Lippencott Williams and Wilkins (2004)；Kibbe等人, Handbook of Pharmaceutical Excipients, 第3版, Pharmaceutical Press (2000))。可採用各種醫藥學上可接受之載劑，其包括媒劑、佐劑及稀釋劑。此外，亦可採用各種醫藥學上可接受之輔助物質，諸如pH調節劑及緩衝劑、張力調節劑、穩定劑、潤濕劑及其類似者。非限制性例示性載劑包括生理鹽水、緩衝生理鹽水、右旋糖、水、甘油、乙醇及其組合。
在一些實施例中，醫藥組合物包含濃度為至少10 mg/mL、20 mg/mL、30 mg/mL、40 mg/mL、50 mg/mL、60 mg/mL、70 mg/mL、80 mg/mL、90 mg/mL、100 mg/mL、125 mg/mL、150 mg/mL、175 mg/mL、200 mg/mL、225 mg/mL或250 mg/mL的含經修飾IL-2之多肽。 組合療法
含經修飾IL-2之多肽可單獨或與其他治療模式(諸如，其他抗癌劑)組合投與。其可在其他治療模式之前、實質上同時或之後(亦即，並行或依序)提供。在一些實施例中，本文所描述之治療方法可進一步包括投與：放射療法、化學療法、疫苗接種、靶向腫瘤療法、CAR-T療法、溶瘤病毒療法、癌症免疫療法、細胞介素療法、手術切除、染色體修飾、消融、冷凍療法、針對腫瘤目標的反義藥劑、針對腫瘤目標的siRNA藥劑、針對腫瘤目標的微小RNA藥劑或抗癌/腫瘤藥劑，或生物製劑，諸如抗體、細胞介素或受體胞外域-Fc融合體。
在一些實施例中，本文所提供之含經修飾IL-2之多肽係與第二治療劑(例如PD-1抗體)並行給與。PD-1抗體之實例包括納武單抗(BMS)；派立珠單抗(Merck)；AMP-514 (Amplimmune)；TSR-042 (Tesaro/AnaptysBio，ANB-011)；STI-A1110 (Sorrento Therapeutics)；及針對程式化死亡-1 (PD-1)之其他藥劑。
在一些實施例中，本文所提供之含經修飾IL-2之多肽係與第二治療劑(例如PD-L1療法)並行給與。PD-L1療法之實例包括皮立珠單抗(pidilizumab) (CureTech，CT-011)；德瓦魯單抗(Medimmune/AstraZeneca)；阿特珠單抗(Genentech/Roche)；阿維魯單抗(Pfizer)；AMP-224 (Amplimmune)；BMS-936559 (Bristol-Myers Squibb)；STI-A1010 (Sorrento Therapeutics)；及針對程式化死亡-1配位體(PD-L1)之其他藥劑。
在一些實施例中，本文所提供之含經修飾IL-2之多肽係與CAR-T (嵌合抗原受體T細胞)療法、溶瘤病毒療法、細胞介素療法及/或靶向其他檢查點分子之藥劑(諸如VISTA、gpNMB、B7H3、B7H4、HHLA2、CD73、CTLA4、TIGIT等)並行給與。 非限制性例示性診斷及治療方法
在一些實施例中，本文所描述之方法適用於評估受試者及/或來自受試者(例如，癌症患者)之試樣。在一些實施例中，評估係診斷、預後及/或對治療之反應中之一或多者。
在一些實施例中，本文所描述之方法包含評估蛋白質之存在、不存在或含量。在一些實施例中，本文所描述之方法包含評估核酸之存在、不存在或表現量。本文所描述之組合物可用於此等量測。舉例而言，在一些實施例中，本文所描述之方法包含使腫瘤或由腫瘤培養之細胞的試樣與如本文中所描述之治療劑接觸。
在一些實施例中，評估可導引治療(包括用本文所描述之多肽進行治療)。在一些實施例中，評估可導引輔助療法在切除之後的使用或保留。輔助療法(亦稱作輔助護理)為除初級、主要或初步治療以外給與之治療。藉助於非限制性實例，輔助療法可為通常在手術後當所有可偵測疾病已移除，但由於隱性疾病而仍存在統計學復發風險時所給與之額外治療。在一些實施例中，多肽用作癌症治療中之輔助療法。在一些實施例中，抗體用作癌症治療中唯一之輔助療法。在一些實施例中，本文所描述之抗體被拒絕作為癌症治療中之輔助療法。舉例而言，若患者不大可能對本文所描述之抗體起反應或將具有最低反應，則為生活品質起見及為避免來自無效化學療法之不必要毒性，可不投與治療。在此等情況下，可使用姑息性照護。
在一些實施例中，投與多肽作為切除前之新輔助療法。在一些實施例中，新輔助療法係指在任何手術之前使腫瘤縮小及/或降級之療法。在一些實施例中，新輔助療法意謂在手術之前向癌症患者投與之化學療法。在一些實施例中，新輔助療法意謂在手術之前向癌症患者投與之多肽。通常考慮新輔助化學療法之癌症類型包括例如乳癌、結腸直腸癌、卵巢癌、子宮頸癌、膀胱癌及肺癌。在一些實施例中，抗體用作癌症治療中之新輔助療法。在一些實施例中，在切除之前使用。
在一些實施例中，本文所描述之方法中所涵蓋之腫瘤微環境為以下中之一或多者：腫瘤脈管；腫瘤浸潤淋巴球；纖維母細胞網狀細胞；內皮先驅細胞(EPC)；癌症相關纖維母細胞；外被細胞；其他基質細胞；胞外基質(ECM)之組分；樹突狀細胞；抗原呈遞細胞；T細胞；調節性T細胞；巨噬細胞；嗜中性球；及位於靠近腫瘤處之其他免疫細胞。 套組
亦提供製品及套組，其包括如本文中所描述之含經修飾IL-2之多肽中之任一者及適合之包裝。在一些實施例中，本發明包括一種套組，其具有(i)含經修飾IL-2之多肽，及(ii)關於使用向個體投與含經修飾IL-2之多肽之套組的說明書。
適用於本文所描述之組合物的包裝為此項技術中已知的，且包括例如小瓶(例如，密封小瓶)、容器、安瓿、瓶子、罐、可撓性包裝(例如，密封聚酯薄膜(Mylar)或塑膠袋)及其類似者。此等製品可進一步經滅菌及/或密封。亦提供包含本文所描述之組合物之單位劑型。此等單位劑型可以單個或多個單位劑量儲存於適合包裝中且亦可經進一步滅菌及密封。本發明套組中供應之說明書為通常在標記或藥品說明書(例如，套組中包括之紙張)上之書面說明書，但機器可讀說明書(例如，磁性或光學儲存盤上載有的說明書)亦為可接受的。與使用抗體相關之說明一般包括關於用於預期治療或工業用途之劑量、給藥時程及投藥途徑的資訊。套組可進一步包含關於選擇適合之個體或治療的描述。
容器可為單位劑量、散裝(例如，多劑量包裝)或次單位劑量。舉例而言，亦可提供含有足夠劑量之本文所揭示分子以對個體提供延長週期之有效治療的套組，該延長週期諸如約1週、2週、3週、4週、6週、8週、3個月、4個月、5個月、6個月、7個月、8個月、9個月或更多個月中之任一者。套組亦可包括多個單位劑量之分子及使用說明，且以對於在藥房(例如，醫院藥房及配藥房)中儲存及使用而言足夠之量進行包裝。在一些實施例中，套組包括乾燥(例如，凍乾)組合物，其可經復原、再懸浮或復水以形成一般穩定之多肽水性懸浮液。 實例
下文所論述之實例僅意欲例示本發明，且不應視為以任何方式限制本發明。該等實例並不意欲表示下述實驗為所進行之所有實驗或唯一實驗。已努力確保關於所使用之數字(例如量、溫度等)的準確度，但應考慮一些實驗誤差及偏差。除非另外指示，否則份數為重量份，分子量為平均分子量，溫度係以攝氏度計，且壓力為大氣壓或接近大氣壓。 實例 1 ： IL-2 之基本上消除 CD25 結合之 P65R 突變
IL-2突變體經設計以經由空間阻塞破壞CD25界面(P65R及P65E)，且測試與經IL-2受體之一或多種組分(CD25、CD122及/或CD132)短暫轉染之293F細胞的結合。將突變體與IL-2-F42K (一種據報導與CD25之親和力降低的突變體)進行比較。將增加濃度的包含與「杵」Fc之N端融合且與「臼」Fc (SEQ ID NO: 44)複合的野生型人類IL-2 (SEQ ID NO: 32)、IL-2-F42K (SEQ ID NO: 33)、IL-2-P65R (SEQ ID NO:35)或IL-2-P65E (SEQ ID NO: 34)的融合蛋白添加至經轉染293F細胞中且在4℃下培育45分鐘。
藉由流式細胞測量術分析結合，實質上如下。將細胞在200 µL FACS緩衝液(PBS、2% FBS、0.05%疊氮化鈉)中洗滌一次，且將細胞集結粒再懸浮於100 µl表面標記物染色溶液(含有1:300稀釋於FACS緩衝液中之A647結合抗人類Fcg二級抗體)中。將細胞在4℃下培育45分鐘，隨後進行最終洗滌，且在流式細胞儀上分析。藉由FSC/SSC尺寸排阻排除細胞碎屑，且基於其陽性碘化丙錠信號排除死亡細胞。使用FSC-A/FSC-H雙聯體及聚集排除來選擇單個細胞。經短暫轉染之細胞亦表現細胞質EGFP，且分析為FL1陽性之細胞。抗人類二級抗體之MFI含量增加指示IL-2結合。將FlowJo軟體用於分析細胞群體。隨後使用Excel及GraphPad PRISM導出及分析各標記物之原始平均螢光強度(「MFI」)。用圖表示值，且使用非線性回歸單點-全曲線擬合(One-site--Total curve fit)擬合滴定曲線以評定劑量-反應關係。
如圖2A至圖2C中所示，包含IL-2-P65E變異體之融合蛋白相對於包含野生型IL-2之融合蛋白展現對IL-2R之親和力略微降低。包含IL-2 F42K之融合蛋白展現比包含IL-2-P65E之融合蛋白低的親和力，而包含IL-2-P65R之融合蛋白展現對雜三聚體IL-2R之最低親和力(圖2A)。此外，包含IL-2-P65R之融合蛋白未展現與CD25/CD132之可偵測結合且僅微弱結合CD25/CD122 (圖2C)，而包含IL-2-F42K之融合蛋白保留對CD25/CD132之一些親和力(圖2B)且以比包含IL-2-P65R之融合蛋白更大的親和力結合CD25/CD122(圖2B及圖2C)。因此，P65R處突變之IL-2顯著降低與含有IL-2受體之CD25的結合。 實例 2 ： 降低對 CD122 之 親和力的 IL-2 修飾
如實例1中所指出，P65R IL-2突變經設計以經由空間阻塞破壞CD25界面。另外，IL-2突變經設計以經由消除某些接觸殘基相互作用來降低對CD122界面之親和力(例如，D84S、E95Q、M23A、H16A及E15S)。單或雙重突變體與雜二聚體Fc之「杵」半部之N端融合(包含「臼」Fc SEQ ID NO: 44之二硫鍵穩定化臼包杵)，以供單價IL-2結合於IL-2R。藉由用CD25及CD122短暫轉染293F細胞來評定相對結合親和力(與CD132共轉染顯示類似結果，但額外結合親合力降低觀測到之親和力差異)。用螢光抗人類二級抗體偵測結合之IL-2-Fc融合蛋白，且實質上如實例1中所描述藉由流式細胞測量術分析。
如圖3A至圖3B中所示，包含併入在CD122界面中具有突變之F42K的雙重IL-2突變體(SEQ ID NO: 36至39)之所有融合蛋白相對於包含單突變IL-2-F42K (SEQ ID NO: 33)之彼等融合蛋白顯示對CD25/CD122之結合親和力降低，IL-2-F42K-E15S (SEQ ID NO: 85)除外。 實例 3 ： IL-2-RAS (P65R 、 H16A 及 D84S) 在 IL-2R 之三聚體及二聚體形式之情形下對 CD122 之 親和力降低
將實例2中所描述之降低CD122親和力之突變與P65R突變組合以構築IL-2雙重及三重突變體。將IL-2突變體與雜二聚體Fc之「杵」半部之N端融合且與包含SEQ ID NO: 44之「臼」Fc配對，以供單價IL-2結合於IL-2受體(IL-2R)。針對經IL-2R次單元短暫轉染之293F細胞評定所得融合蛋白之相對結合親和力，實質上如實例1中所描述。
相對於包含野生型IL-2 (SEQ ID NO: 32)之融合蛋白，包含IL-2-P65R-H16A (SEQ ID NO: 41)之融合蛋白及包含IL-2-P65R-D84S (SEQ ID NO: 42)之融合蛋白對CD122/CD132 (雜二聚體IL-2R) (圖4A)及雜三聚體IL-2R (圖4B)兩者的親和力均降低，而包含三重突變體IL-2 P65R-H16A-D84S (「IL-2-RAS」，SEQ ID NO: 43)之融合蛋白之親和力減弱得更多(圖4A至圖4B)。針對此等IL-2突變體在最大結合及EC 50兩方面觀測到之結合偏移表明，此等突變降低結合速率(EC 50之右移)及解離速率(最大結合降低)。 實例 4. IL-2-RAS 對靜息 T 細胞及預活化 T 細胞之親和力降低
為了分離T細胞，在室溫下用針對CD14、CD16、CD19、CD20、CD36、CD56、CD123、TCRγ/δ (BioLegend)之經生物素標記抗系標記物抗體標記非T細胞群體20分鐘。隨後藉由在室溫下用磁性抗生蛋白鏈菌素粒子(每100×10 6中500 µl珠粒漿料加500 µl細胞懸浮液，在磁體上培育2×8分鐘)培育20分鐘耗盡非T細胞群體。未結合之細胞上清液含有經分離之T細胞。
將一些經分離T細胞(5.5×10 6於3 mL中)藉由在用1 µg/ml 抗CD3 OKT3抗體(BD Biosciences)預塗之6孔培養盤中培育來活化2天，隨後用PBS/2% FBS洗滌，且在2×10 6/mL於RPMI + 10% FBS中擱置1天。將靜息或預活化T細胞直接用於結合分析。除使用以下二級抗體以外，實質上如實例1中所描述藉由流式細胞測量術量測非靶向VHH-Fc同型對照及包含與連接至雜二聚體Fc之非靶向VHH之C端融合之IL-2-RAS或野生型IL-2的融合蛋白與靜息或預活化T細胞之結合：AF647抗人類Fc (1:1000)、PI (1:2000)、BV785-CD4 (1:300)、APC/Fire-CD8 (1:500)及PE/Cy7-CD25 (1:100)。
相較於包含非靶向VHH域及野生型IL-2之融合蛋白(包含SEQ ID NO: 45)，非靶向IL-2-RAS融合蛋白(包含SEQ ID NO: 46)以降低之親和力結合靜息(圖5A)及預活化(圖5B) T細胞。不包含IL-2之同型對照不結合靜息或預活化T細胞，如圖5A及圖5B中所示。 實例 5 ： IL-2-RAS 對 Treg 之 親和力降低
調節性T細胞(「Treg」)具有CD25以及CD122及CD132之高內源性表現，且對野生型IL-2具高度反應性。量測包含與非靶向VHH之雜二聚體Fc (二硫鍵穩定化臼包杵)之「杵」半部之C端融合的野生型IL-2 (包含SEQ ID NO: 45)或IL-2-RAS三重突變體(包含SEQ ID NO: 46)的融合蛋白與Treg之結合。
使Treg及CD4+ T反應細胞(Tresp)富集，且藉由遵循製造商之說明書使用EasySep人類CD4 +CD127 lowCD25 +調節性T細胞分離套組(Stemcell)自新鮮健康供體PBMC分離。經由在補充有rhTGF-B1、全反式視黃酸、CD3/CD28 T細胞活化劑及IL-2之ImmunoCult-XF T細胞擴增培養基中培養7天來自原生CD4+ T細胞產生Treg。
為了區分兩種細胞群體，將富集之Treg及CD4 +反應T細胞分別在37℃下用增殖性染料CellTrace Violet (CTV)及CFSE標記10分鐘。在洗滌之後，將Treg及CD4 +T細胞在補充有10% FBS及1×抗生素/抗黴劑之RPMI中再懸浮至每毫升1.5×10 6個細胞。將Treg接種於50 µl體積中，從而在96孔圓底培養盤中產生每孔75,000個Treg。如實例1中所描述藉由流式細胞測量術，將Treg在37℃下在10 nM之IL-2-RAS的存在下培育隔夜。
如圖6中所示，與包含野生型IL-2之融合蛋白形成相比，包含IL-2-RAS之融合蛋白未顯示與自PBMC富集之Treg (圖6A)、經誘導Treg (圖6B)或CD4+ Tresponder (圖6C)之可觀測結合。 實例 6 ： IL-2-RAS 在 靜息 T 細胞上之 活性降低
實質上如實例4中所描述藉由磁珠分離來分離T細胞，用CellTrace Violet (CTV)標記，且用包含與連接至雜二聚體Fc之非靶向VHH之C端融合的野生型IL-2 (包含SEQ ID NO: 45)或IL-2-RAS (包含SEQ ID NO: 46)的融合蛋白處理。藉由流式細胞測量術量測CD4、CD8、CD71及CTV之含量。增殖T細胞使CTV含量降低。
如圖7A及圖7C中所示，誘導靜息CD4+及CD8+ T細胞增殖所需之包含IL-2-RAS之融合蛋白的濃度比達成增殖之相同誘導所需的包含野生型IL-2之融合蛋白之濃度或包含IL-2v-類似物之融合蛋白之濃度大超過100倍。
如圖7B及圖7D中所示，誘導CD8+及CD4+ T細胞上之CD71表現(T細胞活化之標誌)所需的包含IL-2-RAS之融合蛋白的濃度比達成活化之相同誘導所需的包含野生型IL-2或IL-2v-類似物之融合蛋白的濃度大至少100倍。
亦可藉由活化T細胞中增加之磷酸化STAT5含量來量測T細胞活化。藉由磁珠分離來分離T細胞，且用包含與包含雜二聚體Fc之非靶向VHH之C端融合之野生型IL-2 (包含SEQ ID NO: 45)的融合蛋白或包含與包含雜二聚體Fc之非靶向VHH之C端融合之IL-2-RAS (包含SEQ ID NO: 46)的融合蛋白處理15分鐘。將細胞用BD Cytofix/Cytoperm™ (BD Biosciences)固定，在90%冰冷甲醇中滲透，且使用抗pSTAT5-PE抗體(1:70)使用流式細胞測量術量測CD4+及CD8+ T細胞上之磷酸化STAT5 (「pSTAT5」)的含量。將細胞用以下抗體共染色：抗CD3-FITC (1:200)、CD56-BV421 (1:100)、CD4-BV785 (1:200)、CD8-APC-Fire (1:300)。
如圖7E及圖7F中所示，非靶向IL-2-RAS融合蛋白即使在所測試之最高濃度下仍達成靜息CD4+及CD8+ T細胞中之STAT5的最少磷酸化，而非靶向IL-2-野生型融合蛋白在比所測試之最高濃度小超過1000倍之濃度下誘導STAT5磷酸化。 實例 7 ： IL-2 突變體在 Treg 上之活性降低
使用EasySep™人類CD4+CD127lowCD25+調節性T細胞分離套組(Stemcell)自PBMC分離Treg。將Treg用CellTrace Violet標記，且於100 µl之RPMI/10% FBS中以每孔0.15×10 6個細胞(96孔，U形底)平板接種。將細胞與100 µl融合蛋白滴定物組合，以100 nM開始，1:4滴定。將細胞培育7天。在第7天，除使用以下抗體以外，實質上如實例1中所描述藉由流式細胞測量術(Novocyte)量測增殖及活化標記物CD25：BV785-CD4 (1:300)、APC/Fire-CD8 (1:500)、PE/Cy7-CD25 (1:100)、PI (1:2000)。
如圖8A及圖8B中所示，包含與連接至雜二聚體Fc之非靶向VHH之C端融合的野生型IL-2 (包含SEQ ID NO: 45)的融合蛋白誘導Treg增殖及活化標記物CD25之表現，但包含IL-2-RAS而非野生型IL-2 (包含SEQ ID NO: 46)之融合蛋白不誘導。 實例 8 ： 表現 PD-1 之 活化 T 細胞受 靶向 PD-1 之 IL-2-RAS 刺激
使用派立珠單抗(一種習知抗PD-1抗體)及包含連接至重鏈之C端的派立珠單抗類似物及IL-2-RAS之融合蛋白(參見圖1F)測試結合及刺激表現PD-1之T細胞的能力。
實質上如實例4中所描述，活化來自健康供體之富集T細胞。在4℃下用1 µg/ml OKT3抗體塗佈6孔培養盤隔夜。次日，將培養盤洗滌兩次以移除未結合之OKT3抗體。使用CTL培養基將富集之T細胞解凍，且於全RPMI中再懸浮至5.5×10 6個細胞/毫升，並且在經塗佈培養盤中以每孔3 mL接種。兩天後，收集活化T細胞，且洗滌一次，隨後平板接種於無OKT3抗體之培養基中24小時以靜置。將細胞用增殖性染料CellTrace™ Violet (CTV)標記。對T細胞計數，隨後再懸浮至2×10 6個細胞/毫升。在96孔圓底培養盤中每孔接種100 µL經再懸浮細胞。添加派立珠單抗或派立珠單抗類似物-IL-2-RAS融合體，以100 nM之最終濃度開始，且1:5滴定。在第三天，在室溫下用活力標記物PI及以下經螢光標記之抗體將T細胞染色20 min：CD4-BV785、CD8-APC/Fire、CD25-PE/Cy7、CD71-FITC及CD69-APC。實質上如實例7中所描述於Novocyte流式細胞儀上讀取培養盤以量測增殖及如在實例1中量測結合，且將資料導出至Excel中以供進一步分析。
如圖9中所示，派立珠單抗類似物-IL-2-RAS融合蛋白刺激CD8+ T細胞增殖(圖9A)及CD4+ T細胞增殖(圖9B)，而單獨的派立珠單抗不會。在不意欲受任何特定理論束縛之情況下，觀測之增殖之雙相性質可表明，低濃度下之活性係歸因於PD-1靶向活性，且較高濃度下之活性增加係歸因於非靶向活性。如圖9C及圖9D中所示，派立珠單抗及派立珠單抗類似物-IL-2-RAS兩者均以類似親和力結合活化CD8+及CD4+ T細胞，不同之處在於對於包含IL-2-RAS之融合蛋白，在超過10 nM之稀釋範圍之上端觀測到額外結合，其可由結合至IL-2R之IL-2-RAS介導。 實例 9 ： 預阻斷活化 T 細胞上之 PD-1 防止藉由 靶向 PD-1 之 IL-2-RAS 的 信號傳導
藉由磁珠分離自健康供體分離及富集T細胞，且在塗佈有OKT3抗體之培養盤上培育以使其活化，實質上如實例4中所描述。用CTV標記細胞。用派立珠單抗(一種抗PD-1抗體)培育預活化T細胞以阻斷PD-1結合位點，或用作為對照之非靶向抗體培育。隨後用包含與派立珠單抗類似物融合之IL-2-RAS的融合蛋白或包含與非靶向抗體融合之IL-2-RAS的融合蛋白作為對照培育細胞3天。實質上如實例7中所描述藉由用流式細胞測量術量測CD4+及CD8+ T細胞增殖來評估IL-2信號傳導之程度。
如圖10A至圖10D中所示，野生型IL-2誘導CD8+及CD4+ T細胞兩者之穩固增殖，而用派立珠單抗或包含IL-2-RAS及非靶向抗體之融合蛋白處理的CD4+ T細胞及CD8+ T細胞展現不受PD-1之預阻斷影響的低水準之增殖。相比之下，用包含IL-2-RAS及派立珠單抗類似物之融合蛋白處理的CD4+ T細胞(圖10B及圖10D)及CD8+ T細胞(圖10A及圖10C)兩者均展現顯著的PD-1依賴性增殖(圖10A及圖10B)，其藉由用抗PD-1抗體預培育阻斷(圖10C及圖10D)。因此，僅當PD-1表現於T細胞上且可獲得時，包含IL-2-RAS及抗PD-1抗體之融合蛋白活化T細胞。 實例 10 ：靶向 PD-1 之 IL-2-RAS 克服 Treg 抑制
如實例5中所描述分離CD4+ T反應細胞及Treg。將CD4+反應細胞用CTV標記，以2:1之比率與經分離Treg混合，且用抗CD3珠粒(每2個T細胞1個珠粒)活化。將所得混合物用如圖1B中所示與非靶向VHH之C端融合的野生型IL-2、包含如圖1B中所示與非靶向VHH之C端融合的IL-2-RAS的融合蛋白或包含與抗PD-1抗體融合之IL-2-RAS (派立珠單抗類似物-IL-2-RAS)的融合蛋白之稀釋系列處理7天。實質上如實例7中所描述藉由流式細胞測量術量測增殖。
如圖11中所示，Tresponder細胞受Treg抑制，但即使存在Treg，非靶向野生型IL-2及包含IL-2-RAS及抗PD-1抗體之融合蛋白(派立珠單抗類似物-IL-2-RAS)仍誘導CD4+ T反應細胞增殖。用包含IL-2-RAS及非靶向抗體之融合蛋白處理細胞並不會在類似程度上防止增殖損失。非靶向IL-2-RAS僅能夠在比靶向PD-1之IL-2-RAS融合蛋白高得多之濃度下對抗Treg對Tresponder之抑制作用。因此，靶向PD-1之IL-2-RAS克服Treg之抑制作用，且此活性視表現於T細胞上之結合PD-1而定。 實例 11 ： 靶向 PD-1 之 IL-2-RAS 不反式地傳導信號
根據製造商推薦之塗佈程序用每4×10 8個珠粒200 µg PD-1抗原塗佈珠粒。簡言之，將珠粒在緩衝液1 (0.1 M磷酸鈉緩衝液，pH 7.4-8.0)中洗滌一次，且隨後在室溫下於含有PD-1抗原之緩衝液1中在試管旋轉機中培育18小時。隨後將珠粒用緩衝液2 (PBS、0.1% BSA、2 mM EDTA pH 7.4)洗滌4次。藉由將珠粒在37℃下於緩衝液3 (0.2 M Tris、0.1% BSA，pH 8.5)中培育4小時來使游離甲苯磺醯基失活。隨後將珠粒在緩衝液2中洗滌一次且再懸浮至400×10 6個珠粒/毫升之濃度。
將經塗佈珠粒用包含野生型IL-2或與抗PD-1抗體融合之IL-2-RAS的融合蛋白培育且洗滌。隨後用經分離之靜息T細胞培育珠粒。藉由經由流式細胞測量術量測pSTAT5含量來評估IL-2信號傳導。
結合至珠粒的包含野生型IL-2之融合蛋白穩固地活化CD8+ T細胞及CD4+ T細胞，而結合至珠粒的包含IL-2-RAS之融合蛋白在CD4+或CD8+ T細胞上沒有達至所測試之最高濃度的活性。因此，IL-2信號傳導需要IL-2-RAS之T細胞靶向，且靶向IL-2-RAS之信號傳導不會反式地發生。 實例 12 ： IL-2-RAS 不反式地傳導信號
在分析盤上塗佈非靶向野生型IL-2及非靶向IL-2-RAS之稀釋系列(以1000 nM起始且1:4稀釋)，培育隔夜且洗滌。添加T細胞且在37℃下培育30分鐘。藉由偵測磷酸化STAT5含量來量測CD8+及CD4+ T細胞之活化，實質上如實例6中所描述。
如圖12A及圖12B中所示，藉由野生型IL-2反式地活化CD8+及CD4+ T細胞，如藉由pSTAT5誘導所量測；然而，非靶向IL-2-RAS不能反式地活化。在不意欲受任何特定理論束縛之情況下，IL-2-RAS對IL-2受體之親和力降低可避免IL-2R之有效結合及聚集以誘導下游信號傳導。因此，僅靶向IL-2-RAS融合蛋白驅動pSTAT5信號傳導。 實例 13 ： 靶向 NKp46 之 IL-2-RAS 特異性驅動 NK 細胞 增殖
測定包含如圖1H中所示與靶向NKp46之雜二聚體scFv抗體之C端融合的IL-2-RAS之融合蛋白、包含如圖1B中所示與連接至雜二聚體Fc之非靶向VHH之C端融合的野生型IL-2或IL-2-RAS之融合蛋白以及單獨的靶向NKp46之雜二聚體scFv抗體對NK細胞、CD4+ T細胞及CD8+ T細胞之影響。
將來自健康供體之新鮮PBMC用CellTrace™ Violet標記，且在96孔圓底培養盤中以200,000個細胞/孔平板接種。將融合蛋白及NKp46 scFv-Fc對照之稀釋液添加至經平板接種之細胞且在37℃下培育7天。在第7天，除使用以下抗體以外，實質上如實例7中所描述量測細胞增殖：抗CD3-BV785 (1:200)、抗CD56-APC (1:100)、抗CD4-PE (1:200)、抗CD8-APC-Fire (1:300)及PI (1:2000)。
另外，將來自健康供體之新鮮PBMC用相同融合蛋白或NKp46 scFv-Fc對照處理，且在37℃下培育15分鐘。藉由偵測磷酸化STAT5含量來量測CD8+ T細胞、CD4+ T細胞及NK細胞(CD3-，CD56+)中之pSTAT5含量，實質上如實例6中所描述。
除使用以下抗體以外，實質上如實例1中所描述量測融合蛋白及NKp46 scFv-Fc對照與來自健康供體之新鮮PBMC的結合：抗CD3-FITC (1:100)、抗CD56-BV421 (1:100)、抗CD4-BV785 (1:200)、抗CD8-APC-Fire (1:300)、抗人類IgG-Alexa Fluor 647 (1:500)及PI (1:2000)。
如圖13A至圖13I中所示，靶向NKp46之IL-2-RAS有力地活化NK細胞增殖及活化，而不影響CD4+或CD8+ T細胞。相比之下，非靶向野生型IL-2驅動所有所測試之淋巴球(NK、CD4+及CD8+ T細胞)之增殖及活化。NKp46 scFv-Fc (無IL-2-RAS)之結合並不驅動NK增殖或pSTAT5誘導。因此，靶向NKp46之IL-2-RAS驅動IL-2在NK細胞上之順式信號傳導，但並不反式地活化CD4+或CD8+ T細胞。 實例 14 ： 靶向 LAG3 之 IL-2-RAS 刺激預活化 LAG3+ T 細胞
分析包含如圖1G中所示與抗LAG3雜二聚體習知抗體(MAb)之C端融合、如圖1B中所示與具有雜二聚體Fc之抗LAG3 VHH融合、如圖1B中所示與非靶向VHH融合的IL-2-RAS的融合蛋白，或包含如圖1B中所示與非靶向雜二聚體Fc之C端融合的野生型IL-2的融合蛋白，或LAG3靶向Mab (對照)或LAG3靶向VHH-Fc (對照)對CD4+ T細胞及CD8+ T細胞的影響。
用1 µg/mL經塗佈抗CD3 (OKT3)及10 µg/mL可溶性抗CD28刺激來自健康供體之富集T細胞48小時，隨後使其靜置24小時。將預活化細胞用CellTrace™ Violet標記且以200,000個細胞/孔接種。添加融合蛋白及對照蛋白之稀釋液且培育3天。實質上如實例7中但使用以下此等額外抗體量測活化標記物CD25及CD71之增殖及表現：抗CD25-FITC (1:100)及抗CD71-PE/Cy7。
經刺激之CD8+ T細胞將LAG3上調至45%之CD8+ T細胞，而CD4+ T細胞將LAG3上調至22%之CD4+ T細胞。相比之下，未經刺激之T細胞對於CD8+或CD4+ T細胞上之LAG3表現而言接近0%陽性。
如圖14A至圖14D中所示，抗LAG3 Mab-IL-2-RAS及抗LAG3 VHH-IL-2-RAS增加CD8+及CD4+增殖(圖14A及圖14B)及活化，如由CD25 (圖14C及圖14D)及CD71 (圖14E及圖14F)表現量所指示。非靶向野生型IL-2為CD8+及CD4+ T細胞增殖及活化之強力誘導劑，且以較高親和力及飽和度結合經刺激之T細胞。 實例 15 ： IL-2 之組合突變體進一步降低非靶向活性
使用HEK-Blue IL-2報導細胞(InvivoGen)量測非靶向IL-2突變體之相對活性。使用與非靶向VHH之C端融合的IL-2突變體之稀釋液處理報導細胞且培育20小時，隨後使用比色酶受質QUANTI-Blue™ (Invivogen)，定量報導細胞受IL-2誘導所分泌之鹼性磷酸酶。
如圖15中所示，IL-2突變體顯示一定範圍之活性。上文所描述之實驗顯示IL-2-RAS (P65R、H16A及D84S)相較於野生型IL-2，顯著降低了與IL-2R之結合(參見圖4至圖6)，且相較於野生型IL-2降低活性(參見圖7A至圖7E)。具有額外M23A突變之IL-2-RAS及具有額外E95Q突變之IL-2-RAS兩者相較於IL-2-RAS均顯示降低的活性，且具有M23A及E95Q兩者之IL-2-RAS的組合更進一步減弱活性。在關於表現PD-1之報導細胞之實驗中，此等親和力降低之IL-2突變體全部顯示類似的PD-1靶向活性(未出示數據)，從而認為與PD-1之高親和力順式結合可補償IL-2突變體對IL-2R降低的親和力。雖然HEK-Blue IL-2報導子系統適用於相對活性量測，但報導子系統中針對IL-2突變體觀測到之EC 50相較於初級淋巴球顯著向左偏移，此可能歸因於相較於初級細胞上之較低IL-2R含量，IL-2R組分在報導細胞中過度表現。 實例 16 ：包含經修飾 IL-2 之 多肽之活性
使用HEK-Blue IL-2報導細胞(InvivoGen)或表現PD-1之經修飾IL-2報導細胞純系來量測包含與PD-1結合性VHH之C端融合的經修飾IL-2之多肽之相對活性。各經修飾IL-2之IL-2修飾及SEQ ID NO示於表2及表3中。亦測試包含僅包含T3G及C125S突變之IL-2或野生型IL-2的對照多肽。使用不表現PD-1之報導細胞來量測非靶向IL-2活性。使用多肽之稀釋液處理報導細胞且培育20小時，隨後如實例15中所描述進行Quanti-Blue分析。在Prism 8中使用四參數非線性曲線擬合法計算所測試多肽在缺少PD-1之細胞上之EC 50([促效劑]相對於反應-可變斜率)且示於下表2中，且劑量反應曲線示於圖16A中。 表2：包含經修飾IL-2之多肽在缺少PD-1之細胞上的EC 50
IL-2修飾 EC 50(nM) SEQ ID NO
T3A, H16A, F42R, P65R, D84S, C125S 2.1 282
T3A, H16A, Δ42, P65R, D84S, C125S 4.2 278
T3A, H16A, K43E, Y45R, P65R, D84S, C125S 1.5 279
T3A, H16A, P65R, D84S, C125S (INBRX-108) 0.9 28
T3A, H16A, K43E, P65R, D84S, C125S 1.1 280
T3A, H16A, P65R, D84S, I114F, C125S 1.4 281
T3A, H16A, E61R, P65R, D84S, C125S 3.2 108
T3A, H16A, R38A, P65R, D84S, C125S 2.0 109
如表2及圖16A中所示，包含經修飾IL-2之所測試多肽顯示一定範圍之活性。相較於IL-2-RAS-T3A-C125S，具有額外F42R、Δ42、K43E及/或Y45R、I114F、E61R或R38A修飾之IL-2-RAS-T3A-C125S顯示降低之活性。如圖25A至圖25C中所示，報導細胞對野生型IL-2及包含T3G及C125S突變之IL-2起反應。
在表現PD-1之IL-2報導細胞中測試相同多肽之PD-1靶向IL-2活性。在Prism 8中使用四參數非線性曲線擬合計算表現PD-1之細胞上之EC 50([促效劑]相對於反應-不同斜率)且示於下表3中，且劑量反應曲線示於圖16B中。 表3：包含經修飾IL-2之多肽在表現PD-1之細胞上的EC 50
IL-2修飾 EC 50(nM) SEQ ID NO.
T3A, H16A, F42R, P65R, D84S, C125S 0.003 282
T3A, H16A, Δ42, P65R, D84S, C125S 0.005 278
T3A, H16A, K43E, Y45R, P65R, D84S, C125S 0.002 279
T3A, H16A, P65R, D84S, C125S (INBRX-108) 0.001 28
T3A, H16A, K43E, P65R, D84S, C125S 0.001 280
T3A, H16A, P65R, D84S, I114F, C125S 0.002 281
T3A, H16A, E61R, P65R, D84S, C125S 0.002 108
T3A, H16A, R38A, P65R, D84S, C125S 0.002 109
如表3及圖16B中所示，包含具有額外F42R、Δ42、K43E及/或Y45R、I114F、E61R或R38A修飾之IL-2-RAS-T3A-C125S的多肽之PD-1靶向IL-2活性顯示在IL-2-RAS-T3A-C125S之活性的2倍至5倍內之活性。 實例 17 ：阻斷 CD25 對 包含經修飾 IL-2 之 多肽之活性的影響
不表現PD-1之HEK-Blue IL-2報導細胞(InvivoGen)用於在存在或不存在阻斷IL-2與CD25之結合的CD25抗體之情況下量測包含與PD-1結合VHH之C端融合的經修飾IL-2之多肽之相對活性。經修飾IL-2之IL-2修飾及SEQ ID NO示於表4中。將報導細胞用多肽之稀釋液處理且培育20小時，隨後如實例15中所描述進行Quanti-Blue分析。劑量反應曲線示於圖17A至圖17C中，且CD25阻斷對IL-2活性之影響列於下表4中。 表4：阻斷CD25對缺少PD-1之細胞之影響
IL-2修飾 CD25抗體是否阻斷活性? SEQ ID NO.
T3A, H16A, F42R, P65R, D84S, C125S 否 282
T3A, H16A, Δ42, P65R, D84S, C125S 否 278
T3A, H16A, K43E, Y45R, P65R, D84S, C125S 否 279
T3A, H16A, P65R, D84S, C125S (INBRX-108) 是 28
T3A, H16A, K43E, P65R, D84S, C125S 是 280
T3A, H16A, P65R, D84S, I114F, C125S 是 281
T3A, H16A, E61R, P65R, D84S, C125S 否 108
T3A, H16A, R38A, P65R, D84S, C125S 否 109
如表4及圖17A至圖17C中所示，包含IL-2-RAS-T3A-C125S或包含具有額外K43E或I114F修飾之IL-2-RAS-T3A-C125S的多肽在存在CD25阻斷抗體之情況下不保留完全IL-2活性，指示CD25對於其活性而言為必需的。包含具有額外F42R、Δ42、E61R或R38A修飾或包含額外K43E及Y45R修飾之IL-2-RAS-T3A-C125S的多肽在存在CD25阻斷抗體之情況下保留完全活性，指示CD25對於其活性而言並非必需的。 實例 18 ：包含經修飾 IL-2 之 多肽之活性
實例16中所描述之HEK-Blue IL-2報導細胞用於量測包含與PD-1結合VHH之C端融合的經修飾IL-2之多肽之相對活性。各經修飾IL-2之IL-2修飾及SEQ ID NO示於表5中。使用不表現PD-1之報導細胞來量測非靶向IL-2活性。將報導細胞用多肽之稀釋液處理且培育20小時，隨後如實例15中所描述進行Quanti-Blue分析。在Prism 8中使用四參數非線性曲線擬合計算所測試多肽在缺少PD-1之細胞上之EC 50([促效劑]相對於反應-不同斜率)且示於下表5中，且劑量反應曲線示於圖18A中。 表5：包含經修飾IL-2之多肽在缺少PD-1之細胞上的EC 50
IL-2修飾 EC 50(nM) SEQ ID NO.
T3A, H16A, L19A, P65R, D84S, C125S ＞ 100 110
T3A, H16A, P65R, D84S, N88S, C125S 3.1 111
T3A, H16A, P65R, D84S, E95Q, C125S 3.9 112
T3A, H16A, M23A, P65R, D84S, C125S 3.1 113
T3A, H16A, M23A, P65R, D84S, E95Q, C125S 8.7 114
T3A, H16A, P65R, D84S, C125S (INBRX-108) 0.9 28
如表5及圖18A中所示，包含經修飾IL-2之所測試多肽顯示一定範圍之活性。相較於IL-2-RAS-T3A-C125S，具有額外N88S、E95Q及/或M23A修飾之IL-2-RAS-T3A-C125S顯示降低之活性。添加L19A修飾導致IL-2活性極大地降低。
在表現PD-1之IL-2報導細胞中測試相同多肽之PD-1靶向IL-2活性。在Prism 8中使用四參數非線性曲線擬合計算表現PD-1之細胞上之EC 50([促效劑]相對於反應-不同斜率)且示於下表6中，且劑量反應曲線示於圖18B中。 表6：包含經修飾IL-2之多肽在表現PD-1之細胞上的EC 50
IL-2修飾 EC 50(nM) SEQ ID NO.
T3A, H16A, L19A, P65R, D84S, C125S ＞ 100 110
T3A, H16A, P65R, D84S, N88S, C125S 0.001 111
T3A, H16A, P65R, D84S, E95Q, C125S 0.0006 112
T3A, H16A, M23A, P65R, D84S, C125S 0.001 113
T3A, H16A, M23A, P65R, D84S, E95Q, C125S 0.002 114
T3A, H16A, P65R, D84S, C125S (INBRX-108) 0.001 28
如表6及圖18B中所示，包含具有額外N88S、M23A或M23A及E95Q修飾之IL-2-RAS-T3A-C125S之多肽的PD-1靶向IL-2活性顯示在IL-2-RAS-T3A-C125S之活性的2倍內之活性。儘管存在PD-1，但添加L19A修飾導致IL-2活性極大地降低。 實例 19 ：包含經修飾 IL-2 之 多肽之活性
實例16中所描述之HEK-Blue IL-2報導細胞用於量測包含與PD-1結合VHH之C端融合的經修飾IL-2之多肽之相對活性。將報導細胞用多肽之稀釋液處理且培育20小時，隨後如實例15中所描述進行Quanti-Blue分析。所測試多肽之經修飾IL-2及EC 50之標識及SEQ ID NO示於下表7中，且劑量反應曲線示於圖19A至圖19E中。 表7：包含經修飾IL-2之多肽之EC 50
細胞株 IL-2修飾 EC 50(nM) SEQ ID NO.
HEK-Blue IL-2 + PD-1 T3A, H16A, L19A, E61R, P65R, D84S, C125S 0.002 115
HEK-Blue IL-2 10.13
HEK-Blue IL-2 + PD-1 T3A, H16A, M23A, E61R, P65R, D84S, E95Q, C125S 0.003 116
HEK-Blue IL-2 39.42
HEK-Blue IL-2 + PD-1 T3A, H16A, M23A, E61R, P65R, D84S, N88S, C125S 0.02 117   
HEK-Blue IL-2 ＞100
HEK-Blue IL-2 + PD-1 T3A, H16A, E61R, P65R, D84S, N88S, E95Q, C125S 0.02 118
HEK-Blue IL-2 ＞100
HEK-Blue IL-2 + PD-1 T3A, H16A, M23A, E61R, P65R, D84S, N88S, E95Q, C125S 0.6 119
HEK-Blue IL-2 ＞100
HEK-Blue IL-2 + PD-1 T3A, H16A, P65R, D84S, C125S (INBRX-108) 0.001 28
HEK-Blue IL-2 0.512
如表7及圖19A至圖19E中所示，包含經修飾IL-2之所測試多肽顯示一定範圍之活性。雖然包含具有額外修飾之IL-2-RAS-T3A-C125S的所有多肽相較於包含IL-2-RAS-T3A-C125S之多肽展現顯著降低之非靶向活性，但包含具有額外L19A及E61R修飾之IL-2-RAS-T3A-C125S之多肽及具有額外M23A、E61R及E95Q修飾之彼等多肽展現與包含IL-2-RAS-T3A-C125S之多肽相當的PD-1靶向活性。實例18顯示在不存在E61R突變的情況下，L19A突變降低包含IL-2-RAS-T3A-C125S之多肽的非靶向 及靶向活性；然而，此等結果顯示添加E61R突變恢復PD-1靶向活性。因此，難以預測組合個別突變之影響。 實例 20 ：包含經修飾 IL-2 之 多肽之活性
實例16中所描述之HEK-Blue IL-2報導細胞用於量測包含與PD-1結合VHH之C端融合的經修飾IL-2之多肽之相對活性。將報導細胞用多肽之稀釋液處理且培育20小時，隨後如實例15中所描述進行Quanti-Blue分析。所測試多肽之經修飾IL-2及EC 50之標識及SEQ ID NO示於下表8中，且劑量反應曲線示於圖20A至圖20E中。 表8：包含經修飾IL-2之多肽之EC 50
細胞株 IL-2修飾 EC 50(nM) SEQ ID NO.
HEK-Blue IL-2 + PD-1 T3A, H16A, L19A, R38A, P65R, D84S, C125S 0.002 120
HEK-Blue IL-2 3.6
HEK-Blue IL-2 + PD-1 T3A, H16A, M23A, R38A, P65R, D84S, E95Q, C125S 0.004 121
HEK-Blue IL-2 17.5
HEK-Blue IL-2 + PD-1 T3A, H16A, M23A, R38A, P65R, D84S, N88S, E95Q, C125S 0.05 124
HEK-Blue IL-2 ＞100
HEK-Blue IL-2 + PD-1 T3A, H16A, M23A, R38A, P65R, D84S, N88S, C125S 0.008 122
HEK-Blue IL-2 ＞100
HEK-Blue IL-2 + PD-1 T3A, H16A, R38A, P65R, D84S, N88S, E95Q, C125S 0.06 123
HEK-Blue IL-2 ＞100
HEK-Blue IL-2 + PD-1 T3A, H16A, P65R, D84S, C125S (INBRX-108) 0.001 28
HEK-Blue IL-2 0.512
如表8及圖20A至圖20E中所示，包含經修飾IL-2之所測試多肽顯示一定範圍之活性。包含具有額外修飾之IL-2-RAS-T3A-C125S的所有多肽相較於包含IL-2-RAS-T3A-C125S之多肽展現降低之非靶向活性，且一些多肽不展現非靶向活性。包含具有額外L19A及R38A修飾之IL-2-RAS-T3A-C125S的多肽及具有額外M23A、R38A及E95Q修飾之彼等多肽展現與包含IL-2-RAS-T3A-C125S之多肽相當的PD-1靶向活性。 實例 21 ：包含經修飾 IL-2 之 多肽之活性
實例16中所描述之HEK-Blue IL-2報導細胞用於量測包含與PD-1結合VHH之C端融合的經修飾IL-2之多肽之相對活性。將報導細胞用多肽之稀釋液處理且培育20小時，隨後如實例15中所描述進行Quanti-Blue分析。所測試多肽之經修飾IL-2及EC 50之標識及SEQ ID NO示於下表9中，且劑量反應曲線示於圖21A至圖21D中。 表9：包含經修飾IL-2之多肽之EC 50
細胞株 IL-2修飾 EC 50(nM) SEQ ID NO.
HEK-Blue IL-2 + PD-1 T3A, H16A, L19N, P65R, D84S, C125S 0.001 125
HEK-Blue IL-2 20.1
HEK-Blue IL-2 + PD-1 T3A, H16A, L19S, P65R, D84S, C125S 0.002 126
HEK-Blue IL-2 4.02
HEK-Blue IL-2 + PD-1 T3A, H16A, L19T, P65R, D84S, C125S 0.005 127
HEK-Blue IL-2 4.37
HEK-Blue IL-2 + PD-1 T3A, H16A, L19V, P65R, D84S, C125S 0.002 128
HEK-Blue IL-2 3.72
HEK-Blue IL-2 + PD-1 T3A, H16A, P65R, D84S, C125S (INBRX-108) 0.001 28
HEK-Blue IL-2 0.512
如表9及圖21A至圖21D中所示，包含具有額外L19修飾之IL-2-RAS-T3A-C125S的多肽展現與包含IL-2-RAS-T3A-C125S之多肽相當的PD-1靶向活性，而相較於包含IL-2-RAS-T3A-C125S之多肽，所測試多肽之非靶向活性自略微降低變為顯著降低。 實例 22 ：包含經修飾 IL-2 之 多肽之活性
實例16中所描述之HEK-Blue IL-2報導細胞用於量測包含與PD-1結合VHH之C端融合的經修飾IL-2之多肽之相對活性。多肽藉由經設計以破壞IL-2-CD25界面之IL-2突變修飾，且將其與包含IL-2-RAS-T3A-C125S之對照多肽進行比較。將報導細胞用多肽之稀釋液處理且培育20小時，隨後如實例15中所描述進行Quanti-Blue分析。所測試多肽之經修飾IL-2及EC 50之標識及SEQ ID NO示於下表10中，且劑量反應曲線示於圖22A (缺少PD-1之細胞)及圖22B (表現PD-1之細胞)中。 表10：包含經修飾IL-2之多肽之EC 50
細胞株 IL-2修飾 EC 50(nM) SEQ ID NO.
HEK-Blue IL-2 + PD-1 T3A, H16A, P65R, D84S, C125S (INBRX-108) 0.003 28
HEK-Blue IL-2 0.3
HEK-Blue IL-2 + PD-1 T3A, K43E, C125S 0.005 286
HEK-Blue IL-2 0.004
HEK-Blue IL-2 + PD-1 T3A, K43E, Y45R, C125S 0.004 283
HEK-Blue IL-2 0.006
HEK-Blue IL-2 + PD-1 T3A, E61R, P65R, C125S 0.005 106
HEK-Blue IL-2 0.01
HEK-Blue IL-2 + PD-1 T3A, R38A, P65R, C125S 0.006 107
HEK-Blue IL-2 0.01
HEK-Blue IL-2 + PD-1 T3A, K43E, P65R, C125S 0.005 288
HEK-Blue IL-2 0.007
HEK-Blue IL-2 + PD-1 T3A, K43E, Y45R, P65R, C125S 0.005 289
HEK-Blue IL-2 0.009
HEK-Blue IL-2 + PD-1 T3A, P65R, I114F, C125S 0.007 287
HEK-Blue IL-2 0.01
HEK-Blue IL-2 + PD-1 T3A, E61R, C125S 0.006 284
HEK-Blue IL-2 0.004
HEK-Blue IL-2 + PD-1 T3A, I114F, C125S 0.02 285
HEK-Blue IL-2 ＞100
HEK-Blue IL-2 + PD-1 T3A, R38A, C125S 0.02 290
HEK-Blue IL-2 0.01
如表10及圖22A中所示，包含IL-2-T3A-R38A-C125S之多肽不展現非靶向活性，且所測試之其餘多肽相較於包含IL-2-RAS-T3A-C125S之多肽展現顯著增加的非靶向活性。如圖22B中所示，包含IL-2-T3A-R38A-C125S之多肽展現一定PD-1靶向活性，其相較於包含IL-2-RAS-T3A-C125S之多肽顯著降低。所測試之其餘多肽展現與包含IL-2-RAS-T3A-C125S之多肽相當的PD-1靶向活性。 實例 23 ：包含經修飾 IL-2 之 多肽之活性
實例16中所描述之IL-2報導細胞用於量測包含與PD-1結合VHH之C端融合的經修飾IL-2之多肽之相對活性。將報導細胞用多肽之稀釋液處理且培育20小時，隨後如實例15中所描述進行Quanti-Blue分析。所測試多肽之經修飾IL-2及EC 50之標識及SEQ ID NO示於下表11中，且劑量反應曲線示於圖23A (缺少PD-1之細胞)及圖23B (表現PD-1之細胞)中。 表11：包含經修飾IL-2之多肽之EC 50
細胞株 IL-2修飾 EC 50(nM) SEQ ID NO.
HEK-Blue IL-2 + PD-1 T3A, H16A, P65R, D84S, C125S (INBRX-108) 0.003 28
HEK-Blue IL-2 0.3
HEK-Blue IL-2 + PD-1 T3A, H16A, L19N, M23A, E61R, P65R, D84S, E95Q, C125S 0.017 129
HEK-Blue IL-2 38.46
HEK-Blue IL-2 + PD-1 T3A, H16A, L19N, M23A, R38A, P65R, D84S, E95Q, C125S 0.044 130
HEK-Blue IL-2 37.98
HEK-Blue IL-2 + PD-1 T3A, H16A, L19N, M23A, R38A, P65R, D84S, C125S 0.015 131
HEK-Blue IL-2 43.33
HEK-Blue IL-2 + PD-1 T3A, H16A, L19N, R38A, P65R, D84S, E95Q C125S 0.019 132
HEK-Blue IL-2 60.14
HEK-Blue IL-2 + PD-1 T3A, H16A, L19N, R38A, P65R, D84S, C125S 0.007 133
HEK-Blue IL-2 13.81
HEK-Blue IL-2 + PD-1 T3A, H16A, L19N, E61R, P65R, D84S, C125S 0.006 134
HEK-Blue IL-2 17.23
HEK-Blue IL-2 + PD-1 T3A, H16A, L19N, E61R, P65R, D84S, E95Q, C125S 0.022 135
HEK-Blue IL-2 40.08
HEK-Blue IL-2 + PD-1 T3A, H16A, L19N, M23A, E61R, P65R, D84S, C125S 0.016 136
HEK-Blue IL-2 29.27
如表11及圖23A中所示，相較於包含IL-2-RAS-T3A-C125S之多肽，包含具有額外修飾之IL-2-RAS-T3A-C125S的所測試多肽展現顯著降低之非靶向活性。如圖23B中所示，包含具有額外修飾之IL-2-RAS-T3A-C125S的所測試多肽展現一定範圍之PD-1靶向活性，其相較於包含IL-2-RAS-T3A-C125S之多肽介於略微降低至顯著降低。包含具有額外L19N及R38A或E61R突變之IL-2-RAS-T3A-C125S的多肽展現包含具有額外修飾之IL-2-RAS-T3A-C125S之所測試多肽的最高PD-1靶向活性。 實例 24 ：包含經修飾 IL-2 之 多肽的 CD25 結合
使用生物膜層干涉量測術(Biolayer Interferometry) (ForteBio)測試包含與PD-1結合VHH之C端融合的經修飾IL-2之多肽及對照多肽與CD25之結合。固定經組胺酸標記之CD25，且添加300 nM的下表中所列之多肽。所得結合結果示於下表12中。 表12：測試與CD25結合之多肽
多肽 與CD25結合 SEQ ID NO.
IL-2-T3A-RAS-C125S 是 28
WT IL-2 是 1
WT IL-15 否 284
IL-2-T3A-H16A-Δ42-P65R-D84S-C125S 否 278
IL-2-T3A-H16A-E61R-P65R-D84S-C125S 否 108
IL-2-T3A-H16A-F42R-P65R-D84S-C125S 是 282
IL-2-T3A-H16A-R38A-P65R-D84S-C125S 否 109
IL-2-T3A-H16A-K43E-Y45R-P65R-D84S-C125S 否 279
PD-1-IL-2v融合體 否 2
IL-2-T3A-H16A-K43E-P65R-D84S-C125S 否 280
IL-2-T3A-H16A-P65R-D84S-I114F-C125S 否 281
儘管包含經設計以破壞CD25-IL-2界面之突變，但包含IL-2-RAS-T3A-C125S之多肽結合CD25。相較於包含僅包含RAS-T3A-C125S突變之IL-2之多肽，包含含有E61R及P65R突變之IL-2之多肽展現顯著減少之CD25結合或無CD25結合。 實例 25 ：包含經修飾 IL-2 之 多肽之活性
使用HEK-Blue IL-2報導細胞(InvivoGen)或表現PD-1之經修飾細胞純系來量測包含與PD-1結合VHH之C端融合的經修飾IL-2之多肽之相對活性，如實例16中所描述。經修飾IL-2之IL-2修飾及SEQ ID NO示於表13中。
使用HEK-Blue IL-2報導細胞(InvivoGen)或表現表現NKp46之細胞的經修飾細胞純系來量測包含與NKp46結合VHH之C端融合的經修飾IL-2之多肽之相對活性。經修飾IL-2之IL-2修飾及SEQ ID NO示於表13中。
使用HEK-Blue IL-2報導細胞(InvivoGen)或表現表現CD8a之細胞之經修飾細胞純系來量測包含與CD8a結合VHH之C端融合的經修飾IL-2之多肽之相對活性。經修飾IL-2之IL-2修飾及SEQ ID NO示於表14中。
使用缺少PD-1、缺少NKp46及缺少CD8a表現之細胞量測非靶向活性。
結果示於下表13及表14中，且對應於表14之劑量反應曲線示於圖24A (缺乏CD8a之細胞)及圖24B (表現CD8a之細胞)。將50.000 nM之最大值用於非靶向EC 50輸入，包括用於由於活性不佳及與非線性回歸計算擬合不佳而無法計算之非靶向EC 50。使用包含PD-1結合VHH之多肽及表現PD-1之報導細胞計算PD-1靶向EC 50。使用包含NKp46結合VHH之多肽及表現NKp46之報導細胞計算NKp46靶向EC 50。使用包含CD8a結合VHH之多肽及表現CD8a之報導細胞計算CD8a靶向EC 50。「窗口」為非靶向EC 50除以靶向EC 50且表示靶向IL-2活性之濃度差異。空白輸入指示在對應實驗中不測試多肽。 表13：包含經修飾IL-2之多肽之EC 50
IL-2修飾 非靶向EC 50(nM) 靶向PD-1之EC 50(nM) 靶向NKp46之EC 50(nM) PD-1 窗口 NKp46 窗口 SEQ ID NO.
T3G, C125S 0.020 0.020    1.056    105
無(IL-2 WT) 0.018 0.020    0.943    1
T3A, E61R, P65R, C125S 0.010 0.004    2.308    106
T3A, R38A, P65R, C125S 0.010 0.005    1.786    107
T3A, H16A, E61R, P65R, D84S, C125S 3.178 0.002    1570.934    108
T3A, H16A, R38A, P65R, D84S, C125S 1.971 0.002    977.679    109
T3A, H16A, L19A, P65R, D84S, C125S 50.000 50.000    1.000    110
T3A, H16A, P65R, D84S, N88S, C125S 3.089 0.001    2214.337    111
T3A, H16A, P65R, D84S, E95Q, C125S 3.859 0.001    6093.479    112
T3A, H16A, M23A, P65R, D84S, C125S 3.125 0.001    2698.618    113
T3A, H16A, M23A, P65R, D84S, E95Q, C125S 8.695 0.002    5420.823    114
T3A, H16A, L19A, E61R, P65R, D84S, C125S 10.130 0.002 0.017 6481.126 581.850 115
T3A, H16A, M23A, E61R, P65R, D84S, E95Q, C125S 39.420 0.003 0.020 11522.947 1976.931 116
T3A, H16A, M23A, E61R, P65R, D84S, N88S, C125S 50.000 0.022    2289.377    117
T3A, H16A, E61R, P65R, D84S, N88S, E95Q, C125S 50.000 0.020    2515.091    118
T3A, H16A, M23A, E61R, P65R, D84S, N88S, E95Q, C125S 50.000 0.592    84.517    119
T3A, H16A, L19A, R38A, P65R, D84S, C125S 3.552 0.002    1481.852    120
T3A, H16A, M23A, R38A, P65R, D84S, E95Q, C125S 17.460 0.004 0.017 4100.517 1006.920 121
T3A, H16A, M23A, R38A, P65R, D84S, N88S, C125S 50.000 0.008 0.098 6344.373 509.892 122
T3A, H16A, R38A, P65R, D84S, N88S, E95Q, C125S 50.000 0.062    806.712    123
T3A, H16A, M23A, R38A, P65R, D84S, N88S, E95Q, C125S 50.000 0.050    992.654    124
T3A, H16A, L19N, P65R, D84S, C125S 20.090 0.001    21808.511    125
T3A, H16A, L19S, P65R, D84S, C125S 4.017 0.002    2376.923    126
T3A, H16A, L19T, P65R, D84S, C125S 4.372 0.005    858.939    127
T3A, H16A, L19V, P65R, D84S, C125S 3.716 0.002    1554.812    128
T3A, H16A, L19N, M23A, E61R, P65R, D84S, E95Q, C125S 38.460 0.017 0.051 2293.381 748.686 129
T3A, H16A, L19N, M23A, R38A, P65R, D84S, E95Q, C125S 37.980 0.044    854.059    130
T3A, H16A, L19N, M23A, R38A, P65R, D84S, C125S 43.330 0.015    2975.962    131
T3A, H16A, L19N, R38A, P65R, D84S, E95Q, C125S 50.000 0.019 0.102 2597.403 491.159 132
T3A, H16A, L19N, R38A, P65R, D84S, C125S 13.810 0.007    1943.155    133
T3A, H16A, L19N, E61R, P65R, D84S, C125S 17.230 0.006 0.053 2784.421 324.482 134
T3A, H16A, L19N, E61R, P65R, D84S, E95Q, C125S 40.080 0.022 0.100 1852.982 400.000 135
T3A, H16A, L19N, M23A, E61R, P65R, D84S, C125S 29.270 0.016    1854.880    136
T3A, H16A, L19N, Q22A, E61R, P65R, D84S, C125S 50.000    0.021    2373.042 137
T3A, H16A, L19N, E61R, P65R, D84S, R120A, C125S 50.000    0.021    2394.636 138
T3A, H16A, L19N, E61R, P65R, D84S, C125S, Q126A 50.000    0.043    1170.412 139
T3A, H16S, L19N, E61R, P65R, D84S, C125S 0.211             140
T3A, H16T, L19N, E61R, P65R, D84S, C125S 7.801    0.486    16.048 141
T3A, H16V, L19N, E61R, P65R, D84S, C125S 7.606    0.803    9.478 142
T3A, H16N, L19N, E61R, P65R, D84S, C125S 16.260    0.071    228.467 143
T3A, H16A, L19N, E61R, P65R, D84T, C125S 3.944    0.019    210.684 144
T3A, H16A, L19N, E61R, P65R, D84V, C125S 5.757    0.032    178.567 145
T3A, H16A, D20S, E61R, P65R, D84S, C125S 7.658    4.445    1.723 146
T3A, H16A, D20T, E61R, P65R, D84S, C125S 6.151    3.657    1.682 147
T3A, H16A, D20N, E61R, P65R, D84S, C125S 5.554    5.952    0.933 148
T3A, H16A, D20A, E61R, P65R, D84S, C125S 2.994    2.638    1.135 149
T3A, H16A, L19N, E61R, P65R, D84N, C125S 17.260    0.019    930.458 150
T3A, H16A, E61R, P65R, D84S, N88T C125S 50.000    0.510    98.116 151
T3A, H16A, E61R, P65R, D84S, N88A C125S 50.000    0.146    341.997 152
T3A, H16P, L19A, E61R, P65R, D84S, C125S 50.000    3.707    13.488 153
T3A, H16A, L19H, E61R, P65R, D84S, C125S 17.320    0.048    360.833 154
T3A, H16A, L19P, E61R, P65R, D84S, C125S 50.000    50.000    1.000 155
T3A, H16A, L19Q, E61R, P65R, D84S, C125S 17.870    0.042    423.560 156
T3A, H16A, L19Y, E61R, P65R, D84S, C125S 3.936    0.017    228.704 157
T3A, H16A, L19A, E61R, P65R, D84P, C125S 0.122    50.000    0.002 158
T3A, H16A, L19A, E61R, P65R, D84V, C125S 2.822    0.003    857.230 159
T3A, H16A, L19A, E61R, P65R, D84Y, C125S 3.185    0.001    4696.255 160
T3A, H16A, M23A, E61R, P65R, D84S, E95H, C125S 7.203    0.012    603.772 161
T3A, H16A, M23A, E61R, P65R, D84S, E95N, C125S 34.230    0.022    1583.989 162
T3A, H16A, M23A, E61R, P65R, D84S, E95P, C125S 4.867    0.002    2919.616 163
T3A, H16A, M23A, E61R, P65R, D84S, E95S, C125S 50.000    50.000    1.000 164
T3A, H16A, M23A, E61R, P65R, D84S, E95T, C125S 13.220    0.012    1111.859 165
T3A, H16A, M23A, E61R, P65R, D84S, E95V, C125S 13.850    0.064    216.711 166
T3A, H16A, M23A, E61R, P65R, D84S, E95Y, C125S 20.410    0.088    230.726 167
T3A, H16A, L19A, E61A, P65R, D84S, C125S 2.067    0.001    2145.304 168
T3A, H16A, L19A, E61G, P65R, D84S, C125S 3.263    0.000    12202.693 169
T3A, H16A, L19A, E61H, P65R, D84S, C125S 4.534    0.001    8458.955 170
T3A, H16A, L19A, E61N, P65R, D84S, C125S 1.997    0.000    12044.632 171
T3A, H16A, L19A, E61P, P65R, D84S, C125S 8.436    0.002    5137.637 172
T3A, H16A, L19A, E61Q, P65R, D84S, C125S 2.384    0.002    1129.323 173
T3A, H16A, L19A, E61S, P65R, D84S, C125S 3.269    0.001    2534.109 174
T3A, H16A, L19A, E61T, P65R, D84S, C125S 3.233    0.001    3725.942 175
T3A, H16A, L19A, E61V, P65R, D84S, C125S 0.643    0.003    195.797 176
T3A, H16A, L19A, E61Y, P65R, D84S, C125S 4.446    0.004    992.632 177
T3A, H16A, M23D, E61R, P65R, D84S, E95Q, C125S 50.000    0.217    230.627 178
T3A, H16A, M23E, E61R, P65R, D84S, E95Q, C125S 24.940    0.020    1275.703 179
T3A, H16A, M23G, E61R, P65R, D84S, E95Q, C125S 19.120    0.063    301.958 180
T3A, H16A, M23I, E61R, P65R, D84S, E95Q, C125S 17.790    0.011    1648.749 181
T3A, H16A, M23K, E61R, P65R, D84S, E95Q, C125S 50.000    0.015    3405.995 182
T3A, H16A, M23L, E61R, P65R, D84S, E95Q, C125S 5.657    0.004    1589.045 183
T3A, H16A, M23N, E61R, P65R, D84S, E95Q, C125S 50.000    0.013    3808.073 184
T3A, H16A, M23P, E61R, P65R, D84S, E95Q, C125S 50.000    50.000    1.000 185
T3A, H16A, M23Q, E61R, P65R, D84S, E95Q, C125S 18.060    0.024    740.771 186
T3A, H16A, M23R, E61R, P65R, D84S, E95Q, C125S 50.000    0.031    1627.604 187
T3A, H16A, M23T, E61R, P65R, D84S, E95Q, C125S 22.720    0.030    746.632 188
T3A, H16A, M23V, E61R, P65R, D84S, E95Q, C125S 8.393    0.019    449.545 189
T3A, H16A, Q22A, E61R, P65R, D84S, C125S 6.656    0.052    128.222 190
T3A, H16A, Q22D, E61R, P65R, D84S, C125S 8.855    0.065    136.042 191
T3A, H16A, Q22E, E61R, P65R, D84S, C125S 50.000    14.320    3.492 192
T3A, H16A, Q22G, E61R, P65R, D84S, C125S 8.201    0.083    98.310 193
T3A, H16A, Q22H, E61R, P65R, D84S, C125S 6.329    0.064    98.721 194
T3A, H16A, Q22K, E61R, P65R, D84S, C125S 2.178    0.020    110.111 195
T3A, H16A, Q22N, E61R, P65R, D84S, C125S 3.134    0.022    140.854 196
T3A, H16A, Q22P, E61R, P65R, D84S, C125S 50.000    45.710    1.094 197
T3A, H16A, Q22R, E61R, P65R, D84S, C125S 2.745    0.017    159.315 198
T3A, H16A, Q22S, E61R, P65R, D84S, C125S 3.131    0.024    129.273 199
T3A, H16A, Q22T, E61R, P65R, D84S, C125S 3.338    0.031    108.061 200
T3A, H16A, Q22V, E61R, P65R, D84S, C125S 4.837    0.050    96.759 201
T3A, H16A, Q22Y, E61R, P65R, D84S, C125S 5.823    0.090    65.061 202
T3A, H16A, E61R, P65R, D84S, R120A, C125S 1.628    0.011    153.440 203
T3A, H16A, E61R, P65R, D84S, R120D, C125S 3.164    0.049    65.210 204
T3A, H16A, E61R, P65R, D84S, R120E, C125S 1.115    0.014    82.531 205
T3A, H16A, E61R, P65R, D84S, R120F, C125S 2.017    0.018    114.278 206
T3A, H16A, E61R, P65R, D84S, R120G, C125S 1.829    0.013    141.345 207
T3A, H16A, E61R, P65R, D84S, R120H, C125S 1.512    0.012    130.570 208
T3A, H16A, E61R, P65R, D84S, R120K, C125S 2.594    0.023    114.323 209
T3A, H16A, E61R, P65R, D84S, R120N, C125S 3.724    0.040    92.522 210
T3A, H16A, E61R, P65R, D84S, R120P, C125S 50.000    50.000    1.000 211
T3A, H16A, E61R, P65R, D84S, R120Q, C125S 2.308    0.026    90.227 212
T3A, H16A, E61R, P65R, D84S, R120S, C125S 3.528    0.032    110.250 213
T3A, H16A, E61R, P65R, D84S, R120T, C125S 50.000    50.000    1.000 214
T3A, H16A, E61R, P65R, D84S, R120V, C125S 4.939    0.062    80.231 215
T3A, H16A, E61R, P65R, D84S, R120Y, C125S 2.385    0.021    116.341 216
T3A, H16A, E61R, P65R, D84S, T123D, C125S 13.010    0.041    320.364 217
T3A, H16A, E61R, P65R, D84S, T123E, C125S 2.191    0.019    115.865 218
T3A, H16A, E61R, P65R, D84S, T123H, C125S 18.790    0.053    352.798 219
T3A, H16A, E61R, P65R, D84S, T123K, C125S 11.010    0.050    219.279 220
T3A, H16A, E61R, P65R, D84S, T123N, C125S 18.150    0.094    192.389 221
T3A, H16A, E61R, P65R, D84S, T123Q, C125S 2.337    0.036    64.665 222
T3A, H16A, E61R, P65R, D84S, T123R, C125S 1.934    0.043    44.634 223
T3A, H16A, E61R, P65R, D84S, C125S, S130D 50.000    50.000    1.000 224
T3A, H16A, E61R, P65R, D84S, C125S, S130E 50.000    0.064    784.437 225
T3A, H16A, E61R, P65R, D84S, C125S, S130K 11.950    0.033    361.683 226
T3A, H16A, E61R, P65R, D84S, C125S, S130N 10.390    0.028    374.549 227
T3A, H16A, E61R, P65R, D84S, C125S, S130Q 7.463    0.022    340.776 228
T3A, H16A, E61R, P65R, D84S, C125S, S130R 8.598    0.029    291.853 229
T3A, H16A, E61R, P65R, D84S, C125S, S127D 50.000    0.085    591.296 230
T3A, H16A, E61R, P65R, D84S, C125S, S127E 5.134    0.015    351.403 231
T3A, H16A, E61R, P65R, D84S, C125S, S127H 7.078    0.020    349.531 232
T3A, H16A, E61R, P65R, D84S, C125S, S127P 50.000    0.017    2915.452 233
T3A, H16A, E61R, P65R, D84S, C125S, S127Q 50.000    50.000    1.000 234
T3A, H16A, E61R, P65R, D84S, C125S, S127R 4.921    50.000    0.098 235
T3A, H16A, L19A, Q22A, R38A, P65R, D84S, C125S 5.448    0.017    315.278 236
T3A, H16A, L19A, R38A, P65R, D84S, R120A, C125S 5.476    0.035    154.340 237
T3A, H16A, L19A, Q22A, R38A, P65R, D84S, R120A, C125S 7.176    0.045    158.691 238
T3A, H16A, Q22A, M23A, R38A, P65R, D84S, E95Q, C125S 50.000    0.184    272.331 239
T3A, H16A, M23A, R38A, P65R, D84S, E95Q, R120A, C125S 21.330    0.057    372.707 240
T3A, H16A, Q22A, M23A, R38A, P65R, D84S, E95Q, R120A, C125S 50.000    0.274    182.216 241
T3A, H16A, L19N, Q22A, R38A, P65R, D84S, C125S 50.000    0.524    95.511 242
T3A, H16A, L19N, R38A, P65R, D84S, R120A, C125S 41.050    0.064    643.720 243
T3A, H16A, L19N, Q22A, R38A, P65R, D84S, R120A, C125S 50.000    0.197    253.936 244
A1G, P2G, T3S, S4G, S5G, H16A, L19A, R38A, P65R, D84S, C125S 4.674    0.018    256.531 245
Δ1-5, H16A, L19A, R38A, P65R, D84S, C125S 5.030    0.015    328.758 246
Δ1-5, H16A, L19A, R38A, P65R, D84S, C125V 5.170    0.015    349.561 247
T3A, L19N, R38A, P65R, D84S, C125S 10.300    0.021    499.515 248
T3A, H16A, L19N, R38A, P65R, C125S 2.102    0.008    276.216 249
T3A, L19N, Q22A, R38A, P65R, D84S, C125S 15.060    0.048    314.208 250
T3A, H16A, L19N, Q22A, R38A, P65R, C125S 3.184    0.017    189.186 251
T3A, L19N, Q22A, R38A, P65R, D84S, R120A, C125S 13.730    0.073    188.910 252
T3A, H16A, L19N, Q22A, R38A, P65R, R120A, C125S 2.064    0.021    98.993 253
T3A, Q22A, M23A, R38A, P65R, D84S, E95Q, C125S 10.370    0.140    73.966 254
T3A, Q22A, M23A, R38A, P65R, E95Q, C125S 2.063    0.028    73.364 255
T3A, Q22A, M23A, R38A, P65R, D84S, E95Q, R120A, C125S 10.600    0.148    71.767 256
T3A, H16A, Q22A, M23A, R38A, P65R, E95Q, R120A, C125S 4.556    0.126    36.187 257
T3A, L19A, Q22A, R38A, P65R, D84S, C125S 2.091    0.054    38.946 258
T3A, H16A, L19A, Q22A, R38A, P65R, C125S 0.503    0.024    21.148 259
T3A, L19A, Q22A, R38A, P65R, D84S, R120A, C125S 1.796    0.054    33.265 260
T3A, H16A, L19A, Q22A, R38A, P65R, R120A, C125S 0.327    0.013    24.837 261
T3A, H16A, L19A, E61R, P65R, D84S, C125S 6.083    0.023    264.134 115
T3A, H16A, E61R, P65R, D84S, C125S, I129A 2.062    0.0422    49 262
T3A, H16A, E61R, P65R, D84S, C125S, I129H 1.435    0.0697    21 263
T3A, H16A, E61R, P65R, D84S, C125S, I129R 26.220    0.0648    405 264
T3A, H16A, E61R, P65R, D84S, C125S, I129S 16.170    0.0561    288 265
T3A, H16A, E61R, P65R, D84S, C125C, Q126N 2.062    0.042    49 266
T3A, H16A, E61R, P65R, D84S, C125C, Q126Y 1.435    0.070    21 267
T3A, H16A, E61R, P65R, D84S, C125C, S127N 26.220    0.065    405 268
T3A, H16A, E61R, P65R, D84S, C125C, S130P 16.170    0.056    288 269
表14：包含經修飾IL-2之多肽之EC 50
IL-2修飾 非靶向EC 50(nM) 靶向CD8a之EC 50(nM) CD8a窗口 SEQ ID NO.
T3A, H16A, E61R, P65R, D84Y, C125S 4.515 0.011 400 270
T3A, H16A, M23T, E61R, P65R, D84Y, E95Q, C125S 50.000 0.057 871 271
T3A, H16A, L19N, E61R, P65R, D84Y, C125S 50.000 0.074 673 272
T3A, H16A, L19N, M23T, E61R, P65R, D84Y, E95Q, C125S 50.000 50.000 1 273
T3A, H16A, E61R, P65R, D84Y, C125S, S127D 50.000 0.088 568 274
T3A, H16A, M23T, E61R, P65R, D84Y, E95Q, C125S, S127D 50.000 50.000 1 275
T3A, H16A, L19N, E61R, P65R, D84Y, C125S, S127D 50.000 50.000 1 276
T3A, H16A, L19N, M23T, E61R, P65R, D84Y, E95Q, C125S, S127D 50.000 50.000 1 277
實例 26 ：包含經修飾 IL-2 之 多肽之非靶向相對於靶向活性
分析本文所描述之多肽之非靶向及靶向IL-2報導子活性，且藉由繪製上文所描述之IL-2報導子分析中測定的非靶向及靶向EC 50進行比較。圖26A顯示分析中所包括之IL-2突變體之非靶向活性。此圖顯示IL-2突變體對三聚體IL-2受體之親和力降低。圖26B及圖26C分別顯示對PD-1及NKp46之靶向EC 50相對於非靶向EC 50的圖。此等比較顯示在藉由高親和力VHH靶向PD-1或NKp46時親和力降低之IL-2突變體傳導信號的能力增強。圖26D及圖26E分別顯示PD-1及NKp46靶向窗，其如實例25中所描述來計算。此等圖式顯示達成靶向活性，同時避免非靶向IL-2活性之濃度範圍。 實例 27 ：包含經修飾 IL-2 之 多肽之活性
藉由經由流式細胞測量術量測PBMC之pSTAT5含量來測定包含與γδTCR結合VHH之C端融合的經修飾IL-2之多肽之相對活性。多肽包含經選擇以形成單價或二價γδTCR結合多肽之Fc區。多肽之結構指示於下表中。 表15：包含經修飾IL-2之γδTCR靶向多肽
多肽 價數 SEQ ID NO(s).
γδTCR 5C8 VHH-xELL臼T366S, L368A, Y407V, H435R Fc; xELL杵Fc-IL-2-T3G-P65R-H16A-D84S-C125S; 圖27A, B 單價 294, 295
γδTCR 5C8 VHH-xELL臼T366S, L368A, Y407V, H435R Fc; γδTCR 5C8 VHH-xELL杵Fc-IL-2-T3A-H16A-E61R-P65R-D84Y-C125S; 圖27C, D 二價 295, 296
γδTCR 6C4 VHH-xELL臼T366S, L368A, Y407V H435R Fc; γδTCR 6C4 VHH-xELL-杵Fc-IL-2-T3A-H16A-E61R-P65R-D84Y-C125S; 圖27E, F 二價 298, 299
410A9v1 (非靶向) VHH-xELL臼T366S, L368A, Y407V H435R Fc; γδTCR 6C4 VHH-xELL-杵Fc-IL-2- T3A-H16A- E61R-P65R-D84Y-C125S; 圖27G, H 單價 298, 300
藉由淋巴球分離劑(lymphoprep)密度梯度離心自健康供體白血球去除物(leukopak)分離PBMC。將細胞在室溫下用以下螢光結合抗體標記20分鐘：非競爭性抗γδTCR-FITC、抗CD3-BV785及抗CD56-BV421。在洗滌之後，在96孔培養盤中接種200,000個PBMC/孔。細胞利用上述表中所列之融合蛋白之滴定物處理，以100 nM之初始濃度開始且在培養盤中1:5滴定，重複兩次。將培養盤在37℃/5% CO 2下培育20分鐘。將細胞用BD Cytofix/Cytoperm™ (BD Biosciences)固定，在90%冰冷甲醇中滲透，且使用磷酸特異性抗pSTAT5-PE抗體(1:70)使用流式細胞測量術量測γδT細胞上之磷酸化STAT5 (「pSTAT5」)的含量。
如圖27A至圖27H中所示，用各種靶向二價或單價γδTCR之經修飾IL-2多肽處理導致pSTAT5+ γδT細胞之百分比及專門針對γδT細胞之pSTAT5中值螢光強度的劑量依賴性增加。相比之下，在低於100 nM之NK或αβT細胞上存在少量的pSTAT5活化。 實例 28 ：包含經修飾 IL-2 之 多肽之活性
藉由量測γδT細胞及αβT細胞增殖及積聚來測定包含與γδTCR結合VHH或非靶向VHH之C端融合的經修飾IL-2之多肽之相對活性。多肽包含經選擇以形成單價或二價多肽之Fc區。多肽之結構指示於下表中。 表16：包含經修飾IL-2之γδTCR靶向及非靶向多肽
多肽 價數 SEQ ID NO(s).
γδTCR 5C8 VHH-xELL杵Fc-IL-2-T3A-H16A-E61R-P65R-D84Y-C125S; xELL臼Fc H435R, T366S, L368A, Y407V 單價 64, 296
非靶向VHH-xELL臼T366S, L368A, Y407V H435R Fc; 非靶向VHH-xELL杵Fc-IL-2-T3A-H16A- E61R-P65R-D84Y-C125S N/A 300, 301
IL-2促進T細胞群之活化及增殖。為了評定靶向γδTCR之經修飾IL-2對T細胞增殖的影響，使用淋巴球分離劑密度梯度介質自健康供體白血球去除物分離PBMC。將細胞在37℃下用CellTrace Violet增殖性染料標記10分鐘。在洗滌之後，將細胞再懸浮於RPMI+10% FBS中，且將每孔300,000個細胞添加至96孔培養盤中。細胞利用上述表中所列之融合蛋白之滴定物處理，以100 nM之初始濃度開始且在培養盤中1:5滴定，重複兩次。將培養盤在37℃/5% CO 2下培育7天。將細胞在4℃下用以下螢光結合抗體：CD3-BV785、γδTCR-FITC，及活力染料碘化丙錠標記30分鐘。洗滌細胞且藉由流式細胞測量術分析。
如圖28A至圖28D中所示，用靶向γδTCR之經修飾IL-2處理導致γδT細胞之增殖及積聚的劑量依賴性增加(圖28A及圖28B)。在總CD3 +群體當中γδT細胞之百分比亦隨著靶向γδTCR之經修飾IL-2處理以及T細胞之同時減少而增加。該效應對γδT細胞具有特異性，因為αβT細胞群回應於用靶向γδTCR之經修飾IL-2處理而不會增殖或積聚(圖28C及圖28D)。與經修飾IL-2融合之非靶向VHH並不促進所測試之劑量下之γδT細胞或αβT細胞的增殖，表明所靶向之經修飾IL-2多肽之目標特異性。 實例 29 ：包含經修飾 IL-2 之 多肽之活性
藉由經由流式細胞測量術量測PBMC之pSTAT5含量來測定包含經修飾IL-2之多肽的相對活性。多肽之結構指示於下表中。 表17：包含經修飾IL-2之多肽
多肽 SEQ ID NO(s).
野生型IL-2 1
非靶向VHH-xELL臼T366S, L368A, Y407V H435R Fc; 410A9v1非靶向VHH-xELL杵Fc-IL-2-T3A-H16A- E61R-P65R-D84Y-C125S 300, 301
pSTAT5之含量係藉由胞內流式細胞測量術量測為IL-2受體接合及信號傳導之近端讀數。將人類PBMC以1,000,000個細胞/孔平板接種於完全生長培養基(RPMI，10% FBS，1%抗生素-抗黴劑)中之96孔培養盤中。隨後稀釋測試多肽，且製得5倍連續稀釋液。將連續稀釋液添加至細胞中且在37℃下培育15分鐘。隨後將細胞在4℃下於100 µL之Cytofix固定緩衝液(BD)中固定30分鐘。隨後將細胞在200 µL FACS緩衝液中洗滌一次且在4℃下於Perm緩衝液III (BD Phosflow)中滲透30分鐘。將經滲透細胞在滲透緩衝液(eBioscience)中洗滌總共三次，且隨後在4℃下於含有針對以下之經螢光標記之抗體的滲透緩衝液中培育隔夜：CD4 (OKT4，1:100)、CD3 (SP34-2，1:50)、CD16 (3G8，1:1000)、pSTAT5 (SRBCZX，1:70)、CD56 (NCAM16.2，1:500)及CD8 (RPA-T8，1:4000)。次日，細胞用150 µL FACS緩衝液洗滌且使用ACEA Biosciences Novocyte-Quanteon流式細胞儀分析。經由偵測NK細胞上之pSTAT5的經螢光標記之抗體(CD3-CD56brightCD16-)之頻率及中值螢光強度水準的增加來定量IL-2信號傳導。使用GraphPad Prism分析軟體繪製及分析資料。
如圖29A至圖29B中所示，野生型IL-2以劑量依賴性方式活化細胞，其中野生型重組IL-2之EC 50為大致0.06 nM。相較於野生型IL-2，包含含有T3A、H16A、E61R、P65R、D84Y及C125S突變之IL-2變異體的多肽顯示顯著減弱之活性。
在不脫離本發明之精神或基本特徵之情況下，本發明可以其他特定形式體現。因此，前述實施例在所有態樣中均視為說明性的而非限制本發明。本發明之範疇因此由隨附申請專利範圍而非前述描述指示，且因此本文意欲涵蓋申請專利範圍等效性之含義及範圍內出現的所有變化。 某些序列之表格
SEQ ID NO 描述 序列
1 野生型人類IL-2 APTSSSTKKTQLQLEHLLLDLQMILNGINNYKNPKLTRMLTFKFYMPKKATELKHLQCLEEELKPLEEVLNLAQSKNFHLRPRDLISNINVIVLELKGSETTFMCEYADETATIVEFLNRWITFCQSIISTLT
2 IL-2v APASSSTKKTQLQLEHLLLDLQMILNGINNYKNPKLTRMLTAKFAMPKKATELKHLQCLEEELKPLEEVLNGAQSKNFHLRPRDLISNINVIVLELKGSETTFMCEYADETATIVEFLNRWITFAQSIISTLT
3 IL-2-P65R APTSSSTKKTQLQLEHLLLDLQMILNGINNYKNPKLTRMLTFKFYMPKKATELKHLQCLEEELKRLEEVLNLAQSKNFHLRPRDLISNINVIVLELKGSETTFMCEYADETATIVEFLNRWITFCQSIISTLT
4 IL-2-H16A APTSSSTKKTQLQLEALLLDLQMILNGINNYKNPKLTRMLTFKFYMPKKATELKHLQCLEEELKPLEEVLNLAQSKNFHLRPRDLISNINVIVLELKGSETTFMCEYADETATIVEFLNRWITFCQSIISTLT
5 IL-2-D84S APTSSSTKKTQLQLEHLLLDLQMILNGINNYKNPKLTRMLTFKFYMPKKATELKHLQCLEEELKPLEEVLNLAQSKNFHLRPRSLISNINVIVLELKGSETTFMCEYADETATIVEFLNRWITFCQSIISTLT
6 IL-2-E15S APTSSSTKKTQLQLSHLLLDLQMILNGINNYKNPKLTRMLTFKFYMPKKATELKHLQCLEEELKPLEEVLNLAQSKNFHLRPRDLISNINVIVLELKGSETTFMCEYADETATIVEFLNRWITFCQSIISTLT
7 IL-2-M23A APTSSSTKKTQLQLEHLLLDLQAILNGINNYKNPKLTRMLTFKFYMPKKATELKHLQCLEEELKPLEEVLNLAQSKNFHLRPRDLISNINVIVLELKGSETTFMCEYADETATIVEFLNRWITFCQSIISTLT
8 IL-2-E95Q APTSSSTKKTQLQLEHLLLDLQMILNGINNYKNPKLTRMLTFKFYMPKKATELKHLQCLEEELKPLEEVLNLAQSKNFHLRPRDLISNINVIVLQLKGSETTFMCEYADETATIVEFLNRWITFCQSIISTLT
9 IL-2-P65E APTSSSTKKTQLQLEHLLLDLQMILNGINNYKNPKLTRMLTFKFYMPKKATELKHLQCLEEELKELEEVLNLAQSKNFHLRPRDLISNINVIVLELKGSETTFMCEYADETATIVEFLNRWITFCQSIISTLT
10 IL-2-F42K APTSSSTKKTQLQLEHLLLDLQMILNGINNYKNPKLTRMLTKKFYMPKKATELKHLQCLEEELKPLEEVLNLAQSKNFHLRPRDLISNINVIVLELKGSETTFMCEYADETATIVEFLNRWITFCQSIISTLT
11 IL-2-H16A-F42K APTSSSTKKTQLQLEALLLDLQMILNGINNYKNPKLTRMLTKKFYMPKKATELKHLQCLEEELKPLEEVLNLAQSKNFHLRPRDLISNINVIVLELKGSETTFMCEYADETATIVEFLNRWITFCQSIISTLT
12 IL-2-D84S-F42K APTSSSTKKTQLQLEHLLLDLQMILNGINNYKNPKLTRMLTKKFYMPKKATELKHLQCLEEELKPLEEVLNLAQSKNFHLRPRSLISNINVIVLELKGSETTFMCEYADETATIVEFLNRWITFCQSIISTLT
13 IL-2-E15S-F42K APTSSSTKKTQLQLSHLLLDLQMILNGINNYKNPKLTRMLTKKFYMPKKATELKHLQCLEEELKPLEEVLNLAQSKNFHLRPRDLISNINVIVLELKGSETTFMCEYADETATIVEFLNRWITFCQSIISTLT
14 IL-2-M23A-F42K APTSSSTKKTQLQLEHLLLDLQAILNGINNYKNPKLTRMLTKKFYMPKKATELKHLQCLEEELKPLEEVLNLAQSKNFHLRPRDLISNINVIVLELKGSETTFMCEYADETATIVEFLNRWITFCQSIISTLT
15 IL-2-E95Q-F42K APTSSSTKKTQLQLEHLLLDLQMILNGINNYKNPKLTRMLTKKFYMPKKATELKHLQCLEEELKPLEEVLNLAQSKNFHLRPRDLISNINVIVLQLKGSETTFMCEYADETATIVEFLNRWITFCQSIISTLT
16 IL-2-P65R-H16A APTSSSTKKTQLQLEALLLDLQMILNGINNYKNPKLTRMLTFKFYMPKKATELKHLQCLEEELKRLEEVLNLAQSKNFHLRPRDLISNINVIVLELKGSETTFMCEYADETATIVEFLNRWITFCQSIISTLT
17 IL-2-P65R-D84S APTSSSTKKTQLQLEHLLLDLQMILNGINNYKNPKLTRMLTFKFYMPKKATELKHLQCLEEELKRLEEVLNLAQSKNFHLRPRSLISNINVIVLELKGSETTFMCEYADETATIVEFLNRWITFCQSIISTLT
18 IL-2-P65R-E15S APTSSSTKKTQLQLSHLLLDLQMILNGINNYKNPKLTRMLTFKFYMPKKATELKHLQCLEEELKRLEEVLNLAQSKNFHLRPRDLISNINVIVLELKGSETTFMCEYADETATIVEFLNRWITFCQSIISTLT
19 IL-2-P65R-M23A APTSSSTKKTQLQLEHLLLDLQAILNGINNYKNPKLTRMLTFKFYMPKKATELKHLQCLEEELKRLEEVLNLAQSKNFHLRPRDLISNINVIVLELKGSETTFMCEYADETATIVEFLNRWITFCQSIISTLT
20 IL-2-P65R-E95Q APTSSSTKKTQLQLEHLLLDLQMILNGINNYKNPKLTRMLTFKFYMPKKATELKHLQCLEEELKRLEEVLNLAQSKNFHLRPRDLISNINVIVLQLKGSETTFMCEYADETATIVEFLNRWITFCQSIISTLT
21 IL-2-P65R-H16A-D84S (IL-2-RAS) APTSSSTKKTQLQLEALLLDLQMILNGINNYKNPKLTRMLTFKFYMPKKATELKHLQCLEEELKRLEEVLNLAQSKNFHLRPRSLISNINVIVLELKGSETTFMCEYADETATIVEFLNRWITFCQSIISTLT
22 IL-2-T3A-C125S APASSSTKKTQLQLEHLLLDLQMILNGINNYKNPKLTRMLTFKFYMPKKATELKHLQCLEEELKPLEEVLNLAQSKNFHLRPRDLISNINVIVLELKGSETTFMCEYADETATIVEFLNRWITFSQSIISTLT
23 IL-2-T3A-P65R-C125S APASSSTKKTQLQLEHLLLDLQMILNGINNYKNPKLTRMLTFKFYMPKKATELKHLQCLEEELKRLEEVLNLAQSKNFHLRPRDLISNINVIVLELKGSETTFMCEYADETATIVEFLNRWITFSQSIISTLT
24 IL-2-T3A-H16A-C125S APASSSTKKTQLQLEALLLDLQMILNGINNYKNPKLTRMLTFKFYMPKKATELKHLQCLEEELKPLEEVLNLAQSKNFHLRPRDLISNINVIVLELKGSETTFMCEYADETATIVEFLNRWITFSQSIISTLT
25 IL-2-T3A-D84S-C125S APASSSTKKTQLQLEHLLLDLQMILNGINNYKNPKLTRMLTFKFYMPKKATELKHLQCLEEELKPLEEVLNLAQSKNFHLRPRSLISNINVIVLELKGSETTFMCEYADETATIVEFLNRWITFSQSIISTLT
26 IL-2-T3A-H16A-P65R-C125S    APASSSTKKTQLQLEALLLDLQMILNGINNYKNPKLTRMLTFKFYMPKKATELKHLQCLEEELKRLEEVLNLAQSKNFHLRPRDLISNINVIVLELKGSETTFMCEYADETATIVEFLNRWITFSQSIISTLT
27 IL-2-T3A-P65R-D84S-C125S APASSSTKKTQLQLEHLLLDLQMILNGINNYKNPKLTRMLTFKFYMPKKATELKHLQCLEEELKRLEEVLNLAQSKNFHLRPRSLISNINVIVLELKGSETTFMCEYADETATIVEFLNRWITFSQSIISTLT   
28 IL-2-T3A-H16A-P65R-D84S-C125S APASSSTKKTQLQLEALLLDLQMILNGINNYKNPKLTRMLTFKFYMPKKATELKHLQCLEEELKRLEEVLNLAQSKNFHLRPRSLISNINVIVLELKGSETTFMCEYADETATIVEFLNRWITFSQSIISTLT   
29 IL-2-no9-H16A-P65R-C125S    TQLQLEALLLDLQMILNGINNYKNPKLTRMLTFKFYMPKKATELKHLQCLEEELKRLEEVLNLAQSKNFHLRPRDLISNINVIVLELKGSETTFMCEYADETATIVEFLNRWITFSQSIISTLT
30 IL-2-no9-P65R-D84S-C125S TQLQLEHLLLDLQMILNGINNYKNPKLTRMLTFKFYMPKKATELKHLQCLEEELKRLEEVLNLAQSKNFHLRPRSLISNINVIVLELKGSETTFMCEYADETATIVEFLNRWITFSQSIISTLT
31 IL-2-no9-H16A-P65R-D84S-C125S TQLQLEALLLDLQMILNGINNYKNPKLTRMLTFKFYMPKKATELKHLQCLEEELKRLEEVLNLAQSKNFHLRPRSLISNINVIVLELKGSETTFMCEYADETATIVEFLNRWITFSQSIISTLT
32 野生型IL-2-xELL「杵」Fc APTSSSTKKTQLQLEHLLLDLQMILNGINNYKNPKLTRMLTFKFYMPKKATELKHLQCLEEELKPLEEVLNLAQSKNFHLRPRDLISNINVIVLELKGSETTFMCEYADETATIVEFLNRWITFCQSIISTLT PGGGGDKTHTCPPCPAPGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPCRDELTKNQVSLWCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK   
33 IL-2-F42K-xELL「杵」Fc APTSSSTKKTQLQLEHLLLDLQMILNGINNYKNPKLTRMLTKKFYMPKKATELKHLQCLEEELKPLEEVLNLAQSKNFHLRPRDLISNINVIVLELKGSETTFMCEYADETATIVEFLNRWITFCQSIISTLT PGGGGDKTHTCPPCPAPGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPCRDELTKNQVSLWCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK   
34 IL-2-P65E-xELL「杵」Fc APTSSSTKKTQLQLEHLLLDLQMILNGINNYKNPKLTRMLTFKFYMPKKATELKHLQCLEEELKELEEVLNLAQSKNFHLRPRDLISNINVIVLELKGSETTFMCEYADETATIVEFLNRWITFCQSIISTLT PGGGGDKTHTCPPCPAPGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPCRDELTKNQVSLWCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK   
35 IL-2-P65R-xELL「杵」Fc APTSSSTKKTQLQLEHLLLDLQMILNGINNYKNPKLTRMLTFKFYMPKKATELKHLQCLEEELKRLEEVLNLAQSKNFHLRPRDLISNINVIVLELKGSETTFMCEYADETATIVEFLNRWITFCQSIISTLT PGGGGDKTHTCPPCPAPGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPCRDELTKNQVSLWCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK   
36 IL-2-F42K-D84S-xELL「杵」Fc APTSSSTKKTQLQLEHLLLDLQMILNGINNYKNPKLTRMLTKKFYMPKKATELKHLQCLEEELKPLEEVLNLAQSKNFHLRPRSLISNINVIVLELKGSETTFMCEYADETATIVEFLNRWITFCQSIISTLT PGGGGDKTHTCPPCPAPGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPCRDELTKNQVSLWCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK   
37 IL-2-F42K-E95Q-xELL「杵」Fc APTSSSTKKTQLQLEHLLLDLQMILNGINNYKNPKLTRMLTKKFYMPKKATELKHLQCLEEELKPLEEVLNLAQSKNFHLRPRDLISNINVIVLQLKGSETTFMCEYADETATIVEFLNRWITFCQSIISTLT PGGGGDKTHTCPPCPAPGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPCRDELTKNQVSLWCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK   
38 IL-2-F42K-M23A-xELL「杵」Fc APTSSSTKKTQLQLEHLLLDLQAILNGINNYKNPKLTRMLTKKFYMPKKATELKHLQCLEEELKPLEEVLNLAQSKNFHLRPRDLISNINVIVLELKGSETTFMCEYADETATIVEFLNRWITFCQSIISTLT PGGGGDKTHTCPPCPAPGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPCRDELTKNQVSLWCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK   
85 IL-2-F42K-E15S-xELL「杵」Fc APTSSSTKKTQLQLSHLLLDLQMILNGINNYKNPKLTRMLTKKFYMPKKATELKHLQCLEEELKPLEEVLNLAQSKNFHLRPRDLISNINVIVLELKGSETTFMCEYADETATIVEFLNRWITFCQSIISTLT PGGGGDKTHTCPPCPAPGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPCRDELTKNQVSLWCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK   
39 IL-2-H16A-F42K- xELL「杵」Fc APTSSSTKKTQLQLEALLLDLQMILNGINNYKNPKLTRMLTKKFYMPKKATELKHLQCLEEELKPLEEVLNLAQSKNFHLRPRDLISNINVIVLELKGSETTFMCEYADETATIVEFLNRWITFCQSIISTLT PGGGGDKTHTCPPCPAPGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPCRDELTKNQVSLWCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK   
40 IL-2-H16A-xELL「杵」Fc APTSSSTKKTQLQLEALLLDLQMILNGINNYKNPKLTRMLTFKFYMPKKATELKHLQCLEEELKPLEEVLNLAQSKNFHLRPRDLISNINVIVLELKGSETTFMCEYADETATIVEFLNRWITFCQSIISTLT PGGGGDKTHTCPPCPAPGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPCRDELTKNQVSLWCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK
41 IL-2-P65R-H16A-xELL「杵」Fc APTSSSTKKTQLQLEALLLDLQMILNGINNYKNPKLTRMLTFKFYMPKKATELKHLQCLEEELKRLEEVLNLAQSKNFHLRPRDLISNINVIVLELKGSETTFMCEYADETATIVEFLNRWITFCQSIISTLT PGGGGDKTHTCPPCPAPGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPCRDELTKNQVSLWCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK   
42 IL-2-P65R-D84S-xELL「杵」Fc APTSSSTKKTQLQLEHLLLDLQMILNGINNYKNPKLTRMLTFKFYMPKKATELKHLQCLEEELKRLEEVLNLAQSKNFHLRPRSLISNINVIVLELKGSETTFMCEYADETATIVEFLNRWITFCQSIISTLT PGGGGDKTHTCPPCPAPGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPCRDELTKNQVSLWCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK   
43 IL-2-RAS-xELL「杵」Fc APTSSSTKKTQLQLEALLLDLQMILNGINNYKNPKLTRMLTFKFYMPKKATELKHLQCLEEELKRLEEVLNLAQSKNFHLRPRSLISNINVIVLELKGSETTFMCEYADETATIVEFLNRWITFCQSIISTLT PGGGGDKTHTCPPCPAPGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPCRDELTKNQVSLWCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK
44 連接子-EVN xELL「臼」Fc KPGGGGDKTHTCPPCPAPGGPSVFLFPPKPKDTLMRSRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVCTLPPSRDELTKNQVSLSCAVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLVSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK
45 xELL「杵」Fc-IL-2-T3G-C125S DKTHTCPPCPAPGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPCRDELTKNQVSLWCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGG SGGSAPGSSSTKKTQLQLEHLLLDLQMILNGINNYKNPKLTRMLTFKFYMPKKATELKHLQCLEEELKPLEEVLNLAQSKNFHLRPRDLISNINVIVLELKGSETTFMCEYADETATIVEFLNRWITFSQSIISTLT
46 xELL「杵」Fc-IL-2-RAS-T3G-C125S DKTHTCPPCPAPGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPCRDELTKNQVSLWCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGG SGGSAPGSSSTKKTQLQLEALLLDLQMILNGINNYKNPKLTRMLTFKFYMPKKATELKHLQCLEEELKRLEEVLNLAQSKNFHLRPRSLISNINVIVLELKGSETTFMCEYADETATIVEFLNRWITFSQSIISTLT
47 Fc區1 (人類野生型IgG1) DKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPG
48 Fc區2 (人類IgG1 xELL「杵」) DKTHTCPPCPAPGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPCRDELTKNQVSLWCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPG
49 Fc區3 (人類IgG1 EVN xELL「臼」I253R) DKTHTCPPCPAPGGPSVFLFPPKPKDTLMRSRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVCTLPPSRDELTKNQVSLSCAVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLVSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPG
50 Fc區 DKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPG
51 Fc區xELL DKTHTCPPCPAPGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALP APIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPG
52 Fc區xELL H435R DKTHTCPPCPAPGGPSVFLFPPKPKDTLMISRTPETCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNRYTQKSLSLSPG
53 Fc區xELL M252Y及M428V (YV) DKTHTCPPCPAPGGPSVFLFPPKPKDTLYISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALP APIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVVHEALHNHYTQKSLSLSPG
54 Fc區xELL M252Y及M428L (YL) DKTHTCPPCPAPGGPSVFLFPPKPKDTLYISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALP APIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVLHEALHNHYTQKSLSLSPG
55 Fc區xELL M252Y, M428L, H435R (YLR) DKTHTCPPCPAPGGPSVFLFPPKPKDTLYISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALP APIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVLHEALHNRYTQKSLSLSPG
56 Fc區xELL M252Y, M428V, H435R (YVR) DKTHTCPPCPAPGGPSVFLFPPKPKDTLYISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALP APIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVVHEALHNRYTQKSLSLSPG
57 Fc區xELL S354C T366W杵 DKTHTCPPCPAPGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALP APIEKTISKAKGQPREPQVYTLPPCRDELTKNQVSLWCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPG
58 Fc區xELL H435R S354C T366W杵 DKTHTCPPCPAPGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALP APIEKTISKAKGQPREPQVYTLPPCRDELTKNQVSLWCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNRYTQKSLSLSPG
59 Fc區xELL M252Y及M428V (YV) S354C T366W杵 DKTHTCPPCPAPGGPSVFLFPPKPKDTLYISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPCRDELTKNQVSLWCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVVHEALHNHYTQKSLSLSPG
60 Fc區xELL M252Y及M428L (YL) S354C T366W杵 DKTHTCPPCPAPGGPSVFLFPPKPKDTLYISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPCRDELTKNQVSLWCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVLHEALHNHYTQKSLSLSPG
61 Fc區xELL M252Y, M428L, H435R (YLR) S354C T366W杵 DKTHTCPPCPAPGGPSVFLFPPKPKDTLYISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPCRDELTKNQVSLWCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVLHEALHNRYTQKSLSLSPG
62 Fc區xELL M252Y, M428V, H435R (YVR) S354C T366W杵 DKTHTCPPCPAPGGPSVFLFPPKPKDTLYISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPCRDELTKNQVSLWCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVVHEALHNRYTQKSLSLSPG
63 Fc區xELL T366S, L368A, Y407V臼 DKTHTCPPCPAPGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVCTLPPSRDELTKNQVSLSCAVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLVSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPG
64 Fc區xELL H435R, T366S, L368A, Y407V臼 DKTHTCPPCPAPGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVCTLPPSRDELTKNQVSLSCAVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLVSKLTVDKSRWQQGNVFSCSVMHEALHNRYTQKSLSLSPG
65 Fc區xELL M252Y及M428V (YV) T366S, L368A, Y407V臼 DKTHTCPPCPAPGGPSVFLFPPKPKDTLYISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVCTLPPSRDELTKNQVSLSCAVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLVSKLTVDKSRWQQGNVFSCSVVHEALHNHYTQKSLSLSPG
66 Fc區xELL M252Y及M428L (YL) T366S, L368A, Y407V臼 DKTHTCPPCPAPGGPSVFLFPPKPKDTLYISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVCTLPPSRDELTKNQVSLSCAVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLVSKLTVDKSRWQQGNVFSCSVLHEALHNHYTQKSLSLSPG
67 Fc區xELL M252Y, M428L, H435R (YLR) T366S, L368A, Y407V臼 DKTHTCPPCPAPGGPSVFLFPPKPKDTLYISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVCTLPPSRDELTKNQVSLSCAVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLVSKLTVDKSRWQQGNVFSCSVLHEALHNRYTQKSLSLSPG
68 Fc區xELL M252Y, M428V, H435R (YVR) T366S, L368A, Y407V臼 DKTHTCPPCPAPGGPSVFLFPPKPKDTLYISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVCTLPPSRDELTKNQVSLSCAVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLVSKLTVDKSRWQQGNVFSCSVVHEALHNRYTQKSLSLSPG
69 Fc區H435R DKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAV EWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNRYTQKSLSLSPG
70 Fc區M252Y及M428V (YV) DKTHTCPPCPAPELLGGPSVFLFPPKPKDTLYISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAV EWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVVHEALHNHYTQKSLSLSPG
71 Fc區M252Y及M428L (YL) DKTHTCPPCPAPELLGGPSVFLFPPKPKDTLYISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAV EWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVLHEALHNHYTQKSLSLSPG
72 Fc區M252Y, M428L, H435R (YLR) DKTHTCPPCPAPELLGGPSVFLFPPKPKDTLYISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAV EWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVLHEALHNRYTQKSLSLSPG
73 Fc區M252Y, M428V, H435R (YVR) DKTHTCPPCPAPELLGGPSVFLFPPKPKDTLYISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAV EWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVVHEALHNRYTQKSLSLSPG
74 Fc區S354C T366W杵 DKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPCRDELTKNQVSLWCLVKGFYPSDIAV EWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPG
75 Fc區H435R S354C T366W杵 DKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPCRDELTKNQVSLWCLVKGFYPSDIAV EWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNRYTQKSLSLSPG
76 Fc區M252Y及M428L (YL) S354C T366W杵 DKTHTCPPCPAPELLGGPSVFLFPPKPKDTLYISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPCRDELTKNQVSLWCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVLHEALHNHYTQKSLSLSPG
77 Fc區M252Y, M428L, H435R (YLR) S354C T366W杵 DKTHTCPPCPAPELLGGPSVFLFPPKPKDTLYISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPCRDELTKNQVSLWCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVLHEALHNRYTQKSLSLSPG
78 Fc區M252Y, M428V, H435R (YVR) S354C T366W杵 DKTHTCPPCPAPELLGGPSVFLFPPKPKDTLYISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPCRDELTKNQVSLWCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVVHEALHNRYTQKSLSLSPG
79 Fc區T366S, L368A, Y407V臼 DKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVCTLPPSRDELTKNQVSLSCAVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLVSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPG
80 Fc區H435R, T366S, L368A, Y407V臼 DKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVCTLPPSRDELTKNQVSLSCAVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLVSKLTVDKSRWQQGNVFSCSVMHEALHNRYTQKSLSLSPG
81 Fc區M252Y及M428V (YV) T366S, L368A, Y407V臼 DKTHTCPPCPAPELLGGPSVFLFPPKPKDTLYISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVCTLPPSRDELTKNQVSLSCAVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLVSKLTVDKSRWQQGNVFSCSVVHEALHNHYTQKSLSLSPG
82 Fc區M252Y及M428L (YL) T366S, L368A, Y407V臼 DKTHTCPPCPAPELLGGPSVFLFPPKPKDTLYISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVCTLPPSRDELTKNQVSLSCAVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLVSKLTVDKSRWQQGNVFSCSVLHEALHNHYTQKSLSLSPG
83 Fc區M252Y, M428L, H435R (YLR) T366S, L368A, Y407V臼 DKTHTCPPCPAPELLGGPSVFLFPPKPKDTLYISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVCTLPPSRDELTKNQVSLSCAVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLVSKLTVDKSRWQQGNVFSCSVLHEALHNRYTQKSLSLSPG
84 截短野生型人類IL-2 QLQLEHLLLDLQMILNGINNYKNPKLTRMLTFKFYMPKKATELKHLQCLEEELKPLEEVLNLAQSKNFHLRPRDLISNINVIVLELKGSETTFMCEYADETATIVEFLNRWITFCQSII
86 xELL-杵Fc-IL-2-T3A, C125S DKTHTCPPCPAPGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPCRDELTKNQVSLWCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGG SGGSAPASSSTKKTQLQLEHLLLDLQMILNGINNYKNPKLTRMLTFKFYMPKKATELKHLQCLEEELKPLEEVLNLAQSKNFHLRPRDLISNINVIVLELKGSETTFMCEYADETATIVEFLNRWITFSQSIISTLT
87 xELL-杵Fc-IL-2-RAS-T3A, C125S DKTHTCPPCPAPGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPCRDELTKNQVSLWCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGG SGGSAPASSSTKKTQLQLEALLLDLQMILNGINNYKNPKLTRMLTFKFYMPKKATELKHLQCLEEELKRLEEVLNLAQSKNFHLRPRSLISNINVIVLELKGSETTFMCEYADETATIVEFLNRWITFSQSIISTLT
88 派立珠單抗類似物杵Fc-IL-2-RAS-T3A, C125S QVQLVQSGVEVKKPGASVKVSCKASGYTFTNYYMYWVRQAPGQGLEWMGGINPSNGGTNFNEKFKNRVTLTTDSSTTTAYMELKSLQFDDTAVYYCARRDYRFDMGFDYWGQGTTVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPCRDELTKNQVSLWCLVKGFYPSDIAVEWESNGQPENNYDTTPPVLDSDGSFFLYSDLTVDKSRWQQGNVFSCSVMHEALHNRYTQKSLSLSPGGSGGSAPASSSTKKTQLQLEALLLDLQMILNGINNYKNPKLTRMLTFKFYMPKKATELKHLQCLEEELKRLEEVLNLAQSKNFHLRPRSLISNINVIVLELKGSETTFMCEYADETATIVEFLNRWITFSQSIISTLT
89 派立珠單抗類似物臼Fc QVQLVQSGVEVKKPGASVKVSCKASGYTFTNYYMYWVRQAPGQGLEWMGGINPSNGGTNFNEKFKNRVTLTTDSSTTTAYMELKSLQFDDTAVYYCARRDYRFDMGFDYWGQGTTVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVCTLPPSRDKLTKNQVSLSCAVKGFYPSDIAVEWKSNGQPENNYKTTPPVLDSKGSFFLVSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK
90 派立珠單抗輕鏈類似物 EIVLTQSPATLSLSPGERATLSCRASKGVSTSGYSYLHWYQQKPGQAPRLLIYLASYLESGVPARFSGSGSGTDFTLTISSLEPEDFAVYYCQHSRDLPLTFGGGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC
91 派立珠單抗類似物IL-2-RAS-T3G, C125S QVQLVQSGVEVKKPGASVKVSCKASGYTFTNYYMYWVRQAPGQGLEWMGGINPSNGGTNFNEKFKNRVTLTTDSSTTTAYMELKSLQFDDTAVYYCARRDYRFDMGFDYWGQGTTVTVSSASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKYGPPCPPCPAPEFLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLGGSGGSAPGSSSTKKTQLQLEALLLDLQMILNGINNYKNPKLTRMLTFKFYMPKKATELKHLQCLEEELKRLEEVLNLAQSKNFHLRPRSLISNINVIVLELKGSETTFMCEYADETATIVEFLNRWITFSQSIISTLT
92 NKp46-scFv xELL-杵Fc-IL-2-RAS-T3A, C125S QVQLQQSGPELVKPGASVKMSCKASGYTFTDYVINWGKQRSGQGLEWIGEIYPGSGTNYYNEKFKAKATLTADKSSNIAYMQLSSLTSEDSAVYFCARRGRYGLYAMDYWGQGTSVTVSSVEGGSGGSGGSGGSGGVDDIQMTQTTSSLSASLGDRVTISCRASQDISNYLNWYQQKPDGTVKLLIYYTSRLHSGVPSRFSGSGSGTDYSLTINNLEQEDIATYFCQQGNTRPWTFGGGTKLEIKPGGGGDKTHTCPPCPAPGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPCRDELTKNQVSLWCLVKGFYPSDIAVEWESNGQPENNYDTTPPVLDSDGSFFLYSDLTVDKSRWQQGNVFSCSVMHEALHNRYTQKSLSLSPGGSGGSAPASSSTKKTQLQLEALLLDLQMILNGINNYKNPKLTRMLTFKFYMPKKATELKHLQCLEEELKRLEEVLNLAQSKNFHLRPRSLISNINVIVLELKGSETTFMCEYADETATIVEFLNRWITFSQSIISTLT
93 NKp46-scFv xELL-臼Fc QVQLQQSGPELVKPGASVKMSCKASGYTFTDYVINWGKQRSGQGLEWIGEIYPGSGTNYYNEKFKAKATLTADKSSNIAYMQLSSLTSEDSAVYFCARRGRYGLYAMDYWGQGTSVTVSSVEGGSGGSGGSGGSGGVDDIQMTQTTSSLSASLGDRVTISCRASQDISNYLNWYQQKPDGTVKLLIYYTSRLHSGVPSRFSGSGSGTDYSLTINNLEQEDIATYFCQQGNTRPWTFGGGTKLEIKPGGGGDKTHTCPPCPAPGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVCTLPPSRDKLTKNQVSLSCAVKGFYPSDIAVEWKSNGQPENNYKTTPPVLDSKGSFFLVSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK
94 NKp46-scFv xELL-Fc QVQLQQSGPELVKPGASVKMSCKASGYTFTDYVINWGKQRSGQGLEWIGEIYPGSGTNYYNEKFKAKATLTADKSSNIAYMQLSSLTSEDSAVYFCARRGRYGLYAMDYWGQGTSVTVSSVEGGSGGSGGSGGSGGVDDIQMTQTTSSLSASLGDRVTISCRASQDISNYLNWYQQKPDGTVKLLIYYTSRLHSGVPSRFSGSGSGTDYSLTINNLEQEDIATYFCQQGNTRPWTFGGGTKLEIKPGGGGDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK
95 LAG3-MAb xELL-杵Fc-IL-2-RAS-TGCS QVQLVQSGAEVKKPGASVKVSCKASGYTFTGYYMHWVRQAPGQGLEWMGWINANSGGTNYAQKFQGRVTMTRDTSISTAYMELSRLRSDDTAVYYCARDIYDSSDQLNVWGQGTMVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPCRDELTKNQVSLWCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGGSGGSAPGSSSTKKTQLQLEALLLDLQMILNGINNYKNPKLTRMLTFKFYMPKKATELKHLQCLEEELKRLEEVLNLAQSKNFHLRPRSLISNINVIVLELKGSETTFMCEYADETATIVEFLNRWITFSQSIISTLT
96 LAG3-MAb xELL-臼Fc QVQLVQSGAEVKKPGASVKVSCKASGYTFTGYYMHWVRQAPGQGLEWMGWINANSGGTNYAQKFQGRVTMTRDTSISTAYMELSRLRSDDTAVYYCARDIYDSSDQLNVWGQGTMVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPGGPSVFLFPPKPKDTLMRSRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVCTLPPSRDELTKNQVSLSCAVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLVSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK
97 LAG3-MAb輕鏈 EIVLTQSPATLSLSPGERATLSCRASQSVSSYLAWYQQKPGQAPRLLIYDASNRATGIPARFSGSGSGTDFTLTISSLEPEDFAVYYCQQASIWPLTFGGGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC
98 LAG3-MAb IgG1 QVQLVQSGAEVKKPGASVKVSCKASGYTFTGYYMHWVRQAPGQGLEWMGWINANSGGTNYAQKFQGRVTMTRDTSISTAYMELSRLRSDDTAVYYCARDIYDSSDQLNVWGQGTMVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK
99 LAG3-VHH xELL-杵Fc-IL-2-RAS-TGCS EVQLVESGGGWQPGGSLRLSCAASGRTFSDYVMGWFRQAPGKEREFVAAISESGGRTHYADSVKGRFTISRDNSKNTLYLQMNSLRPEDTALYYCATTLLWWTSEYAPIKANDYDYWGQGTLVTVKPGGGGDKTHTCPPCPAPGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPCRDELTKNQVSLWCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGGSGGSAPGSSSTKKTQLQLEALLLDLQMILNGINNYKNPKLTRMLTFKFYMPKKATELKHLQCLEEELKRLEEVLNLAQSKNFHLRPRSLISNINVIVLELKGSETTFMCEYADETATIVEFLNRWITFSQSIISTLT
100 LAG3-VHH xELL-臼T366S, L368A, Y407V, H435R Fc EVQLVESGGGWQPGGSLRLSCAASGRTFSDYVMGWFRQAPGKEREFVAAISESGGRTHYADSVKGRFTISRDNSKNTLYLQMNSLRPEDTALYYCATTLLWWTSEYAPIKANDYDYWGQGTLVTVKPGGGGDKTHTCPPCPAPGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVCTLPPSRDELTKNQVSLSCAVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLVSKLTVDKSRWQQGNVFSCSVMHEALHNRYTQKSLSLSPGK
101 LAG3-VHH xELL-杵Fc EVQLVESGGGWQPGGSLRLSCAASGRTFSDYVMGWFRQAPGKEREFVAAISESGGRTHYADSVKGRFTISRDNSKNTLYLQMNSLRPEDTALYYCATTLLWWTSEYAPIKANDYDYWGQGTLVTVKPGGGGDKTHTCPPCPAPGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPCRDELTKNQVSLWCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK
102 xELL-杵Fc-IL-2-RAS-M23A-T3A, C125S DKTHTCPPCPAPGGPSVFLFPPKPKDTLYISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPCRDELTKNQVSLWCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVVHEALHNHYTQKSLSLSPGGSGGSAPASSSTKKTQLQLEALLLDLQAILNGINNYKNPKLTRMLTFKFYMPKKATELKHLQCLEEELKRLEEVLNLAQSKNFHLRPRSLISNINVIVLELKGSETTFMCEYADETATIVEFLNRWITFSQSIISTLT
103 xELL-杵Fc-IL-2-RAS-E95Q-T3A, C125S DKTHTCPPCPAPGGPSVFLFPPKPKDTLYISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPCRDELTKNQVSLWCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVVHEALHNHYTQKSLSLSPGGSGGSAPASSSTKKTQLQLEALLLDLQMILNGINNYKNPKLTRMLTFKFYMPKKATELKHLQCLEEELKRLEEVLNLAQSKNFHLRPRSLISNINVIVLQLKGSETTFMCEYADETATIVEFLNRWITFSQSIISTLT
104 xELL-杵Fc-IL-2-RAS-M23A-E95Q-T3A, C125S DKTHTCPPCPAPGGPSVFLFPPKPKDTLYISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPCRDELTKNQVSLWCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVVHEALHNHYTQKSLSLSPGGSGGSAPASSSTKKTQLQLEALLLDLQAILNGINNYKNPKLTRMLTFKFYMPKKATELKHLQCLEEELKRLEEVLNLAQSKNFHLRPRSLISNINVIVLQLKGSETTFMCEYADETATIVEFLNRWITFSQSIISTLT
105 IL-2-T3G-C125S APGSSSTKKTQLQLEHLLLDLQMILNGINNYKNPKLTRMLTFKFYMPKKATELKHLQCLEEELKPLEEVLNLAQSKNFHLRPRDLISNINVIVLELKGSETTFMCEYADETATIVEFLNRWITFSQSIISTLT
106 IL-2-T3A-E61R-P65R-C125S APASSSTKKTQLQLEHLLLDLQMILNGINNYKNPKLTRMLTFKFYMPKKATELKHLQCLERELKRLEEVLNLAQSKNFHLRPRDLISNINVIVLELKGSETTFMCEYADETATIVEFLNRWITFSQSIISTLT
107 IL-2-T3A-R38A-P65R-C125S APASSSTKKTQLQLEHLLLDLQMILNGINNYKNPKLTAMLTFKFYMPKKATELKHLQCLEEELKRLEEVLNLAQSKNFHLRPRDLISNINVIVLELKGSETTFMCEYADETATIVEFLNRWITFSQSIISTLT
108 IL-2-T3A-H16A-E61R-P65R-D84S-C125S APASSSTKKTQLQLEALLLDLQMILNGINNYKNPKLTRMLTFKFYMPKKATELKHLQCLERELKRLEEVLNLAQSKNFHLRPRSLISNINVIVLELKGSETTFMCEYADETATIVEFLNRWITFSQSIISTLT
109 IL-2-T3A-H16A-R38A-P65R-D84S-C125S APASSSTKKTQLQLEALLLDLQMILNGINNYKNPKLTAMLTFKFYMPKKATELKHLQCLEEELKRLEEVLNLAQSKNFHLRPRSLISNINVIVLELKGSETTFMCEYADETATIVEFLNRWITFSQSIISTLT
110 IL-2-T3A-H16A-L19A-P65R-D84S-C125S APASSSTKKTQLQLEALLLALQMILNGINNYKNPKLTRMLTFKFYMPKKATELKHLQCLEEELKRLEEVLNLAQSKNFHLRPRSLISNINVIVLELKGSETTFMCEYADETATIVEFLNRWITFSQSIISTLT
111 IL-2-T3A-H16A-P65R-D84S-N88S-C125S APASSSTKKTQLQLEALLLDLQMILNGINNYKNPKLTRMLTFKFYMPKKATELKHLQCLEEELKRLEEVLNLAQSKNFHLRPRSLISSINVIVLELKGSETTFMCEYADETATIVEFLNRWITFSQSIISTLT
112 IL-2-T3A-H16A-P65R-D84S-E95Q-C125S APASSSTKKTQLQLEALLLDLQMILNGINNYKNPKLTRMLTFKFYMPKKATELKHLQCLEEELKRLEEVLNLAQSKNFHLRPRSLISNINVIVLQLKGSETTFMCEYADETATIVEFLNRWITFSQSIISTLT
113 IL-2-T3A-H16A-M23A-P65R-D84S-C125S APASSSTKKTQLQLEALLLDLQAILNGINNYKNPKLTRMLTFKFYMPKKATELKHLQCLEEELKRLEEVLNLAQSKNFHLRPRSLISNINVIVLELKGSETTFMCEYADETATIVEFLNRWITFSQSIISTLT
114 IL-2-T3A-H16A-M23A-P65R-D84S-E95Q-C125S APASSSTKKTQLQLEALLLDLQAILNGINNYKNPKLTRMLTFKFYMPKKATELKHLQCLEEELKRLEEVLNLAQSKNFHLRPRSLISNINVIVLQLKGSETTFMCEYADETATIVEFLNRWITFSQSIISTLT
115 IL-2-T3A-H16A-L19A-E61R-P65R-D84S-C125S APASSSTKKTQLQLEALLADLQMILNGINNYKNPKLTRMLTFKFYMPKKATELKHLQCLERELKRLEEVLNLAQSKNFHLRPRSLISNINVIVLELKGSETTFMCEYADETATIVEFLNRWITFSQSIISTLT
116 IL-2-T3A-H16A-M23A-E61R-P65R-D84S-E95Q-C125S APASSSTKKTQLQLEALLLDLQAILNGINNYKNPKLTRMLTFKFYMPKKATELKHLQCLERELKRLEEVLNLAQSKNFHLRPRSLISNINVIVLQLKGSETTFMCEYADETATIVEFLNRWITFSQSIISTLT
117 IL-2-T3A-H16A-M23A-E61R-P65R-D84S-N88S-C125S APASSSTKKTQLQLEALLLDLQAILNGINNYKNPKLTRMLTFKFYMPKKATELKHLQCLERELKRLEEVLNLAQSKNFHLRPRSLISSINVIVLELKGSETTFMCEYADETATIVEFLNRWITFSQSIISTLT
118 IL-2-T3A-H16A-E61R-P65R-D84S-N88S-E95Q-C125S APASSSTKKTQLQLEALLLDLQMILNGINNYKNPKLTRMLTFKFYMPKKATELKHLQCLERELKRLEEVLNLAQSKNFHLRPRSLISSINVIVLQLKGSETTFMCEYADETATIVEFLNRWITFSQSIISTLT
119 IL-2-T3A-H16A-M23A-E61R-P65R-D84S-N88S-E95Q-C125S APASSSTKKTQLQLEALLLDLQAILNGINNYKNPKLTRMLTFKFYMPKKATELKHLQCLERELKRLEEVLNLAQSKNFHLRPRSLISSINVIVLQLKGSETTFMCEYADETATIVEFLNRWITFSQSIISTLT
120 IL-2-T3A-H16A-L19A-R38A-P65R-D84S-C125S APASSSTKKTQLQLEALLADLQMILNGINNYKNPKLTAMLTFKFYMPKKATELKHLQCLEEELKRLEEVLNLAQSKNFHLRPRSLISNINVIVLELKGSETTFMCEYADETATIVEFLNRWITFSQSIISTLT
121 IL-2-T3A-H16A-M23A-R38A-P65R-D84S-E95Q-C125S APASSSTKKTQLQLEALLLDLQAILNGINNYKNPKLTAMLTFKFYMPKKATELKHLQCLEEELKRLEEVLNLAQSKNFHLRPRSLISNINVIVLQLKGSETTFMCEYADETATIVEFLNRWITFSQSIISTLT
122 IL-2-T3A-H16A-M23A-R38A-P65R-D84S-N88S-C125S APASSSTKKTQLQLEALLLDLQAILNGINNYKNPKLTAMLTFKFYMPKKATELKHLQCLEEELKRLEEVLNLAQSKNFHLRPRSLISSINVIVLELKGSETTFMCEYADETATIVEFLNRWITFSQSIISTLT
123 IL-2-T3A-H16A-R38A-P65R-D84S-N88S-E95Q-C125S APASSSTKKTQLQLEALLLDLQMILNGINNYKNPKLTAMLTFKFYMPKKATELKHLQCLEEELKRLEEVLNLAQSKNFHLRPRSLISSINVIVLQLKGSETTFMCEYADETATIVEFLNRWITFSQSIISTLT
124 IL-2-T3A-H16A-M23A-R38A-P65R-IL-2-D84S-N88S-E95Q-C125S APASSSTKKTQLQLEALLLDLQAILNGINNYKNPKLTAMLTFKFYMPKKATELKHLQCLEEELKRLEEVLNLAQSKNFHLRPRSLISSINVIVLQLKGSETTFMCEYADETATIVEFLNRWITFSQSIISTLT
125 IL-2-T3A-H16A-L19N-P65R-D84S-C125S APASSSTKKTQLQLEALLNDLQMILNGINNYKNPKLTRMLTFKFYMPKKATELKHLQCLEEELKRLEEVLNLAQSKNFHLRPRSLISNINVIVLELKGSETTFMCEYADETATIVEFLNRWITFSQSIISTLT
126 IL-2-T3A-H16A-L19S-P65R-D84S-C125S APASSSTKKTQLQLEALLSDLQMILNGINNYKNPKLTRMLTFKFYMPKKATELKHLQCLEEELKRLEEVLNLAQSKNFHLRPRSLISNINVIVLELKGSETTFMCEYADETATIVEFLNRWITFSQSIISTLT
127 IL-2-T3A-H16A-L19T-P65R-D84S-C125S APASSSTKKTQLQLEALLTDLQMILNGINNYKNPKLTRMLTFKFYMPKKATELKHLQCLEEELKRLEEVLNLAQSKNFHLRPRSLISNINVIVLELKGSETTFMCEYADETATIVEFLNRWITFSQSIISTLT
128 IL-2-T3A-H16A-L19V-P65R-D84S-C125S APASSSTKKTQLQLEALLVDLQMILNGINNYKNPKLTRMLTFKFYMPKKATELKHLQCLEEELKRLEEVLNLAQSKNFHLRPRSLISNINVIVLELKGSETTFMCEYADETATIVEFLNRWITFSQSIISTLT
129 IL-2-T3A-H16A-L19N-M23A-E61R-P65R-D84S-E95Q-C125S APASSSTKKTQLQLEALLNDLQAILNGINNYKNPKLTRMLTFKFYMPKKATELKHLQCLERELKRLEEVLNLAQSKNFHLRPRSLISNINVIVLELQGSETTFMCEYADETATIVEFLNRWITFSQSIISTLT
130 IL-2-T3A-H16A-L19N-M23A-R38A-P65R-D84S-E95Q-C125S APASSSTKKTQLQLEALLNDLQAILNGINNYKNPKLTAMLTFKFYMPKKATELKHLQCLEEELKRLEEVLNLAQSKNFHLRPRSLISNINVIVLQLKGSETTFMCEYADETATIVEFLNRWITFSQSIISTLT
131 IL-2-T3A-H16A-L19N-M23A-R38A-P65R-D84S-C125S APASSSTKKTQLQLEALLNDLQAILNGINNYKNPKLTAMLTFKFYMPKKATELKHLQCLEEELKRLEEVLNLAQSKNFHLRPRSLISNINVIVLELKGSETTFMCEYADETATIVEFLNRWITFSQSIISTLT
132 IL-2-T3A-H16A-L19N-R38A-P65R-D84S-E95Q-C125S APASSSTKKTQLQLEALLNDLQMILNGINNYKNPKLTAMLTFKFYMPKKATELKHLQCLEEELKRLEEVLNLAQSKNFHLRPRSLISNINVIVLQLKGSETTFMCEYADETATIVEFLNRWITFSQSIISTLT
133 IL-2-T3A-H16A-L19N-R38A-P65R-D84S-C125S APASSSTKKTQLQLEALLNDLQMILNGINNYKNPKLTAMLTFKFYMPKKATELKHLQCLEEELKRLEEVLNLAQSKNFHLRPRSLISNINVIVLELKGSETTFMCEYADETATIVEFLNRWITFSQSIISTLT
134 IL-2-T3A-H16A-L19N-E61R-P65R-D84S-C125S APASSSTKKTQLQLEALLNDLQMILNGINNYKNPKLTRMLTFKFYMPKKATELKHLQCLERELKRLEEVLNLAQSKNFHLRPRSLISNINVIVLELKGSETTFMCEYADETATIVEFLNRWITFSQSIISTLT
135 IL-2-T3A-H16A-L19N-E61R-P65R-D84S-E95Q-C125S APASSSTKKTQLQLEALLNDLQMILNGINNYKNPKLTRMLTFKFYMPKKATELKHLQCLERELKRLEEVLNLAQSKNFHLRPRSLISNINVIVLQLKGSETTFMCEYADETATIVEFLNRWITFSQSIISTLT
136 IL-2-T3A-H16A-L19N-M23A-E61R-P65R-D84S-C125S APASSSTKKTQLQLEALLNDLQAILNGINNYKNPKLTRMLTFKFYMPKKATELKHLQCLERELKRLEEVLNLAQSKNFHLRPRSLISNINVIVLELKGSETTFMCEYADETATIVEFLNRWITFSQSIISTLT
137 IL-2-T3A-H16A-L19N-Q22A-E61R-P65R-D84S-C125S APASSSTKKTQLQLEALLNDLAMILNGINNYKNPKLTRMLTFKFYMPKKATELKHLQCLERELKRLEEVLNLAQSKNFHLRPRSLISNINVIVLELKGSETTFMCEYADETATIVEFLNRWITFSQSIISTLT
138 IL-2-T3A-H16A-L19N-E61R-P65R-D84S-R120A-C125S APASSSTKKTQLQLEALLNDLQMILNGINNYKNPKLTRMLTFKFYMPKKATELKHLQCLERELKRLEEVLNLAQSKNFHLRPRSLISNINVIVLELKGSETTFMCEYADETATIVEFLNAWITFSQSIISTLT
139 IL-2-T3A-H16A-L19N-E61R-P65R-D84S-C125S-Q126A APASSSTKKTQLQLEALLNDLQMILNGINNYKNPKLTRMLTFKFYMPKKATELKHLQCLERELKRLEEVLNLAQSKNFHLRPRSLISNINVIVLELKGSETTFMCEYADETATIVEFLNRWITFSASIISTLT
140 IL-2-T3A-H16S-L19N-E61R-P65R-D84S-C125S APASSSTKKTQLQLESLLNDLQMILNGINNYKNPKLTRMLTFKFYMPKKATELKHLQCLERELKRLEEVLNLAQSKNFHLRPRSLISNINVIVLELKGSETTFMCEYADETATIVEFLNRWITFSQSIISTLT
141 IL-2-T3A-H16T-L19N-E61R-P65R-D84S-C125S APASSSTKKTQLQLETLLNDLQMILNGINNYKNPKLTRMLTFKFYMPKKATELKHLQCLERELKRLEEVLNLAQSKNFHLRPRSLISNINVIVLELKGSETTFMCEYADETATIVEFLNRWITFSQSIISTLT
142 IL-2-T3A-H16V-L19N-E61R-P65R-D84S-C125S APASSSTKKTQLQLEVLLNDLQMILNGINNYKNPKLTRMLTFKFYMPKKATELKHLQCLERELKRLEEVLNLAQSKNFHLRPRSLISNINVIVLELKGSETTFMCEYADETATIVEFLNRWITFSQSIISTLT
143 IL-2-T3A-H16N-L19N-E61R-P65R-D84S-C125S APASSSTKKTQLQLENLLNDLQMILNGINNYKNPKLTRMLTFKFYMPKKATELKHLQCLERELKRLEEVLNLAQSKNFHLRPRSLISNINVIVLELKGSETTFMCEYADETATIVEFLNRWITFSQSIISTLT
144 IL-2-T3A-H16A-L19N-E61R-P65R-D84T-C125S APASSSTKKTQLQLEALLNDLQMILNGINNYKNPKLTRMLTFKFYMPKKATELKHLQCLERELKRLEEVLNLAQSKNFHLRPRTLISNINVIVLELKGSETTFMCEYADETATIVEFLNRWITFSQSIISTLT
145 IL-2-T3A-H16A-L19N-E61R-P65R-D84V-C125S APASSSTKKTQLQLEALLNDLQMILNGINNYKNPKLTRMLTFKFYMPKKATELKHLQCLERELKRLEEVLNLAQSKNFHLRPRVLISNINVIVLELKGSETTFMCEYADETATIVEFLNRWITFSQSIISTLT
146 IL-2-T3A-H16A-D20S-E61R-P65R-D84S-C125S APASSSTKKTQLQLEALLLSLQMILNGINNYKNPKLTRMLTFKFYMPKKATELKHLQCLERELKRLEEVLNLAQSKNFHLRPRSLISNINVIVLELKGSETTFMCEYADETATIVEFLNRWITFSQSIISTLT
147 IL-2-T3A-H16A-D20T-E61R-P65R-D84S-C125S APASSSTKKTQLQLEALLLTLQMILNGINNYKNPKLTRMLTFKFYMPKKATELKHLQCLERELKRLEEVLNLAQSKNFHLRPRSLISNINVIVLELKGSETTFMCEYADETATIVEFLNRWITFSQSIISTLT
148 IL-2-T3A-H16A-D20N-E61R-P65R-D84S-C125S APASSSTKKTQLQLEALLLNLQMILNGINNYKNPKLTRMLTFKFYMPKKATELKHLQCLERELKRLEEVLNLAQSKNFHLRPRSLISNINVIVLELKGSETTFMCEYADETATIVEFLNRWITFSQSIISTLT
149 IL-2-T3A-H16A-D20A-E61R-P65R-D84S-C125S APASSSTKKTQLQLEALLLALQMILNGINNYKNPKLTRMLTFKFYMPKKATELKHLQCLERELKRLEEVLNLAQSKNFHLRPRSLISNINVIVLELKGSETTFMCEYADETATIVEFLNRWITFSQSIISTLT
150 IL-2-T3A-H16A-L19N-E61R-P65R-D84N-C125S APASSSTKKTQLQLEALLNDLQMILNGINNYKNPKLTRMLTFKFYMPKKATELKHLQCLERELKRLEEVLNLAQSKNFHLRPRNLISNINVIVLELKGSETTFMCEYADETATIVEFLNRWITFSQSIISTLT
151 IL-2-T3A-H16A-E61R-P65R-D84S-N88T-C125S APASSSTKKTQLQLEALLLDLQMILNGINNYKNPKLTRMLTFKFYMPKKATELKHLQCLERELKRLEEVLNLAQSKNFHLRPRSLISTINVIVLELKGSETTFMCEYADETATIVEFLNRWITFSQSIISTLT
152 IL-2-T3A-H16A-E61R-P65R-D84S-N88A-C125S APASSSTKKTQLQLEALLLDLQMILNGINNYKNPKLTRMLTFKFYMPKKATELKHLQCLERELKRLEEVLNLAQSKNFHLRPRSLISAINVIVLELKGSETTFMCEYADETATIVEFLNRWITFSQSIISTLT
153 IL-2-T3A-H16P-L19A-E61R-P65R-D84S-C125S APASSSTKKTQLQLEPLLADLQMILNGINNYKNPKLTRMLTFKFYMPKKATELKHLQCLERELKRLEEVLNLAQSKNFHLRPRSLISNINVIVLELKGSETTFMCEYADETATIVEFLNRWITFSQSIISTLT
154 IL-2-T3A-H16A-L19H-E61R-P65R-D84S-C125S APASSSTKKTQLQLEALLHDLQMILNGINNYKNPKLTRMLTFKFYMPKKATELKHLQCLERELKRLEEVLNLAQSKNFHLRPRSLISNINVIVLELKGSETTFMCEYADETATIVEFLNRWITFSQSIISTLT
155 IL-2-T3A-H16A-L19P-E61R-P65R-D84S-C125S APASSSTKKTQLQLEALLPDLQMILNGINNYKNPKLTRMLTFKFYMPKKATELKHLQCLERELKRLEEVLNLAQSKNFHLRPRSLISNINVIVLELKGSETTFMCEYADETATIVEFLNRWITFSQSIISTLT
156 IL-2-T3A-H16A-L19Q-E61R-P65R-D84S-C125S APASSSTKKTQLQLEALLQDLQMILNGINNYKNPKLTRMLTFKFYMPKKATELKHLQCLERELKRLEEVLNLAQSKNFHLRPRSLISNINVIVLELKGSETTFMCEYADETATIVEFLNRWITFSQSIISTLT
157 IL-2-T3A-H16A-L19Y-E61R-P65R-D84S-C125S APASSSTKKTQLQLEALLYDLQMILNGINNYKNPKLTRMLTFKFYMPKKATELKHLQCLERELKRLEEVLNLAQSKNFHLRPRSLISNINVIVLELKGSETTFMCEYADETATIVEFLNRWITFSQSIISTLT
158 IL-2-T3A-H16A-L19A-E61R-P65R-D84P-C125S APASSSTKKTQLQLEALLADLQMILNGINNYKNPKLTRMLTFKFYMPKKATELKHLQCLERELKRLEEVLNLAQSKNFHLRPRPLISNINVIVLELKGSETTFMCEYADETATIVEFLNRWITFSQSIISTLT
159 IL-2-T3A-H16A-L19A-E61R-P65R-D84V-C125S APASSSTKKTQLQLEALLADLQMILNGINNYKNPKLTRMLTFKFYMPKKATELKHLQCLERELKRLEEVLNLAQSKNFHLRPRVLISNINVIVLELKGSETTFMCEYADETATIVEFLNRWITFSQSIISTLT
160 IL-2-T3A-H16A-L19A-E61R-P65R-D84Y-C125S APASSSTKKTQLQLEALLADLQMILNGINNYKNPKLTRMLTFKFYMPKKATELKHLQCLERELKRLEEVLNLAQSKNFHLRPRYLISNINVIVLELKGSETTFMCEYADETATIVEFLNRWITFSQSIISTLT
161 IL-2-T3A-H16A-M23A-E61R-P65R-D84S-E95H-C125S APASSSTKKTQLQLEALLLDLQAILNGINNYKNPKLTRMLTFKFYMPKKATELKHLQCLERELKRLEEVLNLAQSKNFHLRPRSLISNINVIVLHLKGSETTFMCEYADETATIVEFLNRWITFSQSIISTLT
162 IL-2-T3A-H16A-M23A-E61R-P65R-D84S-E95N-C125S APASSSTKKTQLQLEALLLDLQAILNGINNYKNPKLTRMLTFKFYMPKKATELKHLQCLERELKRLEEVLNLAQSKNFHLRPRSLISNINVIVLNLKGSETTFMCEYADETATIVEFLNRWITFSQSIISTLT
163 IL-2-T3A-H16A-M23A-E61R-P65R-D84S-E95P-C125S APASSSTKKTQLQLEALLLDLQAILNGINNYKNPKLTRMLTFKFYMPKKATELKHLQCLERELKRLEEVLNLAQSKNFHLRPRSLISNINVIVLPLKGSETTFMCEYADETATIVEFLNRWITFSQSIISTLT
164 IL-2-T3A-H16A-M23A-E61R-P65R-D84S-E95S-C125S APASSSTKKTQLQLEALLLDLQAILNGINNYKNPKLTRMLTFKFYMPKKATELKHLQCLERELKRLEEVLNLAQSKNFHLRPRSLISNINVIVLSLKGSETTFMCEYADETATIVEFLNRWITFSQSIISTLT
165 IL-2-T3A-H16A-M23A-E61R-P65R-D84S-E95T-C125S APASSSTKKTQLQLEALLLDLQAILNGINNYKNPKLTRMLTFKFYMPKKATELKHLQCLERELKRLEEVLNLAQSKNFHLRPRSLISNINVIVLTLKGSETTFMCEYADETATIVEFLNRWITFSQSIISTLT
166 IL-2-T3A-H16A-M23A-E61R-P65R-D84S-E95V-C125S APASSSTKKTQLQLEALLLDLQAILNGINNYKNPKLTRMLTFKFYMPKKATELKHLQCLERELKRLEEVLNLAQSKNFHLRPRSLISNINVIVLVLKGSETTFMCEYADETATIVEFLNRWITFSQSIISTLT
167 IL-2-T3A-H16A-M23A-E61R-P65R-D84S-E95Y-C125S APASSSTKKTQLQLEALLLDLQAILNGINNYKNPKLTRMLTFKFYMPKKATELKHLQCLERELKRLEEVLNLAQSKNFHLRPRSLISNINVIVLYLKGSETTFMCEYADETATIVEFLNRWITFSQSIISTLT
168 IL-2-T3A-H16A-L19A-E61A-P65R-D84S-C125S APASSSTKKTQLQLEALLADLQMILNGINNYKNPKLTRMLTFKFYMPKKATELKHLQCLEAELKRLEEVLNLAQSKNFHLRPRSLISNINVIVLELKGSETTFMCEYADETATIVEFLNRWITFSQSIISTLT
169 IL-2-T3A-H16A-L19A-E61G-P65R-D84S-C125S APASSSTKKTQLQLEALLADLQMILNGINNYKNPKLTRMLTFKFYMPKKATELKHLQCLEGELKRLEEVLNLAQSKNFHLRPRSLISNINVIVLELKGSETTFMCEYADETATIVEFLNRWITFSQSIISTLT
170 IL-2-T3A-H16A-L19A-E61H-P65R-D84S-C125S APASSSTKKTQLQLEALLADLQMILNGINNYKNPKLTRMLTFKFYMPKKATELKHLQCLEHELKRLEEVLNLAQSKNFHLRPRSLISNINVIVLELKGSETTFMCEYADETATIVEFLNRWITFSQSIISTLT
171 IL-2-T3A-H16A-L19A-E61N-P65R-D84S-C125S APASSSTKKTQLQLEALLADLQMILNGINNYKNPKLTRMLTFKFYMPKKATELKHLQCLENELKRLEEVLNLAQSKNFHLRPRSLISNINVIVLELKGSETTFMCEYADETATIVEFLNRWITFSQSIISTLT
172 IL-2-T3A-H16A-L19A-E61P-P65R-D84S-C125S APASSSTKKTQLQLEALLADLQMILNGINNYKNPKLTRMLTFKFYMPKKATELKHLQCLEPELKRLEEVLNLAQSKNFHLRPRSLISNINVIVLELKGSETTFMCEYADETATIVEFLNRWITFSQSIISTLT
173 IL-2-T3A-H16A-L19A-E61Q-P65R-D84S-C125S APASSSTKKTQLQLEALLADLQMILNGINNYKNPKLTRMLTFKFYMPKKATELKHLQCLEQELKRLEEVLNLAQSKNFHLRPRSLISNINVIVLELKGSETTFMCEYADETATIVEFLNRWITFSQSIISTLT
174 IL-2-T3A-H16A-L19A-E61S-P65R-D84S-C125S APASSSTKKTQLQLEALLADLQMILNGINNYKNPKLTRMLTFKFYMPKKATELKHLQCLESELKRLEEVLNLAQSKNFHLRPRSLISNINVIVLELKGSETTFMCEYADETATIVEFLNRWITFSQSIISTLT
175 IL-2-T3A-H16A-L19A-E61T-P65R-D84S-C125S APASSSTKKTQLQLEALLADLQMILNGINNYKNPKLTRMLTFKFYMPKKATELKHLQCLETELKRLEEVLNLAQSKNFHLRPRSLISNINVIVLELKGSETTFMCEYADETATIVEFLNRWITFSQSIISTLT
176 IL-2-T3A-H16A-L19A-E61V-P65R-D84S-C125S APASSSTKKTQLQLEALLADLQMILNGINNYKNPKLTRMLTFKFYMPKKATELKHLQCLEVELKRLEEVLNLAQSKNFHLRPRSLISNINVIVLELKGSETTFMCEYADETATIVEFLNRWITFSQSIISTLT
177 IL-2-T3A-H16A-L19A-E61Y-P65R-D84S-C125S APASSSTKKTQLQLEALLADLQMILNGINNYKNPKLTRMLTFKFYMPKKATELKHLQCLEYELKRLEEVLNLAQSKNFHLRPRSLISNINVIVLELKGSETTFMCEYADETATIVEFLNRWITFSQSIISTLT
178 IL-2-T3A-H16A-M23D-E61R-P65R-D84S-E95Q-C125S APASSSTKKTQLQLEALLLDLQDILNGINNYKNPKLTRMLTFKFYMPKKATELKHLQCLERELKRLEEVLNLAQSKNFHLRPRSLISNINVIVLQLKGSETTFMCEYADETATIVEFLNRWITFSQSIISTLT
179 IL-2-T3A-H16A-M23E-E61R-P65R-D84S-E95Q-C125S APASSSTKKTQLQLEALLLDLQEILNGINNYKNPKLTRMLTFKFYMPKKATELKHLQCLERELKRLEEVLNLAQSKNFHLRPRSLISNINVIVLQLKGSETTFMCEYADETATIVEFLNRWITFSQSIISTLT
180 IL-2-T3A-H16A-M23G-E61R-P65R-D84S-E95Q-C125S APASSSTKKTQLQLEALLLDLQGILNGINNYKNPKLTRMLTFKFYMPKKATELKHLQCLERELKRLEEVLNLAQSKNFHLRPRSLISNINVIVLQLKGSETTFMCEYADETATIVEFLNRWITFSQSIISTLT
181 IL-2-T3A-H16A-M23I-E61R-P65R-D84S-E95Q-C125S APASSSTKKTQLQLEALLLDLQIILNGINNYKNPKLTRMLTFKFYMPKKATELKHLQCLERELKRLEEVLNLAQSKNFHLRPRSLISNINVIVLQLKGSETTFMCEYADETATIVEFLNRWITFSQSIISTLT
182 IL-2-T3A-H16A-M23K-E61R-P65R-D84S-E95Q-C125S APASSSTKKTQLQLEALLLDLQKILNGINNYKNPKLTRMLTFKFYMPKKATELKHLQCLERELKRLEEVLNLAQSKNFHLRPRSLISNINVIVLQLKGSETTFMCEYADETATIVEFLNRWITFSQSIISTLT
183 IL-2-T3A-H16A-M23L-E61R-P65R-D84S-E95Q-C125S APASSSTKKTQLQLEALLLDLQLILNGINNYKNPKLTRMLTFKFYMPKKATELKHLQCLERELKRLEEVLNLAQSKNFHLRPRSLISNINVIVLQLKGSETTFMCEYADETATIVEFLNRWITFSQSIISTLT
184 IL-2-T3A-H16A-M23N-E61R-P65R-D84S-E95Q-C125S APASSSTKKTQLQLEALLLDLQNILNGINNYKNPKLTRMLTFKFYMPKKATELKHLQCLERELKRLEEVLNLAQSKNFHLRPRSLISNINVIVLQLKGSETTFMCEYADETATIVEFLNRWITFSQSIISTLT
185 IL-2-T3A-H16A-M23P-E61R-P65R-D84S-E95Q-C125S APASSSTKKTQLQLEALLLDLQPILNGINNYKNPKLTRMLTFKFYMPKKATELKHLQCLERELKRLEEVLNLAQSKNFHLRPRSLISNINVIVLQLKGSETTFMCEYADETATIVEFLNRWITFSQSIISTLT
186 IL-2-T3A-H16A-M23Q-E61R-P65R-D84S-E95Q-C125S APASSSTKKTQLQLEALLLDLQQILNGINNYKNPKLTRMLTFKFYMPKKATELKHLQCLERELKRLEEVLNLAQSKNFHLRPRSLISNINVIVLQLKGSETTFMCEYADETATIVEFLNRWITFSQSIISTLT
187 IL-2-T3A-H16A-M23R-E61R-P65R-D84S-E95Q-C125S APASSSTKKTQLQLEALLLDLQRILNGINNYKNPKLTRMLTFKFYMPKKATELKHLQCLERELKRLEEVLNLAQSKNFHLRPRSLISNINVIVLQLKGSETTFMCEYADETATIVEFLNRWITFSQSIISTLT
188 IL-2-T3A-H16A-M23T-E61R-P65R-D84S-E95Q-C125S APASSSTKKTQLQLEALLLDLQTILNGINNYKNPKLTRMLTFKFYMPKKATELKHLQCLERELKRLEEVLNLAQSKNFHLRPRSLISNINVIVLQLKGSETTFMCEYADETATIVEFLNRWITFSQSIISTLT
189 IL-2-T3A-H16A-M23V-E61R-P65R-D84S-E95Q-C125S APASSSTKKTQLQLEALLLDLQVILNGINNYKNPKLTRMLTFKFYMPKKATELKHLQCLERELKRLEEVLNLAQSKNFHLRPRSLISNINVIVLQLKGSETTFMCEYADETATIVEFLNRWITFSQSIISTLT
190 IL-2-T3A-H16A-Q22A-E61R-P65R-D84S-C125S APASSSTKKTQLQLEALLLDLAMILNGINNYKNPKLTRMLTFKFYMPKKATELKHLQCLERELKRLEEVLNLAQSKNFHLRPRSLISNINVIVLELKGSETTFMCEYADETATIVEFLNRWITFSQSIISTLT
191 IL-2-T3A-H16A-Q22D-E61R-P65R-D84S-C125S APASSSTKKTQLQLEALLLDLDMILNGINNYKNPKLTRMLTFKFYMPKKATELKHLQCLERELKRLEEVLNLAQSKNFHLRPRSLISNINVIVLELKGSETTFMCEYADETATIVEFLNRWITFSQSIISTLT
192 IL-2-T3A-H16A-Q22E-E61R-P65R-D84S-C125S APASSSTKKTQLQLEALLLDLEMILNGINNYKNPKLTRMLTFKFYMPKKATELKHLQCLERELKRLEEVLNLAQSKNFHLRPRSLISNINVIVLELKGSETTFMCEYADETATIVEFLNRWITFSQSIISTLT
193 IL-2-T3A-H16A-Q22G-E61R-P65R-D84S-C125S APASSSTKKTQLQLEALLLDLGMILNGINNYKNPKLTRMLTFKFYMPKKATELKHLQCLERELKRLEEVLNLAQSKNFHLRPRSLISNINVIVLELKGSETTFMCEYADETATIVEFLNRWITFSQSIISTLT
194 IL-2-T3A-H16A-Q22H-E61R-P65R-D84S-C125S APASSSTKKTQLQLEALLLDLHMILNGINNYKNPKLTRMLTFKFYMPKKATELKHLQCLERELKRLEEVLNLAQSKNFHLRPRSLISNINVIVLELKGSETTFMCEYADETATIVEFLNRWITFSQSIISTLT
195 IL-2-T3A-H16A-Q22K-E61R-P65R-D84S-C125S APASSSTKKTQLQLEALLLDLKMILNGINNYKNPKLTRMLTFKFYMPKKATELKHLQCLERELKRLEEVLNLAQSKNFHLRPRSLISNINVIVLELKGSETTFMCEYADETATIVEFLNRWITFSQSIISTLT
196 IL-2-T3A-H16A-Q22N-E61R-P65R-D84S-C125S APASSSTKKTQLQLEALLLDLNMILNGINNYKNPKLTRMLTFKFYMPKKATELKHLQCLERELKRLEEVLNLAQSKNFHLRPRSLISNINVIVLELKGSETTFMCEYADETATIVEFLNRWITFSQSIISTLT
197 IL-2-T3A-H16A-Q22P-E61R-P65R-D84S-C125S APASSSTKKTQLQLEALLLDLPMILNGINNYKNPKLTRMLTFKFYMPKKATELKHLQCLERELKRLEEVLNLAQSKNFHLRPRSLISNINVIVLELKGSETTFMCEYADETATIVEFLNRWITFSQSIISTLT
198 IL-2-T3A-H16A-Q22R-E61R-P65R-D84S-C125S APASSSTKKTQLQLEALLLDLRMILNGINNYKNPKLTRMLTFKFYMPKKATELKHLQCLERELKRLEEVLNLAQSKNFHLRPRSLISNINVIVLELKGSETTFMCEYADETATIVEFLNRWITFSQSIISTLT
199 IL-2-T3A-H16A-Q22S-E61R-P65R-D84S-C125S APASSSTKKTQLQLEALLLDLSMILNGINNYKNPKLTRMLTFKFYMPKKATELKHLQCLERELKRLEEVLNLAQSKNFHLRPRSLISNINVIVLELKGSETTFMCEYADETATIVEFLNRWITFSQSIISTLT
200 IL-2-T3A-H16A-Q22T-E61R-P65R-D84S-C125S APASSSTKKTQLQLEALLLDLTMILNGINNYKNPKLTRMLTFKFYMPKKATELKHLQCLERELKRLEEVLNLAQSKNFHLRPRSLISNINVIVLELKGSETTFMCEYADETATIVEFLNRWITFSQSIISTLT
201 IL-2-T3A-H16A-Q22V-E61R-P65R-D84S-C125S APASSSTKKTQLQLEALLLDLVMILNGINNYKNPKLTRMLTFKFYMPKKATELKHLQCLERELKRLEEVLNLAQSKNFHLRPRSLISNINVIVLELKGSETTFMCEYADETATIVEFLNRWITFSQSIISTLT
202 IL-2-T3A-H16A-Q22Y-E61R-P65R-D84S-C125S APASSSTKKTQLQLEALLLDLYMILNGINNYKNPKLTRMLTFKFYMPKKATELKHLQCLERELKRLEEVLNLAQSKNFHLRPRSLISNINVIVLELKGSETTFMCEYADETATIVEFLNRWITFSQSIISTLT
203 IL-2-T3A-H16A-E61R-P65R-D84S-R120A-C125S APASSSTKKTQLQLEALLLDLQMILNGINNYKNPKLTRMLTFKFYMPKKATELKHLQCLERELKRLEEVLNLAQSKNFHLRPRSLISNINVIVLELKGSETTFMCEYADETATIVEFLNAWITFSQSIISTLT
204 IL-2-T3A-H16A-E61R-P65R-D84S-R120D-C125S APASSSTKKTQLQLEALLLDLQMILNGINNYKNPKLTRMLTFKFYMPKKATELKHLQCLERELKRLEEVLNLAQSKNFHLRPRSLISNINVIVLELKGSETTFMCEYADETATIVEFLNDWITFSQSIISTLT
205 IL-2-T3A-H16A-E61R-P65R-D84S-R120E-C125S APASSSTKKTQLQLEALLLDLQMILNGINNYKNPKLTRMLTFKFYMPKKATELKHLQCLERELKRLEEVLNLAQSKNFHLRPRSLISNINVIVLELKGSETTFMCEYADETATIVEFLNEWITFSQSIISTLT
206 IL-2-T3A-H16A-E61R-P65R-D84S-R120F-C125S APASSSTKKTQLQLEALLLDLQMILNGINNYKNPKLTRMLTFKFYMPKKATELKHLQCLERELKRLEEVLNLAQSKNFHLRPRSLISNINVIVLELKGSETTFMCEYADETATIVEFLNFWITFSQSIISTLT
207 IL-2-T3A-H16A-E61R-P65R-D84S-R120G-C125S APASSSTKKTQLQLEALLLDLQMILNGINNYKNPKLTRMLTFKFYMPKKATELKHLQCLERELKRLEEVLNLAQSKNFHLRPRSLISNINVIVLELKGSETTFMCEYADETATIVEFLNGWITFSQSIISTLT
208 IL-2-T3A-H16A-E61R-P65R-D84S-R120H-C125S APASSSTKKTQLQLEALLLDLQMILNGINNYKNPKLTRMLTFKFYMPKKATELKHLQCLERELKRLEEVLNLAQSKNFHLRPRSLISNINVIVLELKGSETTFMCEYADETATIVEFLNHWITFSQSIISTLT
209 IL-2-T3A-H16A-E61R-P65R-D84S-R120K-C125S APASSSTKKTQLQLEALLLDLQMILNGINNYKNPKLTRMLTFKFYMPKKATELKHLQCLERELKRLEEVLNLAQSKNFHLRPRSLISNINVIVLELKGSETTFMCEYADETATIVEFLNKWITFSQSIISTLT
210 IL-2-T3A-H16A-E61R-P65R-D84S-R120N-C125S APASSSTKKTQLQLEALLLDLQMILNGINNYKNPKLTRMLTFKFYMPKKATELKHLQCLERELKRLEEVLNLAQSKNFHLRPRSLISNINVIVLELKGSETTFMCEYADETATIVEFLNNWITFSQSIISTLT
211 IL-2-T3A-H16A-E61R-P65R-D84S-R120P-C125S APASSSTKKTQLQLEALLLDLQMILNGINNYKNPKLTRMLTFKFYMPKKATELKHLQCLERELKRLEEVLNLAQSKNFHLRPRSLISNINVIVLELKGSETTFMCEYADETATIVEFLNPWITFSQSIISTLT
212 IL-2-T3A-H16A-E61R-P65R-D84S-R120Q-C125S APASSSTKKTQLQLEALLLDLQMILNGINNYKNPKLTRMLTFKFYMPKKATELKHLQCLERELKRLEEVLNLAQSKNFHLRPRSLISNINVIVLELKGSETTFMCEYADETATIVEFLNQWITFSQSIISTLT
213 IL-2-T3A-H16A-E61R-P65R-D84S-R120S-C125S APASSSTKKTQLQLEALLLDLQMILNGINNYKNPKLTRMLTFKFYMPKKATELKHLQCLERELKRLEEVLNLAQSKNFHLRPRSLISNINVIVLELKGSETTFMCEYADETATIVEFLNSWITFSQSIISTLT
214 IL-2-T3A-H16A-E61R-P65R-D84S-R120T-C125S APASSSTKKTQLQLEALLLDLQMILNGINNYKNPKLTRMLTFKFYMPKKATELKHLQCLERELKRLEEVLNLAQSKNFHLRPRSLISNINVIVLELKGSETTFMCEYADETATIVEFLNTWITFSQSIISTLT
215 IL-2-T3A-H16A-E61R-P65R-D84S-R120V-C125S APASSSTKKTQLQLEALLLDLQMILNGINNYKNPKLTRMLTFKFYMPKKATELKHLQCLERELKRLEEVLNLAQSKNFHLRPRSLISNINVIVLELKGSETTFMCEYADETATIVEFLNVWITFSQSIISTLT
216 IL-2-T3A-H16A-E61R-P65R-D84S-R120Y-C125S APASSSTKKTQLQLEALLLDLQMILNGINNYKNPKLTRMLTFKFYMPKKATELKHLQCLERELKRLEEVLNLAQSKNFHLRPRSLISNINVIVLELKGSETTFMCEYADETATIVEFLNYWITFSQSIISTLT
217 IL-2-T3A-H16A-E61R-P65R-D84S-T123D-C125S APASSSTKKTQLQLEALLLDLQMILNGINNYKNPKLTRMLTFKFYMPKKATELKHLQCLERELKRLEEVLNLAQSKNFHLRPRSLISNINVIVLELKGSETTFMCEYADETATIVEFLNRWIDFSQSIISTLT
218 IL-2-T3A-H16A-E61R-P65R-D84S-T123E-C125S APASSSTKKTQLQLEALLLDLQMILNGINNYKNPKLTRMLTFKFYMPKKATELKHLQCLERELKRLEEVLNLAQSKNFHLRPRSLISNINVIVLELKGSETTFMCEYADETATIVEFLNRWIEFSQSIISTLT
219 IL-2-T3A-H16A-E61R-P65R-D84S-T123H-C125S APASSSTKKTQLQLEALLLDLQMILNGINNYKNPKLTRMLTFKFYMPKKATELKHLQCLERELKRLEEVLNLAQSKNFHLRPRSLISNINVIVLELKGSETTFMCEYADETATIVEFLNRWIHFSQSIISTLT
220 IL-2-T3A-H16A-E61R-P65R-D84S-T123K-C125S APASSSTKKTQLQLEALLLDLQMILNGINNYKNPKLTRMLTFKFYMPKKATELKHLQCLERELKRLEEVLNLAQSKNFHLRPRSLISNINVIVLELKGSETTFMCEYADETATIVEFLNRWIKFSQSIISTLT
221 IL-2-T3A-H16A-E61R-P65R-D84S-T123N-C125S APASSSTKKTQLQLEALLLDLQMILNGINNYKNPKLTRMLTFKFYMPKKATELKHLQCLERELKRLEEVLNLAQSKNFHLRPRSLISNINVIVLELKGSETTFMCEYADETATIVEFLNRWINFSQSIISTLT
222 IL-2-T3A-H16A-E61R-P65R-D84S-T123Q-C125S APASSSTKKTQLQLEALLLDLQMILNGINNYKNPKLTRMLTFKFYMPKKATELKHLQCLERELKRLEEVLNLAQSKNFHLRPRSLISNINVIVLELKGSETTFMCEYADETATIVEFLNRWIQFSQSIISTLT
223 IL-2-T3A-H16A-E61R-P65R-D84S-T123R-C125S APASSSTKKTQLQLEALLLDLQMILNGINNYKNPKLTRMLTFKFYMPKKATELKHLQCLERELKRLEEVLNLAQSKNFHLRPRSLISNINVIVLELKGSETTFMCEYADETATIVEFLNRWIRFSQSIISTLT
224 IL-2-T3A-H16A-E61R-P65R-D84S-C125S-S130D APASSSTKKTQLQLEALLLDLQMILNGINNYKNPKLTRMLTFKFYMPKKATELKHLQCLERELKRLEEVLNLAQSKNFHLRPRSLISNINVIVLELKGSETTFMCEYADETATIVEFLNRWITFSQSIIDTLT
225 IL-2-T3A-H16A-E61R-P65R-D84S-C125S-S130E APASSSTKKTQLQLEALLLDLQMILNGINNYKNPKLTRMLTFKFYMPKKATELKHLQCLERELKRLEEVLNLAQSKNFHLRPRSLISNINVIVLELKGSETTFMCEYADETATIVEFLNRWITFSQSIIETLT
226 IL-2-T3A-H16A-E61R-P65R-D84S-C125S-S130K APASSSTKKTQLQLEALLLDLQMILNGINNYKNPKLTRMLTFKFYMPKKATELKHLQCLERELKRLEEVLNLAQSKNFHLRPRSLISNINVIVLELKGSETTFMCEYADETATIVEFLNRWITFSQSIIKTLT
227 IL-2-T3A-H16A-E61R-P65R-D84S-C125S-S130N APASSSTKKTQLQLEALLLDLQMILNGINNYKNPKLTRMLTFKFYMPKKATELKHLQCLERELKRLEEVLNLAQSKNFHLRPRSLISNINVIVLELKGSETTFMCEYADETATIVEFLNRWITFSQSIINTLT
228 IL-2-T3A-H16A-E61R-P65R-D84S-C125S-S130Q APASSSTKKTQLQLEALLLDLQMILNGINNYKNPKLTRMLTFKFYMPKKATELKHLQCLERELKRLEEVLNLAQSKNFHLRPRSLISNINVIVLELKGSETTFMCEYADETATIVEFLNRWITFSQSIIQTLT
229 IL-2-T3A-H16A-E61R-P65R-D84S-C125S-S130R APASSSTKKTQLQLEALLLDLQMILNGINNYKNPKLTRMLTFKFYMPKKATELKHLQCLERELKRLEEVLNLAQSKNFHLRPRSLISNINVIVLELKGSETTFMCEYADETATIVEFLNRWITFSQSIIRTLT
230 IL-2-T3A-H16A-E61R-P65R-D84S-C125S-S127D APASSSTKKTQLQLEALLLDLQMILNGINNYKNPKLTRMLTFKFYMPKKATELKHLQCLERELKRLEEVLNLAQSKNFHLRPRSLISNINVIVLELKGSETTFMCEYADETATIVEFLNRWITFSQDIISTLT
231 IL-2-T3A-H16A-E61R-P65R-D84S-C125S-S127E APASSSTKKTQLQLEALLLDLQMILNGINNYKNPKLTRMLTFKFYMPKKATELKHLQCLERELKRLEEVLNLAQSKNFHLRPRSLISNINVIVLELKGSETTFMCEYADETATIVEFLNRWITFSQEIISTLT
232 IL-2-T3A-H16A-E61R-P65R-D84S-C125S-S127H APASSSTKKTQLQLEALLLDLQMILNGINNYKNPKLTRMLTFKFYMPKKATELKHLQCLERELKRLEEVLNLAQSKNFHLRPRSLISNINVIVLELKGSETTFMCEYADETATIVEFLNRWITFSQHIISTLT
233 IL-2-T3A-H16A-E61R-P65R-D84S-C125S-S127P APASSSTKKTQLQLEALLLDLQMILNGINNYKNPKLTRMLTFKFYMPKKATELKHLQCLERELKRLEEVLNLAQSKNFHLRPRSLISNINVIVLELKGSETTFMCEYADETATIVEFLNRWITFSQPIISTLT
234 IL-2-T3A-H16A-E61R-P65R-D84S-C125S-S127Q APASSSTKKTQLQLEALLLDLQMILNGINNYKNPKLTRMLTFKFYMPKKATELKHLQCLERELKRLEEVLNLAQSKNFHLRPRSLISNINVIVLELKGSETTFMCEYADETATIVEFLNRWITFSQQIISTLT
235 IL-2-T3A-H16A-E61R-P65R-D84S-C125S-S127R APASSSTKKTQLQLEALLLDLQMILNGINNYKNPKLTRMLTFKFYMPKKATELKHLQCLERELKRLEEVLNLAQSKNFHLRPRSLISNINVIVLELKGSETTFMCEYADETATIVEFLNRWITFSQRIISTLT
236 IL-2-T3A-H16A-L19A-Q22A-R38A-P65R-D84S-C125S APASSSTKKTQLQLEALLADLAMILNGINNYKNPKLTAMLTFKFYMPKKATELKHLQCLEEELKRLEEVLNLAQSKNFHLRPRSLISNINVIVLELKGSETTFMCEYADETATIVEFLNRWITFSQSIISTLT
237 IL-2-T3A-H16A-L19A-R38A-P65R-D84S-R120A-C125S APASSSTKKTQLQLEALLADLQMILNGINNYKNPKLTAMLTFKFYMPKKATELKHLQCLEEELKRLEEVLNLAQSKNFHLRPRSLISNINVIVLELKGSETTFMCEYADETATIVEFLNAWITFSQSIISTLT
238 IL-2-T3A-H16A-L19A-Q22A-R38A-P65R-D84S-R120A-C125S APASSSTKKTQLQLEALLADLAMILNGINNYKNPKLTAMLTFKFYMPKKATELKHLQCLEEELKRLEEVLNLAQSKNFHLRPRSLISNINVIVLELKGSETTFMCEYADETATIVEFLNAWITFSQSIISTLT
239 IL-2-T3A-H16A-Q22A-M23A-R38A-P65R-D84S-E95Q-C125S APASSSTKKTQLQLEALLLDLAAILNGINNYKNPKLTAMLTFKFYMPKKATELKHLQCLEEELKRLEEVLNLAQSKNFHLRPRSLISNINVIVLQLKGSETTFMCEYADETATIVEFLNRWITFSQSIISTLT
240 IL-2-T3A-H16A-M23A-R38A-P65R-D84S-E95Q-R120A-C125S APASSSTKKTQLQLEALLLDLQAILNGINNYKNPKLTAMLTFKFYMPKKATELKHLQCLEEELKRLEEVLNLAQSKNFHLRPRSLISNINVIVLQLKGSETTFMCEYADETATIVEFLNAWITFSQSIISTLT
241 IL-2-T3A-H16A-Q22A-M23A-R38A-P65R-D84S-E95Q-R120A-C125S APASSSTKKTQLQLEALLLDLAAILNGINNYKNPKLTAMLTFKFYMPKKATELKHLQCLEEELKRLEEVLNLAQSKNFHLRPRSLISNINVIVLQLKGSETTFMCEYADETATIVEFLNAWITFSQSIISTLT
242 IL-2-T3A-H16A-L19N-Q22A-R38A-P65R-D84S-C125S APASSSTKKTQLQLEALLNDLAMILNGINNYKNPKLTAMLTFKFYMPKKATELKHLQCLEEELKRLEEVLNLAQSKNFHLRPRSLISNINVIVLELKGSETTFMCEYADETATIVEFLNRWITFSQSIISTLT
243 IL-2-T3A-H16A-L19N-R38A-P65R-D84S-R120A-C125S APASSSTKKTQLQLEALLNDLQMILNGINNYKNPKLTAMLTFKFYMPKKATELKHLQCLEEELKRLEEVLNLAQSKNFHLRPRSLISNINVIVLELKGSETTFMCEYADETATIVEFLNAWITFSQSIISTLT
244 IL-2-T3A-H16A-L19N-Q22A-R38A-P65R-D84S-R120A-C125S APASSSTKKTQLQLEALLNDLAMILNGINNYKNPKLTAMLTFKFYMPKKATELKHLQCLEEELKRLEEVLNLAQSKNFHLRPRSLISNINVIVLELKGSETTFMCEYADETATIVEFLNAWITFSQSIISTLT
245 IL-2-A1G-P2G-T3S-S4G-S5G-H16A-L19A-R38A-P65R-D84S-C125S GGSGGSTKKTQLQLEALLADLQMILNGINNYKNPKLTAMLTFKFYMPKKATELKHLQCLEEELKRLEEVLNLAQSKNFHLRPRSLISNINVIVLELKGSETTFMCEYADETATIVEFLNRWITFSQSIISTLT
246 IL-2-del1-5-H16A-L19A-R38A-P65R-D84S-C125S STKKTQLQLEALLADLQMILNGINNYKNPKLTAMLTFKFYMPKKATELKHLQCLEEELKRLEEVLNLAQSKNFHLRPRSLISNINVIVLELKGSETTFMCEYADETATIVEFLNRWITFSQSIISTLT
247 IL-2-del1-5-H16A-L19A-R38A-P65R-D84S-C125V STKKTQLQLEALLADLQMILNGINNYKNPKLTAMLTFKFYMPKKATELKHLQCLEEELKRLEEVLNLAQSKNFHLRPRSLISNINVIVLELKGSETTFMCEYADETATIVEFLNRWITFVQSIISTLT
248 IL-2-T3A-L19N-R38A-P65R-D84S-C125S APASSSTKKTQLQLEHLLNDLQMILNGINNYKNPKLTAMLTFKFYMPKKATELKHLQCLEEELKRLEEVLNLAQSKNFHLRPRSLISNINVIVLELKGSETTFMCEYADETATIVEFLNRWITFSQSIISTLT
249 IL-2-T3A-H16A-L19N-R38A-P65R-C125S APASSSTKKTQLQLEALLNDLQMILNGINNYKNPKLTAMLTFKFYMPKKATELKHLQCLEEELKRLEEVLNLAQSKNFHLRPRDLISNINVIVLELKGSETTFMCEYADETATIVEFLNRWITFSQSIISTLT
250 IL-2-T3A-L19N-Q22A-R38A-P65R-D84S-C125S APASSSTKKTQLQLEHLLNDLAMILNGINNYKNPKLTAMLTFKFYMPKKATELKHLQCLEEELKRLEEVLNLAQSKNFHLRPRSLISNINVIVLELKGSETTFMCEYADETATIVEFLNRWITFSQSIISTLT
251 IL-2-T3A-H16A-L19N-Q22A-R38A-P65R-C125S APASSSTKKTQLQLEALLNDLAMILNGINNYKNPKLTAMLTFKFYMPKKATELKHLQCLEEELKRLEEVLNLAQSKNFHLRPRDLISNINVIVLELKGSETTFMCEYADETATIVEFLNRWITFSQSIISTLT
252 IL-2-T3A-L19N-Q22A-R38A-P65R-D84S-R120A-C125S APASSSTKKTQLQLEHLLNDLAMILNGINNYKNPKLTAMLTFKFYMPKKATELKHLQCLEEELKRLEEVLNLAQSKNFHLRPRSLISNINVIVLELKGSETTFMCEYADETATIVEFLNAWITFSQSIISTLT
253 IL-2-T3A-H16A-L19N-Q22A-R38A-P65R-R120A-C125S APASSSTKKTQLQLEALLNDLAMILNGINNYKNPKLTAMLTFKFYMPKKATELKHLQCLEEELKRLEEVLNLAQSKNFHLRPRDLISNINVIVLELKGSETTFMCEYADETATIVEFLNAWITFSQSIISTLT
254 IL-2-T3A-Q22A-M23A-R38A-P65R-D84S-E95Q-C125S APASSSTKKTQLQLEHLLLDLAAILNGINNYKNPKLTAMLTFKFYMPKKATELKHLQCLEEELKRLEEVLNLAQSKNFHLRPRSLISNINVIVLQLKGSETTFMCEYADETATIVEFLNRWITFSQSIISTLT
255 IL-2-T3A-Q22A-M23A-R38A-P65R-E95Q-C125S APASSSTKKTQLQLEALLLDLAAILNGINNYKNPKLTAMLTFKFYMPKKATELKHLQCLEEELKRLEEVLNLAQSKNFHLRPRDLISNINVIVLQLKGSETTFMCEYADETATIVEFLNRWITFSQSIISTLT
256 IL-2-T3A-Q22A-M23A-R38A-P65R-D84S-E95Q-R120A-C125S APASSSTKKTQLQLEHLLLDLAAILNGINNYKNPKLTAMLTFKFYMPKKATELKHLQCLEEELKRLEEVLNLAQSKNFHLRPRSLISNINVIVLQLKGSETTFMCEYADETATIVEFLNAWITFSQSIISTLT
257 IL-2-T3A-H16A-Q22A-M23A-R38A-P65R-E95Q-R120A-C125S APASSSTKKTQLQLEALLLDLAAILNGINNYKNPKLTAMLTFKFYMPKKATELKHLQCLEEELKRLEEVLNLAQSKNFHLRPRDLISNINVIVLQLKGSETTFMCEYADETATIVEFLNAWITFSQSIISTLT
258 IL-2-T3A-L19A-Q22A-R38A-P65R-D84S-C125S APASSSTKKTQLQLEHLLADLAMILNGINNYKNPKLTAMLTFKFYMPKKATELKHLQCLEEELKRLEEVLNLAQSKNFHLRPRSLISNINVIVLELKGSETTFMCEYADETATIVEFLNRWITFSQSIISTLT
259 IL-2-T3A-H16A-L19A-Q22A-R38A-P65R-C125S APASSSTKKTQLQLEALLADLAMILNGINNYKNPKLTAMLTFKFYMPKKATELKHLQCLEEELKRLEEVLNLAQSKNFHLRPRDLISNINVIVLELKGSETTFMCEYADETATIVEFLNRWITFSQSIISTLT
260 IL-2-T3A-L19A-Q22A-R38A-P65R-D84S-R120A-C125S APASSSTKKTQLQLEHLLADLAMILNGINNYKNPKLTAMLTFKFYMPKKATELKHLQCLEEELKRLEEVLNLAQSKNFHLRPRSLISNINVIVLELKGSETTFMCEYADETATIVEFLNAWITFSQSIISTLT
261 IL-2-T3A-H16A-L19A-Q22A-R38A-P65R-R120A-C125S APASSSTKKTQLQLEALLADLAMILNGINNYKNPKLTAMLTFKFYMPKKATELKHLQCLEEELKRLEEVLNLAQSKNFHLRPRDLISNINVIVLELKGSETTFMCEYADETATIVEFLNAWITFSQSIISTLT
262 IL-2-T3A-H16A-E61R-P65R-D84S-C125S-I129A APASSSTKKTQLQLEALLLDLQMILNGINNYKNPKLTRMLTFKFYMPKKATELKHLQCLERELKRLEEVLNLAQSKNFHLRPRSLISNINVIVLELKGSETTFMCEYADETATIVEFLNRWITFSQSIASTLT
263 IL-2-T3A-H16A-E61R-P65R-D84S-C125S-I129H APASSSTKKTQLQLEALLLDLQMILNGINNYKNPKLTRMLTFKFYMPKKATELKHLQCLERELKRLEEVLNLAQSKNFHLRPRSLISNINVIVLELKGSETTFMCEYADETATIVEFLNRWITFSQSIHSTLT
264 IL-2-T3A-H16A-E61R-P65R-D84S-C125S-I129R APASSSTKKTQLQLEALLLDLQMILNGINNYKNPKLTRMLTFKFYMPKKATELKHLQCLERELKRLEEVLNLAQSKNFHLRPRSLISNINVIVLELKGSETTFMCEYADETATIVEFLNRWITFSQSIRSTLT
265 IL-2-T3A-H16A-E61R-P65R-D84S-C125S-I129S APASSSTKKTQLQLEALLLDLQMILNGINNYKNPKLTRMLTFKFYMPKKATELKHLQCLERELKRLEEVLNLAQSKNFHLRPRSLISNINVIVLELKGSETTFMCEYADETATIVEFLNRWITFSQSISSTLT
266 IL-2-T3A-H16A-E61R-P65R-D84S-C125C-Q126N APASSSTKKTQLQLEALLLDLQMILNGINNYKNPKLTRMLTFKFYMPKKATELKHLQCLERELKRLEEVLNLAQSKNFHLRPRSLISNINVIVLELKGSETTFMCEYADETATIVEFLNRWITFSNSIISTLT
267 IL-2-T3A-H16A-E61R-P65R-D84S-C125C-Q126Y APASSSTKKTQLQLEALLLDLQMILNGINNYKNPKLTRMLTFKFYMPKKATELKHLQCLERELKRLEEVLNLAQSKNFHLRPRSLISNINVIVLELKGSETTFMCEYADETATIVEFLNRWITFSYSIISTLT
268 IL-2-T3A-H16A-E61R-P65R-D84S-C125C-S127N APASSSTKKTQLQLEALLLDLQMILNGINNYKNPKLTRMLTFKFYMPKKATELKHLQCLERELKRLEEVLNLAQSKNFHLRPRSLISNINVIVLELKGSETTFMCEYADETATIVEFLNRWITFSQNIISTLT
269 IL-2-T3A-H16A-E61R-P65R-D84S-C125C-S130P APASSSTKKTQLQLEALLLDLQMILNGINNYKNPKLTRMLTFKFYMPKKATELKHLQCLERELKRLEEVLNLAQSKNFHLRPRSLISNINVIVLELKGSETTFMCEYADETATIVEFLNRWITFSQSIIPTLT
270 IL-2-T3A-H16A-E61R-P65R-D84Y-C125S APASSSTKKTQLQLEALLLDLQMILNGINNYKNPKLTRMLTFKFYMPKKATELKHLQCLERELKRLEEVLNLAQSKNFHLRPRYLISNINVIVLELKGSETTFMCEYADETATIVEFLNRWITFSQSIISTLT
271 IL-2-T3A-H16A-M23T-E61R-P65R-D84Y-E95Q-C125S APASSSTKKTQLQLEALLLDLQTILNGINNYKNPKLTRMLTFKFYMPKKATELKHLQCLERELKRLEEVLNLAQSKNFHLRPRYLISNINVIVLQLKGSETTFMCEYADETATIVEFLNRWITFSQSIISTLT
272 IL-2-T3A-H16A-L19N-E61R-P65R-D84Y-C125S APASSSTKKTQLQLEALLNDLQMILNGINNYKNPKLTRMLTFKFYMPKKATELKHLQCLERELKRLEEVLNLAQSKNFHLRPRYLISNINVIVLELKGSETTFMCEYADETATIVEFLNRWITFSQSIISTLT
273 IL-2-T3A-H16A-L19N-M23T-E61R-P65R-D84Y-E95Q-C125S APASSSTKKTQLQLEALLNDLQTILNGINNYKNPKLTRMLTFKFYMPKKATELKHLQCLERELKRLEEVLNLAQSKNFHLRPRYLISNINVIVLQLKGSETTFMCEYADETATIVEFLNRWITFSQSIISTLT
274 IL-2-T3A-H16A-E61R-P65R-D84Y-C125S-S127D APASSSTKKTQLQLEALLLDLQMILNGINNYKNPKLTRMLTFKFYMPKKATELKHLQCLERELKRLEEVLNLAQSKNFHLRPRYLISNINVIVLELKGSETTFMCEYADETATIVEFLNRWITFSQDIISTLT
275 IL-2-T3A-H16A-M23T-E61R-P65R-D84Y-E95Q-C125S-S127D APASSSTKKTQLQLEALLLDLQTILNGINNYKNPKLTRMLTFKFYMPKKATELKHLQCLERELKRLEEVLNLAQSKNFHLRPRYLISNINVIVLQLKGSETTFMCEYADETATIVEFLNRWITFSQDIISTLT
276 IL-2-T3A-H16A-L19N-E61R-P65R-D84Y-C125S-S127D APASSSTKKTQLQLEALLNDLQMILNGINNYKNPKLTRMLTFKFYMPKKATELKHLQCLERELKRLEEVLNLAQSKNFHLRPRYLISNINVIVLELKGSETTFMCEYADETATIVEFLNRWITFSQDIISTLT
277 IL-2-T3A-H16A-L19N-M23T-E61R-P65R-D84Y-E95Q-C125S-S127D APASSSTKKTQLQLEALLNDLQTILNGINNYKNPKLTRMLTFKFYMPKKATELKHLQCLERELKRLEEVLNLAQSKNFHLRPRYLISNINVIVLQLKGSETTFMCEYADETATIVEFLNRWITFSQDIISTLT
278 IL-2-T3A-H16A-∆F42-P65R-D84S-C125S APASSSTKKTQLQLEALLLDLQMILNGINNYKNPKLTRMLT-KFYMPKKATELKHLQCLEEELKRLEEVLNLAQSKNFHLRPRSLISNINVIVLELKGSETTFMCEYADETATIVEFLNRWITFSQSIISTLT
279 IL-2-T3A-H16A-K43E-Y45R-P65R-D84S-C125S APASSSTKKTQLQLEALLLDLQMILNGINNYKNPKLTRMLTFEFRMPKKATELKHLQCLEEELKRLEEVLNLAQSKNFHLRPRSLISNINVIVLELKGSETTFMCEYADETATIVEFLNRWITFSQSIISTLT
280 IL-2-T3A-H16A-K43E-P65R-D84S-C125S APASSSTKKTQLQLEALLLDLQMILNGINNYKNPKLTRMLTFEFYMPKKATELKHLQCLEEELKRLEEVLNLAQSKNFHLRPRSLISNINVIVLELKGSETTFMCEYADETATIVEFLNRWITFSQSIISTLT
281 IL-2-T3A-H16A-P65R-D84S-I114F-C125S APASSSTKKTQLQLEALLLDLQMILNGINNYKNPKLTRMLTFKFYMPKKATELKHLQCLEEELKRLEEVLNLAQSKNFHLRPRSLISNINVIVLELKGSETTFMCEYADETATFVEFLNRWITFSQSIISTLT
282 IL-2-T3A-H16A-F42R-P65R-D84S-C125S APASSSTKKTQLQLEALLLDLQMILNGINNYKNPKLTRMLTRKFYMPKKATELKHLQCLEEELKRLEEVLNLAQSKNFHLRPRSLISNINVIVLELKGSETTFMCEYADETATIVEFLNRWITFSQSIISTLT
283 IL-2-T3A-K43E-Y45R-C125S APASSSTKKTQLQLEHLLLDLQMILNGINNYKNPKLTRMLTFEFRMPKKATELKHLQCLEEELKPLEEVLNLAQSKNFHLRPRDLISNINVIVLELKGSETTFMCEYADETATIVEFLNRWITFSQSIISTLT
284 IL-2-T3A-E61R-C125S APASSSTKKTQLQLEHLLLDLQMILNGINNYKNPKLTRMLTFKFYMPKKATELKHLQCLERELKPLEEVLNLAQSKNFHLRPRDLISNINVIVLELKGSETTFMCEYADETATIVEFLNRWITFSQSIISTLT
285 IL-2-T3A-I114F-C125S APASSSTKKTQLQLEHLLLDLQMILNGINNYKNPKLTRMLTFKFYMPKKATELKHLQCLEEELKPLEEVLNLAQSKNFHLRPRDLISNINVIVLELKGSETTFMCEYADETATFVEFLNRWITFSQSIISTLT
286 IL-2-T3A-K43E-C125S APASSSTKKTQLQLEHLLLDLQMILNGINNYKNPKLTRMLTFEFYMPKKATELKHLQCLEEELKPLEEVLNLAQSKNFHLRPRDLISNINVIVLELKGSETTFMCEYADETATIVEFLNRWITFSQSIISTLT
287 IL-2-T3A-P65R-I114F-C125S APASSSTKKTQLQLEHLLLDLQMILNGINNYKNPKLTRMLTFKFYMPKKATELKHLQCLEEELKRLEEVLNLAQSKNFHLRPRDLISNINVIVLELKGSETTFMCEYADETATFVEFLNRWITFSQSIISTLT
288 IL-2-T3A-K43E-P65R-C125S APASSSTKKTQLQLEHLLLDLQMILNGINNYKNPKLTRMLTFEFYMPKKATELKHLQCLEEELKRLEEVLNLAQSKNFHLRPRDLISNINVIVLELKGSETTFMCEYADETATIVEFLNRWITFSQSIISTLT
289 IL-2-T3A-K43E-Y45R-P65R-C125S APASSSTKKTQLQLEHLLLDLQMILNGINNYKNPKLTRMLTFEFRMPKKATELKHLQCLEEELKRLEEVLNLAQSKNFHLRPRDLISNINVIVLELKGSETTFMCEYADETATIVEFLNRWITFSQSIISTLT
290 IL-2-T3A-R38A-C125S APASSSTKKTQLQLEHLLLDLQMILNGINNYKNPKLTAMLTFKFYMPKKATELKHLQCLEEELKPLEEVLNLAQSKNFHLRPRDLISNINVIVLELKGSETTFMCEYADETATIVEFLNRWITFSQSIISTLT
291 IL-15 WT MNWVNVISDLKKIEDLIQSMHIDATLYTESDVHPSCKVTAMKCFLLELQVISLESGDASIHDTVENLIILANNSLSSNGNVTESGCKECEELEEKNIKEFLQSFVHIVQMFINTS
292 Fc區xELL P329G杵 DKTHTCPPCPAPGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKAL GAPIEKTISKAKGQPREPQVYTLPPCRDELTKNQVSLWCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPG   
293 Fc區xELL P329G, H435R臼 DKTHTCPPCPAPGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKAL GAPIEKTISKAKGQPREPQVCTLPPSRDELTKNQVSLSCAVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLVSKLTVDKSRWQQGNVFSCSVMHEALHNRYTQKSLSLSPG   
294 xELL-杵Fc - IL-2-RAS-T3G, C125S DKTHTCPPCPAPGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPCRDELTKNQVSLWCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGGSGGSAPGSSSTKKTQLQLEALLLDLQMILNGINNYKNPKLTRMLTFKFYMPKKATELKHLQCLEEELKRLEEVLNLAQSKNFHLRPRSLISNINVIVLELKGSETTFMCEYADETATIVEFLNRWITFSQSIISTLT
295 γδTCR 5C8 VHH-xELL-臼T366S, L368A, Y407V, H435R Fc EVQLVESGGGLVQAGGSLRLSCAASGRPFSNYAMGWFRQAPGKEREFVAAISWSGGSTSYADSVKGRFTISRDNAKNTVYLQMNSPKPEDTAIYYCAAQFSGADYGFGRLGIRGYEYDYWGQGTQVTVKPGGGGDKTHTCPPCPAPGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVCTLPPSRDELTKNQVSLSCAVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLVSKLTVDKSRWQQGNVFSCSVMHEALHNRYTQKSLSLSPGK
296 γδTCR 5C8 VHH-xELL-杵Fc-IL-2-T3A-H16A- E61R-P65R-D84Y-C125S EVQLVESGGGLVQAGGSLRLSCAASGRPFSNYAMGWFRQAPGKEREFVAAISWSGGSTSYADSVKGRFTISRDNAKNTVYLQMNSPKPEDTAIYYCAAQFSGADYGFGRLGIRGYEYDYWGQGTQVTVKPGGGGDKTHTCPPCPAPGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPCRDELTKNQVSLWCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGGSGGSAPASSSTKKTQLQLEALLLDLQMILNGINNYKNPKLTRMLTFKFYMPKKATELKHLQCLERELKRLEEVLNLAQSKNFHLRPRYLISNINVIVLELKGSETTFMCEYADETATIVEFLNRWITFSQSIISTLT
298 γδTCR 6C4 VHH-xELL-杵Fc-IL-2- T3A-H16A- E61R-P65R-D84Y-C125S EVQLVESGGGLVQAGGSLRLSCAVSVRTFSDYRMGWFRQAPGKEREFVSTISWSGGLTYYADSVKGRFTISRDNSKNTLYLQMNSLKPEDTAVYYCAAGGGYAGGTYYHPEEWGQGTQVTVKPGGGGDKTHTCPPCPAPGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPCRDELTKNQVSLWCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGGSGGSAPASSSTKKTQLQLEALLLDLQMILNGINNYKNPKLTRMLTFKFYMPKKATELKHLQCLERELKRLEEVLNLAQSKNFHLRPRYLISNINVIVLELKGSETTFMCEYADETATIVEFLNRWITFSQSIISTLT
299 γδTCR 6C4 VHH-xELL-臼T366S, L368A, Y407V H435R Fc EVQLVESGGGLVQAGGSLRLSCAVSVRTFSDYRMGWFRQAPGKEREFVSTISWSGGLTYYADSVKGRFTISRDNSKNTLYLQMNSLKPEDTAVYYCAAGGGYAGGTYYHPEEWGQGTQVTVKPGGGGDKTHTCPPCPAPGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVCTLPPSRDELTKNQVSLSCAVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLVSKLTVDKSRWQQGNVFSCSVMHEALHNRYTQKSLSLSPGK
300 非靶向VHH-xELL-臼T366S, L368A, Y407V H435R Fc EVQLVESGGGEVQPGGSLRLSCAASGSINSINVMEWYRQAPGKERDLVAGITSDGDTNYAESVKGRFTISRDNAKNTLYLQMSSLRAEDTAVYYCRARDWGSLTDYWGQGTLVTVKPGGGGDKTHTCPPCPAPGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVCTLPPSRDELTKNQVSLSCAVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLVSKLTVDKSRWQQGNVFSCSVMHEALHNRYTQKSLSLSPGK
301 非靶向VHH- xELL-杵Fc- IL-2-T3A-H16A- E61R-P65R-D84Y-C125S EVQLVESGGGEVQPGGSLRLSCAASGSINSINVMEWYRQAPGKERDLVAGITSDGDTNYAESVKGRFTISRDNAKNTLYLQMSSLRAEDTAVYYCRARDWGSLTDYWGQGTLVTVKPGGGGDKTHTCPPCPAPGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPCRDELTKNQVSLWCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGGSGGSAPASSSTKKTQLQLEALLLDLQMILNGINNYKNPKLTRMLTFKFYMPKKATELKHLQCLERELKRLEEVLNLAQSKNFHLRPRYLISNINVIVLELKGSETTFMCEYADETATIVEFLNRWITFSQSIISTLT
在含有方框或加下劃線的序列中，個別字母周圍的方框指示相對於對應野生型或親本序列之胺基酸取代；字母組周圍之方框指示連接子序列。加下劃線的字母為連接子序列。不含有方框或加下劃線的序列亦可含有胺基酸取代及/或連接子序列。
圖1A至圖1H展示各種IL-2融合蛋白型式的示意圖。圖1A展示連接至雜二聚體臼包杵IgG1 Fc之N端的IL-2。圖1B展示連接至單域抗體之雜二聚體IgG1 Fc之C端的IL-2。圖1C至圖1E展示連接至一個VHH (圖1E)、兩個相同VHH (圖1C)或兩個不同VHH (圖1D)的IL-2。圖1F展示連接至習知抗體之均二聚體重鏈恆定區之C端的IL-2。圖1G展示連接至習知抗體之雜二聚體重鏈恆定區之C端的IL-2。圖1H展示與雜二聚體scFv抗體之C端融合的IL-2。
圖2A至圖2C展示包含野生型IL-2 (圖2A)或如圖1A中所示與雜二聚體Fc之N端融合之經修飾IL-2 (圖2A至圖2C)的IL-2融合蛋白與經IL-2受體(CD25、CD122及CD132)之各種組合短暫轉染的293F細胞之結合，如藉由流式細胞測量術所量測。「UT 293F」指示未經轉染之293F細胞。
圖3A至圖3B展示包含野生型IL-2或如圖1A中所示與雜二聚體Fc之N端融合之經修飾IL-2的融合蛋白與經CD25及CD122短暫轉染的293F細胞之結合，如藉由流式細胞測量術所量測。
圖4A至圖4B展示包含野生型IL-2或如圖1A中所示與雜二聚體Fc之N端融合之經修飾IL-2的融合蛋白與經CD122及CD132；或CD25、CD122及CD132短暫轉染的293F細胞之結合，如藉由流式細胞測量術所量測。
圖5A至圖5B展示包含如圖1B中所示與連接至雜二聚體Fc之非靶向VHH之C端融合的野生型IL-2或經修飾IL-2之融合蛋白與靜息及活化CD4+ T細胞的結合，如藉由流式細胞測量術所量測。「同型對照」指示不包含IL-2之對照蛋白。
圖6A至圖6B展示包含如圖1B中所示與連接至雜二聚體Fc之非靶向VHH之C端融合的野生型IL-2或經修飾IL-2之融合蛋白與經增濃調節性T細胞(Treg，圖6A)、經誘導調節性T細胞(經誘導Treg，圖6B)及經增濃反應CD4+ T細胞(Tresp，圖6C)的結合，如藉由流式細胞測量術所量測。
圖7A至圖7D展示包含如圖1B中所示與連接至雜二聚體Fc之非靶向VHH之C端融合的野生型IL-2或經修飾IL-2之融合蛋白在靜息CD4+及CD8+ T細胞上的活性。量測增殖(圖7A及圖7C)及CD71含量(圖7B及圖7D)。圖7E至圖7F展示如圖1B中所示與連接至雜二聚體Fc之非靶向VHH之C端融合的野生型IL-2或經修飾IL-2在靜息CD4+及CD8+ T細胞上的活性，如藉由胞內磷酸化STAT5含量之流式細胞測量術偵測所量測。「同型」指示不包含IL-2之對照蛋白。
圖8A至圖8B展示作為在用包含如圖1B中所示與連接至雜二聚體Fc之非靶向VHH之C端融合的野生型IL-2或經修飾IL-2之融合蛋白處理7天後，經增濃Treg之活化之標記物的增殖及CD25含量。
圖9A至圖9D展示派立珠單抗、派立珠單抗類似物連同如圖1F中所示與重鏈C端融合之IL-2-RAS及單獨的IL-2-RAS (圖9C及圖9D)在CD8+及CD4+ T細胞上的活性及結合。藉由CellTrace™ Violet之流式細胞測量術偵測量測在CD8+ (圖9A)及CD4+ (圖9B) T細胞上之活性。藉由流式細胞測量術量測與CD8+ T細胞(圖9C)及CD4+ T細胞(圖9D)之結合程度。
圖10A至圖10D展示CD8+及CD4+ T細胞增殖之誘導對IL-2的依賴性。展示在未經預阻斷(圖10A及圖10B)或用飽和濃度之派立珠單抗(圖10C及圖10D)預阻斷的情況下，派立珠單抗、非靶向IL-2-RAS及派立珠單抗類似物連同如圖1F中所示與重鏈C端融合之IL-2-RAS對CD8+ (圖10A及圖10C)或CD4+ (圖10B及圖10D) T細胞增殖的影響。
圖11展示藉由派立珠單抗類似物連同如圖1F中所示與重鏈C端融合之IL-2-RAS，以及如圖1B中所示與非靶向VHH之C端融合的IL-2-RAS及如圖1B中所示與非靶向VHH之C端融合之野生型IL-2對CD4+ T反應(Tresp)細胞增殖的恢復。藉由CD3接合(Tresp+珠粒)誘導Tresp增殖，隨後使用自體調節性T細胞(Treg)抑制。「Tresp+珠粒」線展示在不存在Treg細胞之情況下使用CD3接合的基線Tresp細胞增殖。「無Ab」線展示在Treg細胞之存在下使用CD3接合的基線Tresp細胞增殖。
圖12A至圖12B展示藉由如圖1B中所示與非靶向VHH之C端融合的培養盤結合之非靶向野生型IL-2 (「IL-2 WT」)或IL-2-RAS對T細胞的反式激活(trans-activation)。藉由胞內磷酸化STAT5含量之流式細胞測量術偵測量測T細胞活化。展示CD8+ T細胞(圖12A)及CD4+ T細胞(圖12B)反應。
圖13A至圖13I展示如圖1H中所示與靶向NKp46之雜二聚體scFv抗體之C端融合的IL-2-RAS、單獨的靶向NKp46之雜二聚體scFv抗體以及包含如圖1B中所示與連接至雜二聚體Fc之非靶向VHH之C端融合的野生型IL-2或IL-2-RAS之融合蛋白對NK細胞、CD8+ T細胞及CD4+ T細胞之活性及結合。藉由流式細胞測量術量測NK細胞(圖13A)、CD8+ T細胞(圖13B)及CD4+ T細胞(圖13C)的增殖以及NK細胞(圖13D)、CD8+ T細胞(圖13E)及CD4+ T細胞(圖13F)的pSTAT含量。亦藉由流式細胞測量術量測所指示多肽與NK細胞(圖13G)、CD8+ T細胞(圖13H)及CD4+ T細胞(圖13I)的結合。
圖14A至圖14H展示如圖1G中所示與抗LAG3雜二聚體習知抗體(MAb)之C端融合的IL-2-RAS、如圖1B中所示與具有雜二聚體Fc之抗LAG3 VHH之C端融合的IL-2-RAS、如圖1B中所示與非靶向VHH之C端融合的IL-2-RAS、如圖1B中所示與非靶向雜二聚體Fc之C端融合的野生型IL-2或不具有IL-2之LAG3靶向MAb或LAG3靶向VHH-Fc分子在CD8+或CD4+ T細胞上的活性及結合。藉由流式細胞測量術量測CD8+ T細胞(圖14A)及CD4+ T細胞(圖14B)之增殖以及活化標記物CD25 (圖14C及圖14D)及CD71 (圖14E及圖14F)於CD8+ T細胞(圖14C及圖14E)及CD4+ T細胞(圖14D及圖14F)上之表現。圖14G及圖14H展示與經預活化之CD8+ T細胞(圖14G)及CD4+ T細胞(圖14H)之結合。
圖15展示包含如圖1B中所示與具有雜二聚體Fc之VHH的C端融合之所指示之經修飾IL-2的融合蛋白在HEK-Blue IL-2報導細胞上之活性，該等HEK-Blue IL-2報導細胞不表現VHH之目標抗原且因此僅依賴於經修飾IL-2與過度表現之IL-2受體的結合以誘導報導基因。量測報導細胞中回應於IL-2受體介導之pSTAT5信號傳導誘導而表現的分泌性胚胎鹼性磷酸酶之活性。
圖16A至圖16B展示包含所指示之經修飾IL-2的多肽在不表現PD-1之HEK-Blue IL-2報導細胞(圖16A)上及在表現PD-1之IL-2報導細胞(圖16B)上的活性。如圖16A至圖16B中所使用之「RAS」意謂IL-2突變T3A、P65R、H16A、D84S及C125S。
圖17A至圖17C展示在存在及不存在CD25阻斷抗體之情況下，包含所指示之經修飾IL-2的多肽在不表現PD-1之HEK-Blue IL-2報導細胞上的活性。如圖17A至圖17C中所使用之「RAS」意謂IL-2突變T3A、P65R、H16A、D84S及C125S。
圖18A至圖18B展示包含所指示之經修飾IL-2的多肽在不表現PD-1之HEK-Blue IL-2報導細胞(圖18A)上及在表現PD-1之IL-2報導細胞(圖18B)上的活性。如圖18A至圖18B中所使用之「RAS」意謂IL-2突變T3A、P65R、H16A、D84S及C125S。如圖18B中所使用之「INBRX-108」意謂包含SEQ ID NO: 28之胺基酸序列的經修飾IL-2。
圖19A至圖19E展示包含所指示之經修飾IL-2的多肽在如所指示表現PD-1或不表現PD-1之IL-2報導細胞上之活性。如圖19A至圖19E中所使用之「NT_突變體」意謂多肽包含圖標題(panel title)中所列之IL-2突變且在不表現PD-1之細胞上進行測試。如圖19A至圖19E中所使用之「PD1_突變體」意謂多肽包含圖標題中所列之IL-2突變且在確實表現PD-1之細胞上進行測試。如圖19A至圖19E中所使用之「RAS」意謂IL-2突變T3A、P65R、H16A、D84S及C125S。如圖19A至圖19E中所使用之「NT_INBRX-108」意謂多肽包含含有SEQ ID NO: 28之胺基酸序列的經修飾IL-2且在不表現PD-1之細胞上進行測試。如圖19A至圖19E中所使用之「PD1_INBRX-108」意謂多肽包含含有SEQ ID NO: 28之胺基酸序列的經修飾IL-2且在確實表現PD-1之細胞上進行測試。亦在實例19及表7中描述包括IL-2突變之多肽。
圖20A至圖20E展示包含所指示之經修飾IL-2的多肽在如所指示表現PD-1或不表現PD-1之IL-2報導細胞上之活性。如圖20A至圖20E中所使用之「NT_突變體」意謂多肽包含圖標題中所列之IL-2突變且在不表現PD-1之細胞上進行測試。如圖20A至圖20E中所使用之「PD1_突變體」意謂多肽包含圖標題中所列之IL-2突變且在確實表現PD-1之細胞上進行測試。如圖20A至圖20E中所使用之「RAS」意謂IL-2突變T3A、P65R、H16A、D84S及C125S。如圖20A至圖20E中所使用之「NT_INBRX-108」意謂多肽包含含有SEQ ID NO: 28之胺基酸序列的經修飾IL-2且在不表現PD-1之細胞上進行測試。如圖20A至圖20E中所使用之「PD1_INBRX-108」意謂多肽包含含有SEQ ID NO: 28之胺基酸序列的經修飾IL-2且在確實表現PD-1之細胞上進行測試。亦在實例20及表8中描述包括IL-2突變之多肽。
圖21A至圖21D展示包含所指示之經修飾IL-2的多肽在如所指示表現PD-1或不表現PD-1之IL-2報導細胞上之活性。如圖21A至圖21D中所使用之「NT_突變體」意謂多肽包含圖標題中所列之IL-2突變且在不表現PD-1之細胞上進行測試。如圖21A至圖21D中所使用之「PD1_突變體」意謂多肽包含圖標題中所列之IL-2突變且在確實表現PD-1之細胞上進行測試。如圖21A至圖21D中所使用之「RAS」意謂IL-2突變T3A、P65R、H16A、D84S及C125S。如圖21A至圖21D中所使用之「NT_INBRX-108」意謂多肽包含含有SEQ ID NO: 28之胺基酸序列的經修飾IL-2且在不表現PD-1之細胞上進行測試。如圖21A至圖21D中所使用之「PD1_INBRX-108」意謂多肽包含含有SEQ ID NO: 28之胺基酸序列的經修飾IL-2且在確實表現PD-1之細胞上進行測試。亦在實例21及表9中描述包括IL-2突變之多肽。
圖22A至圖22B展示包含所指示之經修飾IL-2的多肽在不表現PD-1之HEK-Blue IL-2報導細胞(圖22A)上及在表現PD-1之IL-2報導細胞(圖22B)上的活性。如圖22A至圖22B中所使用之「RAS」意謂IL-2突變T3A、P65R、H16A、D84S及C125S。另外，所有所指示之經修飾IL-2突變包括T3A及C125S以及所列突變。
圖23A至圖23B展示包含所指示之經修飾IL-2的多肽在不表現PD-1之HEK-Blue IL-2報導細胞(圖23A)上及在表現PD-1之IL-2報導細胞(圖23B)上的活性。如圖23A至圖23B中所使用之「RAS」意謂IL-2突變T3A、P65R、H16A、D84S及C125S。
圖24A至圖24B展示包含含有所指示突變之經修飾IL-2的所指示多肽在不表現CD8a之HEK-Blue IL-2報導細胞(圖24A)上及確實表現CD8a之IL-2報導細胞(圖24B)上的活性。如圖24A至圖24B中所使用之「RAS」意謂IL-2突變T3A、P65R、H16A、D84S及C125S。如圖24A至圖24B中所使用之「RAY」意謂IL-2突變T3A、P65R、H16A、D84Y及C125S。
圖25A至圖25C展示包含所指示之經修飾或野生型IL-2的所指示多肽在HEK-Blue IL-2報導細胞(圖25A)上、在表現NKp46之IL-2報導細胞(圖25B)上及在表現CD8a之IL-2報導細胞(圖25C)上的活性。如圖25A至圖25C中所使用之「OprIxIL-2-WT tgcs」意謂包含不結合IL-2報導細胞上之目標的OprI結合域，及包含T3G及C125S突變之IL-2的多肽。
圖26A至圖26E展示包含IL-2突變體之各種多肽之活性的分析。圖26A展示各種IL-2突變體之非靶向活性。圖26B至圖24C為對PD-1 (圖26B)或NKp46 (圖26C)之靶向EC 50相對於非靶向EC 50的圖。圖26D圖至26E展示PD-1 (圖26D)及NKp46 (圖26E)靶向窗口，其展示達成靶向活性同時避免非靶向IL-2活性之濃度範圍。
圖27A至圖27H展示在用包含與具有雜二聚體Fc之γδTCR結合VHH之C端融合的經修飾IL-2之融合蛋白處理PBMC之後的pSTAT5含量，其中γδTCR結合域為單價或二價，如所指示。圖27A、27C、27E及27G展示在用所指示多肽處理之後，γδT細胞、NK細胞及αβT細胞上之胞內pSTAT5染色的中值螢光強度。圖27B、27D、27F及27H展示在用所指示多肽處理後，具有pSTAT5染色之γδT細胞、NK細胞及αβT細胞的百分比。
圖28A至圖28D展示在用包含與具有雜二聚體Fc之γδTCR結合VHH之C端融合的經修飾IL-2之融合蛋白處理PBMC後的γδT細胞增殖(圖28A)、γδT細胞積聚(圖28B)、αβT細胞增殖(圖28C)及αβT細胞積聚(圖28D)。
圖29A至圖29B展示在用野生型IL-2及包含經修飾IL-2之非靶向多肽處理PBMC後的pSTAT5含量。圖29A展示在CD56bringht CD16-NK細胞上具有pSTAT5染色之細胞的百分比。
 

          <![CDATA[<110>  美商英伊布里克斯公司(INHIBRX, INC.)]]>
          <![CDATA[<120>  包含經修飾IL-2多肽之多肽及其用途]]>
          <![CDATA[<130>  01202-0040-00PCT]]>
          <![CDATA[<150>  US 63/047,681]]>
          <![CDATA[<151>  2020-07-02]]>
          <![CDATA[<160>  301   ]]>
          <![CDATA[<170>  PatentIn version 3.5]]>
          <![CDATA[<210>  1]]>
          <![CDATA[<211>  133]]>
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          <![CDATA[<213>  智人]]>
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          <![CDATA[<221>  SITE]]>
          <![CDATA[<222>  (1)..(133)]]>
          <![CDATA[<223>  野生型人類IL-2]]>
          <![CDATA[<400>  1]]>
          Ala Pro Thr Ser Ser Ser Thr Lys Lys Thr Gln Leu Gln Leu Glu His 
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          Leu Leu Leu Asp Leu Gln Met Ile Leu Asn Gly Ile Asn Asn Tyr Lys 
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          Asn Pro Lys Leu Thr Arg Met Leu Thr Phe Lys Phe Tyr Met Pro Lys 
                  35                  40                  45              
          Lys Ala Thr Glu Leu Lys His Leu Gln Cys Leu Glu Glu Glu Leu Lys 
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          Pro Leu Glu Glu Val Leu Asn Leu Ala Gln Ser Lys Asn Phe His Leu 
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          Arg Pro Arg Asp Leu Ile Ser Asn Ile Asn Val Ile Val Leu Glu Leu 
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          Lys Gly Ser Glu Thr Thr Phe Met Cys Glu Tyr Ala Asp Glu Thr Ala 
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          Ile Ser Thr Leu Thr 
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          Ala Pro Ala Ser Ser Ser Thr Lys Lys Thr Gln Leu Gln Leu Glu His 
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          Asn Pro Lys Leu Thr Arg Met Leu Thr Ala Lys Phe Ala Met Pro Lys 
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          Pro Leu Glu Glu Val Leu Asn Gly Ala Gln Ser Lys Asn Phe His Leu 
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          Lys Gly Ser Glu Thr Thr Phe Met Cys Glu Tyr Ala Asp Glu Thr Ala 
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          Asn Pro Lys Leu Thr Arg Met Leu Thr Phe Lys Phe Tyr Met Pro Lys 
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          Lys Ala Thr Glu Leu Lys His Leu Gln Cys Leu Glu Glu Glu Leu Lys 
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          Arg Leu Glu Glu Val Leu Asn Leu Ala Gln Ser Lys Asn Phe His Leu 
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          Arg Pro Arg Asp Leu Ile Ser Asn Ile Asn Val Ile Val Leu Glu Leu 
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          Lys Gly Ser Glu Thr Thr Phe Met Cys Glu Tyr Ala Asp Glu Thr Ala 
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          Ile Ser Thr Leu Thr 
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          Ala Pro Thr Ser Ser Ser Thr Lys Lys Thr Gln Leu Gln Leu Glu Ala 
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                      20                  25                  30          
          Asn Pro Lys Leu Thr Arg Met Leu Thr Phe Lys Phe Tyr Met Pro Lys 
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          Lys Ala Thr Glu Leu Lys His Leu Gln Cys Leu Glu Glu Glu Leu Lys 
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          Pro Leu Glu Glu Val Leu Asn Leu Ala Gln Ser Lys Asn Phe His Leu 
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          Lys Gly Ser Glu Thr Thr Phe Met Cys Glu Tyr Ala Asp Glu Thr Ala 
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                      20                  25                  30          
          Asn Pro Lys Leu Thr Arg Met Leu Thr Phe Lys Phe Tyr Met Pro Lys 
                  35                  40                  45              
          Lys Ala Thr Glu Leu Lys His Leu Gln Cys Leu Glu Glu Glu Leu Lys 
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          Pro Leu Glu Glu Val Leu Asn Leu Ala Gln Ser Lys Asn Phe His Leu 
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                          85                  90                  95      
          Lys Gly Ser Glu Thr Thr Phe Met Cys Glu Tyr Ala Asp Glu Thr Ala 
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          Ile Ser Thr Leu Thr 
              130             
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                      20                  25                  30          
          Asn Pro Lys Leu Thr Arg Met Leu Thr Phe Lys Phe Tyr Met Pro Lys 
                  35                  40                  45              
          Lys Ala Thr Glu Leu Lys His Leu Gln Cys Leu Glu Glu Glu Leu Lys 
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          Pro Leu Glu Glu Val Leu Asn Leu Ala Gln Ser Lys Asn Phe His Leu 
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          Lys Gly Ser Glu Thr Thr Phe Met Cys Glu Tyr Ala Asp Glu Thr Ala 
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          Thr Ile Val Glu Phe Leu Asn Arg Trp Ile Thr Phe Cys Gln Ser Ile 
                  115                 120                 125             
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                      20                  25                  30          
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          Lys Gly Ser Glu Thr Thr Phe Met Cys Glu Tyr Ala Asp Glu Thr Ala 
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          Ile Ser Thr Leu Thr 
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                      20                  25                  30          
          Asn Pro Lys Leu Thr Arg Met Leu Thr Phe Lys Phe Tyr Met Pro Lys 
                  35                  40                  45              
          Lys Ala Thr Glu Leu Lys His Leu Gln Cys Leu Glu Glu Glu Leu Lys 
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          Pro Leu Glu Glu Val Leu Asn Leu Ala Gln Ser Lys Asn Phe His Leu 
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                          85                  90                  95      
          Lys Gly Ser Glu Thr Thr Phe Met Cys Glu Tyr Ala Asp Glu Thr Ala 
                      100                 105                 110         
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                  115                 120                 125             
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          <![CDATA[<210>  9]]>
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          <![CDATA[<400>  9]]>
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          Leu Leu Leu Asp Leu Gln Met Ile Leu Asn Gly Ile Asn Asn Tyr Lys 
                      20                  25                  30          
          Asn Pro Lys Leu Thr Arg Met Leu Thr Phe Lys Phe Tyr Met Pro Lys 
                  35                  40                  45              
          Lys Ala Thr Glu Leu Lys His Leu Gln Cys Leu Glu Glu Glu Leu Lys 
              50                  55                  60                  
          Glu Leu Glu Glu Val Leu Asn Leu Ala Gln Ser Lys Asn Phe His Leu 
          65                  70                  75                  80  
          Arg Pro Arg Asp Leu Ile Ser Asn Ile Asn Val Ile Val Leu Glu Leu 
                          85                  90                  95      
          Lys Gly Ser Glu Thr Thr Phe Met Cys Glu Tyr Ala Asp Glu Thr Ala 
                      100                 105                 110         
          Thr Ile Val Glu Phe Leu Asn Arg Trp Ile Thr Phe Cys Gln Ser Ile 
                  115                 120                 125             
          Ile Ser Thr Leu Thr 
              130             
          <![CDATA[<210>  10]]>
          <![CDATA[<211>  133]]>
          <![CDATA[<212>  PRT]]>
          <![CDATA[<213>  人工序列]]>
          <![CDATA[<220>]]>
          <![CDATA[<223>  合成：IL-2-F42K]]>
          <![CDATA[<400>  10]]>
          Ala Pro Thr Ser Ser Ser Thr Lys Lys Thr Gln Leu Gln Leu Glu His 
          1               5                   10                  15      
          Leu Leu Leu Asp Leu Gln Met Ile Leu Asn Gly Ile Asn Asn Tyr Lys 
                      20                  25                  30          
          Asn Pro Lys Leu Thr Arg Met Leu Thr Lys Lys Phe Tyr Met Pro Lys 
                  35                  40                  45              
          Lys Ala Thr Glu Leu Lys His Leu Gln Cys Leu Glu Glu Glu Leu Lys 
              50                  55                  60                  
          Pro Leu Glu Glu Val Leu Asn Leu Ala Gln Ser Lys Asn Phe His Leu 
          65                  70                  75                  80  
          Arg Pro Arg Asp Leu Ile Ser Asn Ile Asn Val Ile Val Leu Glu Leu 
                          85                  90                  95      
          Lys Gly Ser Glu Thr Thr Phe Met Cys Glu Tyr Ala Asp Glu Thr Ala 
                      100                 105                 110         
          Thr Ile Val Glu Phe Leu Asn Arg Trp Ile Thr Phe Cys Gln Ser Ile 
                  115                 120                 125             
          Ile Ser Thr Leu Thr 
              130             
          <![CDATA[<210>  11]]>
          <![CDATA[<211>  133]]>
          <![CDATA[<212>  PRT]]>
          <![CDATA[<213>  人工序列]]>
          <![CDATA[<220>]]>
          <![CDATA[<223>  合成：IL-2-H16A-F42K]]>
          <![CDATA[<400>  11]]>
          Ala Pro Thr Ser Ser Ser Thr Lys Lys Thr Gln Leu Gln Leu Glu Ala 
          1               5                   10                  15      
          Leu Leu Leu Asp Leu Gln Met Ile Leu Asn Gly Ile Asn Asn Tyr Lys 
                      20                  25                  30          
          Asn Pro Lys Leu Thr Arg Met Leu Thr Lys Lys Phe Tyr Met Pro Lys 
                  35                  40                  45              
          Lys Ala Thr Glu Leu Lys His Leu Gln Cys Leu Glu Glu Glu Leu Lys 
              50                  55                  60                  
          Pro Leu Glu Glu Val Leu Asn Leu Ala Gln Ser Lys Asn Phe His Leu 
          65                  70                  75                  80  
          Arg Pro Arg Asp Leu Ile Ser Asn Ile Asn Val Ile Val Leu Glu Leu 
                          85                  90                  95      
          Lys Gly Ser Glu Thr Thr Phe Met Cys Glu Tyr Ala Asp Glu Thr Ala 
                      100                 105                 110         
          Thr Ile Val Glu Phe Leu Asn Arg Trp Ile Thr Phe Cys Gln Ser Ile 
                  115                 120                 125             
          Ile Ser Thr Leu Thr 
              130             
          <![CDATA[<210>  12]]>
          <![CDATA[<211>  133]]>
          <![CDATA[<212>  PRT]]>
          <![CDATA[<213>  人工序列]]>
          <![CDATA[<220>]]>
          <![CDATA[<223>  合成：IL-2-D84S-F42K]]>
          <![CDATA[<400>  12]]>
          Ala Pro Thr Ser Ser Ser Thr Lys Lys Thr Gln Leu Gln Leu Glu His 
          1               5                   10                  15      
          Leu Leu Leu Asp Leu Gln Met Ile Leu Asn Gly Ile Asn Asn Tyr Lys 
                      20                  25                  30          
          Asn Pro Lys Leu Thr Arg Met Leu Thr Lys Lys Phe Tyr Met Pro Lys 
                  35                  40                  45              
          Lys Ala Thr Glu Leu Lys His Leu Gln Cys Leu Glu Glu Glu Leu Lys 
              50                  55                  60                  
          Pro Leu Glu Glu Val Leu Asn Leu Ala Gln Ser Lys Asn Phe His Leu 
          65                  70                  75                  80  
          Arg Pro Arg Ser Leu Ile Ser Asn Ile Asn Val Ile Val Leu Glu Leu 
                          85                  90                  95      
          Lys Gly Ser Glu Thr Thr Phe Met Cys Glu Tyr Ala Asp Glu Thr Ala 
                      100                 105                 110         
          Thr Ile Val Glu Phe Leu Asn Arg Trp Ile Thr Phe Cys Gln Ser Ile 
                  115                 120                 125             
          Ile Ser Thr Leu Thr 
              130             
          <![CDATA[<210>  13]]>
          <![CDATA[<211>  133]]>
          <![CDATA[<212>  PRT]]>
          <![CDATA[<213>  人工序列]]>
          <![CDATA[<220>]]>
          <![CDATA[<223>  合成：IL-2-E15S-F42K]]>
          <![CDATA[<400>  13]]>
          Ala Pro Thr Ser Ser Ser Thr Lys Lys Thr Gln Leu Gln Leu Ser His 
          1               5                   10                  15      
          Leu Leu Leu Asp Leu Gln Met Ile Leu Asn Gly Ile Asn Asn Tyr Lys 
                      20                  25                  30          
          Asn Pro Lys Leu Thr Arg Met Leu Thr Lys Lys Phe Tyr Met Pro Lys 
                  35                  40                  45              
          Lys Ala Thr Glu Leu Lys His Leu Gln Cys Leu Glu Glu Glu Leu Lys 
              50                  55                  60                  
          Pro Leu Glu Glu Val Leu Asn Leu Ala Gln Ser Lys Asn Phe His Leu 
          65                  70                  75                  80  
          Arg Pro Arg Asp Leu Ile Ser Asn Ile Asn Val Ile Val Leu Glu Leu 
                          85                  90                  95      
          Lys Gly Ser Glu Thr Thr Phe Met Cys Glu Tyr Ala Asp Glu Thr Ala 
                      100                 105                 110         
          Thr Ile Val Glu Phe Leu Asn Arg Trp Ile Thr Phe Cys Gln Ser Ile 
                  115                 120                 125             
          Ile Ser Thr Leu Thr 
              130             
          <![CDATA[<210>  14]]>
          <![CDATA[<211>  133]]>
          <![CDATA[<212>  PRT]]>
          <![CDATA[<213>  人工序列]]>
          <![CDATA[<220>]]>
          <![CDATA[<223>  合成：IL-2-M23A-F42K]]>
          <![CDATA[<400>  14]]>
          Ala Pro Thr Ser Ser Ser Thr Lys Lys Thr Gln Leu Gln Leu Glu His 
          1               5                   10                  15      
          Leu Leu Leu Asp Leu Gln Ala Ile Leu Asn Gly Ile Asn Asn Tyr Lys 
                      20                  25                  30          
          Asn Pro Lys Leu Thr Arg Met Leu Thr Lys Lys Phe Tyr Met Pro Lys 
                  35                  40                  45              
          Lys Ala Thr Glu Leu Lys His Leu Gln Cys Leu Glu Glu Glu Leu Lys 
              50                  55                  60                  
          Pro Leu Glu Glu Val Leu Asn Leu Ala Gln Ser Lys Asn Phe His Leu 
          65                  70                  75                  80  
          Arg Pro Arg Asp Leu Ile Ser Asn Ile Asn Val Ile Val Leu Glu Leu 
                          85                  90                  95      
          Lys Gly Ser Glu Thr Thr Phe Met Cys Glu Tyr Ala Asp Glu Thr Ala 
                      100                 105                 110         
          Thr Ile Val Glu Phe Leu Asn Arg Trp Ile Thr Phe Cys Gln Ser Ile 
                  115                 120                 125             
          Ile Ser Thr Leu Thr 
              130             
          <![CDATA[<210>  15]]>
          <![CDATA[<211>  133]]>
          <![CDATA[<212>  PRT]]>
          <![CDATA[<213>  人工序列]]>
          <![CDATA[<220>]]>
          <![CDATA[<223>  合成：IL-2-E95Q-F42K]]>
          <![CDATA[<400>  15]]>
          Ala Pro Thr Ser Ser Ser Thr Lys Lys Thr Gln Leu Gln Leu Glu His 
          1               5                   10                  15      
          Leu Leu Leu Asp Leu Gln Met Ile Leu Asn Gly Ile Asn Asn Tyr Lys 
                      20                  25                  30          
          Asn Pro Lys Leu Thr Arg Met Leu Thr Lys Lys Phe Tyr Met Pro Lys 
                  35                  40                  45              
          Lys Ala Thr Glu Leu Lys His Leu Gln Cys Leu Glu Glu Glu Leu Lys 
              50                  55                  60                  
          Pro Leu Glu Glu Val Leu Asn Leu Ala Gln Ser Lys Asn Phe His Leu 
          65                  70                  75                  80  
          Arg Pro Arg Asp Leu Ile Ser Asn Ile Asn Val Ile Val Leu Gln Leu 
                          85                  90                  95      
          Lys Gly Ser Glu Thr Thr Phe Met Cys Glu Tyr Ala Asp Glu Thr Ala 
                      100                 105                 110         
          Thr Ile Val Glu Phe Leu Asn Arg Trp Ile Thr Phe Cys Gln Ser Ile 
                  115                 120                 125             
          Ile Ser Thr Leu Thr 
              130             
          <![CDATA[<210>  16]]>
          <![CDATA[<211>  133]]>
          <![CDATA[<212>  PRT]]>
          <![CDATA[<213>  人工序列]]>
          <![CDATA[<220>]]>
          <![CDATA[<223>  合成：IL-2-P65R-H16A]]>
          <![CDATA[<400>  16]]>
          Ala Pro Thr Ser Ser Ser Thr Lys Lys Thr Gln Leu Gln Leu Glu Ala 
          1               5                   10                  15      
          Leu Leu Leu Asp Leu Gln Met Ile Leu Asn Gly Ile Asn Asn Tyr Lys 
                      20                  25                  30          
          Asn Pro Lys Leu Thr Arg Met Leu Thr Phe Lys Phe Tyr Met Pro Lys 
                  35                  40                  45              
          Lys Ala Thr Glu Leu Lys His Leu Gln Cys Leu Glu Glu Glu Leu Lys 
              50                  55                  60                  
          Arg Leu Glu Glu Val Leu Asn Leu Ala Gln Ser Lys Asn Phe His Leu 
          65                  70                  75                  80  
          Arg Pro Arg Asp Leu Ile Ser Asn Ile Asn Val Ile Val Leu Glu Leu 
                          85                  90                  95      
          Lys Gly Ser Glu Thr Thr Phe Met Cys Glu Tyr Ala Asp Glu Thr Ala 
                      100                 105                 110         
          Thr Ile Val Glu Phe Leu Asn Arg Trp Ile Thr Phe Cys Gln Ser Ile 
                  115                 120                 125             
          Ile Ser Thr Leu Thr 
              130             
          <![CDATA[<210>  17]]>
          <![CDATA[<211>  133]]>
          <![CDATA[<212>  PRT]]>
          <![CDATA[<213>  人工序列]]>
          <![CDATA[<220>]]>
          <![CDATA[<223>  合成：IL-2-P65R-D84S]]>
          <![CDATA[<400>  17]]>
          Ala Pro Thr Ser Ser Ser Thr Lys Lys Thr Gln Leu Gln Leu Glu His 
          1               5                   10                  15      
          Leu Leu Leu Asp Leu Gln Met Ile Leu Asn Gly Ile Asn Asn Tyr Lys 
                      20                  25                  30          
          Asn Pro Lys Leu Thr Arg Met Leu Thr Phe Lys Phe Tyr Met Pro Lys 
                  35                  40                  45              
          Lys Ala Thr Glu Leu Lys His Leu Gln Cys Leu Glu Glu Glu Leu Lys 
              50                  55                  60                  
          Arg Leu Glu Glu Val Leu Asn Leu Ala Gln Ser Lys Asn Phe His Leu 
          65                  70                  75                  80  
          Arg Pro Arg Ser Leu Ile Ser Asn Ile Asn Val Ile Val Leu Glu Leu 
                          85                  90                  95      
          Lys Gly Ser Glu Thr Thr Phe Met Cys Glu Tyr Ala Asp Glu Thr Ala 
                      100                 105                 110         
          Thr Ile Val Glu Phe Leu Asn Arg Trp Ile Thr Phe Cys Gln Ser Ile 
                  115                 120                 125             
          Ile Ser Thr Leu Thr 
              130             
          <![CDATA[<210>  18]]>
          <![CDATA[<211>  133]]>
          <![CDATA[<212>  PRT]]>
          <![CDATA[<213>  人工序列]]>
          <![CDATA[<220>]]>
          <![CDATA[<223>  合成：IL-2-P65R-E15S]]>
          <![CDATA[<400>  18]]>
          Ala Pro Thr Ser Ser Ser Thr Lys Lys Thr Gln Leu Gln Leu Ser His 
          1               5                   10                  15      
          Leu Leu Leu Asp Leu Gln Met Ile Leu Asn Gly Ile Asn Asn Tyr Lys 
                      20                  25                  30          
          Asn Pro Lys Leu Thr Arg Met Leu Thr Phe Lys Phe Tyr Met Pro Lys 
                  35                  40                  45              
          Lys Ala Thr Glu Leu Lys His Leu Gln Cys Leu Glu Glu Glu Leu Lys 
              50                  55                  60                  
          Arg Leu Glu Glu Val Leu Asn Leu Ala Gln Ser Lys Asn Phe His Leu 
          65                  70                  75                  80  
          Arg Pro Arg Asp Leu Ile Ser Asn Ile Asn Val Ile Val Leu Glu Leu 
                          85                  90                  95      
          Lys Gly Ser Glu Thr Thr Phe Met Cys Glu Tyr Ala Asp Glu Thr Ala 
                      100                 105                 110         
          Thr Ile Val Glu Phe Leu Asn Arg Trp Ile Thr Phe Cys Gln Ser Ile 
                  115                 120                 125             
          Ile Ser Thr Leu Thr 
              130             
          <![CDATA[<210>  19]]>
          <![CDATA[<211>  133]]>
          <![CDATA[<212>  PRT]]>
          <![CDATA[<213>  人工序列]]>
          <![CDATA[<220>]]>
          <![CDATA[<223>  合成：IL-2-P65R-M23A]]>
          <![CDATA[<400>  19]]>
          Ala Pro Thr Ser Ser Ser Thr Lys Lys Thr Gln Leu Gln Leu Glu His 
          1               5                   10                  15      
          Leu Leu Leu Asp Leu Gln Ala Ile Leu Asn Gly Ile Asn Asn Tyr Lys 
                      20                  25                  30          
          Asn Pro Lys Leu Thr Arg Met Leu Thr Phe Lys Phe Tyr Met Pro Lys 
                  35                  40                  45              
          Lys Ala Thr Glu Leu Lys His Leu Gln Cys Leu Glu Glu Glu Leu Lys 
              50                  55                  60                  
          Arg Leu Glu Glu Val Leu Asn Leu Ala Gln Ser Lys Asn Phe His Leu 
          65                  70                  75                  80  
          Arg Pro Arg Asp Leu Ile Ser Asn Ile Asn Val Ile Val Leu Glu Leu 
                          85                  90                  95      
          Lys Gly Ser Glu Thr Thr Phe Met Cys Glu Tyr Ala Asp Glu Thr Ala 
                      100                 105                 110         
          Thr Ile Val Glu Phe Leu Asn Arg Trp Ile Thr Phe Cys Gln Ser Ile 
                  115                 120                 125             
          Ile Ser Thr Leu Thr 
              130             
          <![CDATA[<210>  20]]>
          <![CDATA[<211>  133]]>
          <![CDATA[<212>  PRT]]>
          <![CDATA[<213>  人工序列]]>
          <![CDATA[<220>]]>
          <![CDATA[<223>  合成：IL-2-P65R-E95Q]]>
          <![CDATA[<400>  20]]>
          Ala Pro Thr Ser Ser Ser Thr Lys Lys Thr Gln Leu Gln Leu Glu His 
          1               5                   10                  15      
          Leu Leu Leu Asp Leu Gln Met Ile Leu Asn Gly Ile Asn Asn Tyr Lys 
                      20                  25                  30          
          Asn Pro Lys Leu Thr Arg Met Leu Thr Phe Lys Phe Tyr Met Pro Lys 
                  35                  40                  45              
          Lys Ala Thr Glu Leu Lys His Leu Gln Cys Leu Glu Glu Glu Leu Lys 
              50                  55                  60                  
          Arg Leu Glu Glu Val Leu Asn Leu Ala Gln Ser Lys Asn Phe His Leu 
          65                  70                  75                  80  
          Arg Pro Arg Asp Leu Ile Ser Asn Ile Asn Val Ile Val Leu Gln Leu 
                          85                  90                  95      
          Lys Gly Ser Glu Thr Thr Phe Met Cys Glu Tyr Ala Asp Glu Thr Ala 
                      100                 105                 110         
          Thr Ile Val Glu Phe Leu Asn Arg Trp Ile Thr Phe Cys Gln Ser Ile 
                  115                 120                 125             
          Ile Ser Thr Leu Thr 
              130             
          <![CDATA[<210>  21]]>
          <![CDATA[<211>  133]]>
          <![CDATA[<212>  PRT]]>
          <![CDATA[<213>  人工序列]]>
          <![CDATA[<220>]]>
          <![CDATA[<223>  合成：IL-2-P65R-H16A-D84S (IL-2-RAS)]]>
          <![CDATA[<400>  21]]>
          Ala Pro Thr Ser Ser Ser Thr Lys Lys Thr Gln Leu Gln Leu Glu Ala 
          1               5                   10                  15      
          Leu Leu Leu Asp Leu Gln Met Ile Leu Asn Gly Ile Asn Asn Tyr Lys 
                      20                  25                  30          
          Asn Pro Lys Leu Thr Arg Met Leu Thr Phe Lys Phe Tyr Met Pro Lys 
                  35                  40                  45              
          Lys Ala Thr Glu Leu Lys His Leu Gln Cys Leu Glu Glu Glu Leu Lys 
              50                  55                  60                  
          Arg Leu Glu Glu Val Leu Asn Leu Ala Gln Ser Lys Asn Phe His Leu 
          65                  70                  75                  80  
          Arg Pro Arg Ser Leu Ile Ser Asn Ile Asn Val Ile Val Leu Glu Leu 
                          85                  90                  95      
          Lys Gly Ser Glu Thr Thr Phe Met Cys Glu Tyr Ala Asp Glu Thr Ala 
                      100                 105                 110         
          Thr Ile Val Glu Phe Leu Asn Arg Trp Ile Thr Phe Cys Gln Ser Ile 
                  115                 120                 125             
          Ile Ser Thr Leu Thr 
              130             
          <![CDATA[<210>  22]]>
          <![CDATA[<211>  133]]>
          <![CDATA[<212>  PRT]]>
          <![CDATA[<213>  人工序列]]>
          <![CDATA[<220>]]>
          <![CDATA[<223>  合成：IL-2-T3A-C125S]]>
          <![CDATA[<400>  22]]>
          Ala Pro Ala Ser Ser Ser Thr Lys Lys Thr Gln Leu Gln Leu Glu His 
          1               5                   10                  15      
          Leu Leu Leu Asp Leu Gln Met Ile Leu Asn Gly Ile Asn Asn Tyr Lys 
                      20                  25                  30          
          Asn Pro Lys Leu Thr Arg Met Leu Thr Phe Lys Phe Tyr Met Pro Lys 
                  35                  40                  45              
          Lys Ala Thr Glu Leu Lys His Leu Gln Cys Leu Glu Glu Glu Leu Lys 
              50                  55                  60                  
          Pro Leu Glu Glu Val Leu Asn Leu Ala Gln Ser Lys Asn Phe His Leu 
          65                  70                  75                  80  
          Arg Pro Arg Asp Leu Ile Ser Asn Ile Asn Val Ile Val Leu Glu Leu 
                          85                  90                  95      
          Lys Gly Ser Glu Thr Thr Phe Met Cys Glu Tyr Ala Asp Glu Thr Ala 
                      100                 105                 110         
          Thr Ile Val Glu Phe Leu Asn Arg Trp Ile Thr Phe Ser Gln Ser Ile 
                  115                 120                 125             
          Ile Ser Thr Leu Thr 
              130             
          <![CDATA[<210>  23]]>
          <![CDATA[<211>  133]]>
          <![CDATA[<212>  PRT]]>
          <![CDATA[<213>  人工序列]]>
          <![CDATA[<220>]]>
          <![CDATA[<223>  合成：IL-2-T3A-P65R-C125S]]>
          <![CDATA[<400>  23]]>
          Ala Pro Ala Ser Ser Ser Thr Lys Lys Thr Gln Leu Gln Leu Glu His 
          1               5                   10                  15      
          Leu Leu Leu Asp Leu Gln Met Ile Leu Asn Gly Ile Asn Asn Tyr Lys 
                      20                  25                  30          
          Asn Pro Lys Leu Thr Arg Met Leu Thr Phe Lys Phe Tyr Met Pro Lys 
                  35                  40                  45              
          Lys Ala Thr Glu Leu Lys His Leu Gln Cys Leu Glu Glu Glu Leu Lys 
              50                  55                  60                  
          Arg Leu Glu Glu Val Leu Asn Leu Ala Gln Ser Lys Asn Phe His Leu 
          65                  70                  75                  80  
          Arg Pro Arg Asp Leu Ile Ser Asn Ile Asn Val Ile Val Leu Glu Leu 
                          85                  90                  95      
          Lys Gly Ser Glu Thr Thr Phe Met Cys Glu Tyr Ala Asp Glu Thr Ala 
                      100                 105                 110         
          Thr Ile Val Glu Phe Leu Asn Arg Trp Ile Thr Phe Ser Gln Ser Ile 
                  115                 120                 125             
          Ile Ser Thr Leu Thr 
              130             
          <![CDATA[<210>  24]]>
          <![CDATA[<211>  133]]>
          <![CDATA[<212>  PRT]]>
          <![CDATA[<213>  人工序列]]>
          <![CDATA[<220>]]>
          <![CDATA[<223>  合成：IL-2-T3A-H16A-C125S]]>
          <![CDATA[<400>  24]]>
          Ala Pro Ala Ser Ser Ser Thr Lys Lys Thr Gln Leu Gln Leu Glu Ala 
          1               5                   10                  15      
          Leu Leu Leu Asp Leu Gln Met Ile Leu Asn Gly Ile Asn Asn Tyr Lys 
                      20                  25                  30          
          Asn Pro Lys Leu Thr Arg Met Leu Thr Phe Lys Phe Tyr Met Pro Lys 
                  35                  40                  45              
          Lys Ala Thr Glu Leu Lys His Leu Gln Cys Leu Glu Glu Glu Leu Lys 
              50                  55                  60                  
          Pro Leu Glu Glu Val Leu Asn Leu Ala Gln Ser Lys Asn Phe His Leu 
          65                  70                  75                  80  
          Arg Pro Arg Asp Leu Ile Ser Asn Ile Asn Val Ile Val Leu Glu Leu 
                          85                  90                  95      
          Lys Gly Ser Glu Thr Thr Phe Met Cys Glu Tyr Ala Asp Glu Thr Ala 
                      100                 105                 110         
          Thr Ile Val Glu Phe Leu Asn Arg Trp Ile Thr Phe Ser Gln Ser Ile 
                  115                 120                 125             
          Ile Ser Thr Leu Thr 
              130             
          <![CDATA[<210>  25]]>
          <![CDATA[<211>  133]]>
          <![CDATA[<212>  PRT]]>
          <![CDATA[<213>  人工序列]]>
          <![CDATA[<220>]]>
          <![CDATA[<223>  合成：IL-2-T3A-D84S-C125S]]>
          <![CDATA[<400>  25]]>
          Ala Pro Ala Ser Ser Ser Thr Lys Lys Thr Gln Leu Gln Leu Glu His 
          1               5                   10                  15      
          Leu Leu Leu Asp Leu Gln Met Ile Leu Asn Gly Ile Asn Asn Tyr Lys 
                      20                  25                  30          
          Asn Pro Lys Leu Thr Arg Met Leu Thr Phe Lys Phe Tyr Met Pro Lys 
                  35                  40                  45              
          Lys Ala Thr Glu Leu Lys His Leu Gln Cys Leu Glu Glu Glu Leu Lys 
              50                  55                  60                  
          Pro Leu Glu Glu Val Leu Asn Leu Ala Gln Ser Lys Asn Phe His Leu 
          65                  70                  75                  80  
          Arg Pro Arg Ser Leu Ile Ser Asn Ile Asn Val Ile Val Leu Glu Leu 
                          85                  90                  95      
          Lys Gly Ser Glu Thr Thr Phe Met Cys Glu Tyr Ala Asp Glu Thr Ala 
                      100                 105                 110         
          Thr Ile Val Glu Phe Leu Asn Arg Trp Ile Thr Phe Ser Gln Ser Ile 
                  115                 120                 125             
          Ile Ser Thr Leu Thr 
              130             
          <![CDATA[<210>  26]]>
          <![CDATA[<211>  133]]>
          <![CDATA[<212>  PRT]]>
          <![CDATA[<213>  人工序列]]>
          <![CDATA[<220>]]>
          <![CDATA[<223>  合成：IL-2-T3A-H16A-P65R-C125S]]>
          <![CDATA[<400>  26]]>
          Ala Pro Ala Ser Ser Ser Thr Lys Lys Thr Gln Leu Gln Leu Glu Ala 
          1               5                   10                  15      
          Leu Leu Leu Asp Leu Gln Met Ile Leu Asn Gly Ile Asn Asn Tyr Lys 
                      20                  25                  30          
          Asn Pro Lys Leu Thr Arg Met Leu Thr Phe Lys Phe Tyr Met Pro Lys 
                  35                  40                  45              
          Lys Ala Thr Glu Leu Lys His Leu Gln Cys Leu Glu Glu Glu Leu Lys 
              50                  55                  60                  
          Arg Leu Glu Glu Val Leu Asn Leu Ala Gln Ser Lys Asn Phe His Leu 
          65                  70                  75                  80  
          Arg Pro Arg Asp Leu Ile Ser Asn Ile Asn Val Ile Val Leu Glu Leu 
                          85                  90                  95      
          Lys Gly Ser Glu Thr Thr Phe Met Cys Glu Tyr Ala Asp Glu Thr Ala 
                      100                 105                 110         
          Thr Ile Val Glu Phe Leu Asn Arg Trp Ile Thr Phe Ser Gln Ser Ile 
                  115                 120                 125             
          Ile Ser Thr Leu Thr 
              130             
          <![CDATA[<210>  27]]>
          <![CDATA[<211>  133]]>
          <![CDATA[<212>  PRT]]>
          <![CDATA[<213>  人工序列]]>
          <![CDATA[<220>]]>
          <![CDATA[<223>  合成：IL-2-T3A-P65R-D84S-C125S]]>
          <![CDATA[<400>  27]]>
          Ala Pro Ala Ser Ser Ser Thr Lys Lys Thr Gln Leu Gln Leu Glu His 
          1               5                   10                  15      
          Leu Leu Leu Asp Leu Gln Met Ile Leu Asn Gly Ile Asn Asn Tyr Lys 
                      20                  25                  30          
          Asn Pro Lys Leu Thr Arg Met Leu Thr Phe Lys Phe Tyr Met Pro Lys 
                  35                  40                  45              
          Lys Ala Thr Glu Leu Lys His Leu Gln Cys Leu Glu Glu Glu Leu Lys 
              50                  55                  60                  
          Arg Leu Glu Glu Val Leu Asn Leu Ala Gln Ser Lys Asn Phe His Leu 
          65                  70                  75                  80  
          Arg Pro Arg Ser Leu Ile Ser Asn Ile Asn Val Ile Val Leu Glu Leu 
                          85                  90                  95      
          Lys Gly Ser Glu Thr Thr Phe Met Cys Glu Tyr Ala Asp Glu Thr Ala 
                      100                 105                 110         
          Thr Ile Val Glu Phe Leu Asn Arg Trp Ile Thr Phe Ser Gln Ser Ile 
                  115                 120                 125             
          Ile Ser Thr Leu Thr 
              130             
          <![CDATA[<210>  28]]>
          <![CDATA[<211>  133]]>
          <![CDATA[<212>  PRT]]>
          <![CDATA[<213>  人工序列]]>
          <![CDATA[<220>]]>
          <![CDATA[<223>  合成：IL-2-T3A-H16A-P65R-D84S-C125S]]>
          <![CDATA[<400>  28]]>
          Ala Pro Ala Ser Ser Ser Thr Lys Lys Thr Gln Leu Gln Leu Glu Ala 
          1               5                   10                  15      
          Leu Leu Leu Asp Leu Gln Met Ile Leu Asn Gly Ile Asn Asn Tyr Lys 
                      20                  25                  30          
          Asn Pro Lys Leu Thr Arg Met Leu Thr Phe Lys Phe Tyr Met Pro Lys 
                  35                  40                  45              
          Lys Ala Thr Glu Leu Lys His Leu Gln Cys Leu Glu Glu Glu Leu Lys 
              50                  55                  60                  
          Arg Leu Glu Glu Val Leu Asn Leu Ala Gln Ser Lys Asn Phe His Leu 
          65                  70                  75                  80  
          Arg Pro Arg Ser Leu Ile Ser Asn Ile Asn Val Ile Val Leu Glu Leu 
                          85                  90                  95      
          Lys Gly Ser Glu Thr Thr Phe Met Cys Glu Tyr Ala Asp Glu Thr Ala 
                      100                 105                 110         
          Thr Ile Val Glu Phe Leu Asn Arg Trp Ile Thr Phe Ser Gln Ser Ile 
                  115                 120                 125             
          Ile Ser Thr Leu Thr 
              130             
          <![CDATA[<210>  29]]>
          <![CDATA[<211>  124]]>
          <![CDATA[<212>  PRT]]>
          <![CDATA[<213>  人工序列]]>
          <![CDATA[<220>]]>
          <![CDATA[<223>  合成：IL-2-no9-H16A-P65R-C125S]]>
          <![CDATA[<400>  29]]>
          Thr Gln Leu Gln Leu Glu Ala Leu Leu Leu Asp Leu Gln Met Ile Leu 
          1               5                   10                  15      
          Asn Gly Ile Asn Asn Tyr Lys Asn Pro Lys Leu Thr Arg Met Leu Thr 
                      20                  25                  30          
          Phe Lys Phe Tyr Met Pro Lys Lys Ala Thr Glu Leu Lys His Leu Gln 
                  35                  40                  45              
          Cys Leu Glu Glu Glu Leu Lys Arg Leu Glu Glu Val Leu Asn Leu Ala 
              50                  55                  60                  
          Gln Ser Lys Asn Phe His Leu Arg Pro Arg Asp Leu Ile Ser Asn Ile 
          65                  70                  75                  80  
          Asn Val Ile Val Leu Glu Leu Lys Gly Ser Glu Thr Thr Phe Met Cys 
                          85                  90                  95      
          Glu Tyr Ala Asp Glu Thr Ala Thr Ile Val Glu Phe Leu Asn Arg Trp 
                      100                 105                 110         
          Ile Thr Phe Ser Gln Ser Ile Ile Ser Thr Leu Thr 
                  115                 120                 
          <![CDATA[<210>  30]]>
          <![CDATA[<211>  124]]>
          <![CDATA[<212>  PRT]]>
          <![CDATA[<213>  人工序列]]>
          <![CDATA[<220>]]>
          <![CDATA[<223>  合成：IL-2-no9-P65R-D84S-C125S]]>
          <![CDATA[<400>  30]]>
          Thr Gln Leu Gln Leu Glu His Leu Leu Leu Asp Leu Gln Met Ile Leu 
          1               5                   10                  15      
          Asn Gly Ile Asn Asn Tyr Lys Asn Pro Lys Leu Thr Arg Met Leu Thr 
                      20                  25                  30          
          Phe Lys Phe Tyr Met Pro Lys Lys Ala Thr Glu Leu Lys His Leu Gln 
                  35                  40                  45              
          Cys Leu Glu Glu Glu Leu Lys Arg Leu Glu Glu Val Leu Asn Leu Ala 
              50                  55                  60                  
          Gln Ser Lys Asn Phe His Leu Arg Pro Arg Ser Leu Ile Ser Asn Ile 
          65                  70                  75                  80  
          Asn Val Ile Val Leu Glu Leu Lys Gly Ser Glu Thr Thr Phe Met Cys 
                          85                  90                  95      
          Glu Tyr Ala Asp Glu Thr Ala Thr Ile Val Glu Phe Leu Asn Arg Trp 
                      100                 105                 110         
          Ile Thr Phe Ser Gln Ser Ile Ile Ser Thr Leu Thr 
                  115                 120                 
          <![CDATA[<210>  31]]>
          <![CDATA[<211>  124]]>
          <![CDATA[<212>  PRT]]>
          <![CDATA[<213>  人工序列]]>
          <![CDATA[<220>]]>
          <![CDATA[<223>  合成：IL-2-no9-H16A-P65R-D84S-C125S]]>
          <![CDATA[<400>  31]]>
          Thr Gln Leu Gln Leu Glu Ala Leu Leu Leu Asp Leu Gln Met Ile Leu 
          1               5                   10                  15      
          Asn Gly Ile Asn Asn Tyr Lys Asn Pro Lys Leu Thr Arg Met Leu Thr 
                      20                  25                  30          
          Phe Lys Phe Tyr Met Pro Lys Lys Ala Thr Glu Leu Lys His Leu Gln 
                  35                  40                  45              
          Cys Leu Glu Glu Glu Leu Lys Arg Leu Glu Glu Val Leu Asn Leu Ala 
              50                  55                  60                  
          Gln Ser Lys Asn Phe His Leu Arg Pro Arg Ser Leu Ile Ser Asn Ile 
          65                  70                  75                  80  
          Asn Val Ile Val Leu Glu Leu Lys Gly Ser Glu Thr Thr Phe Met Cys 
                          85                  90                  95      
          Glu Tyr Ala Asp Glu Thr Ala Thr Ile Val Glu Phe Leu Asn Arg Trp 
                      100                 105                 110         
          Ile Thr Phe Ser Gln Ser Ile Ile Ser Thr Leu Thr 
                  115                 120                 
          <![CDATA[<210>  32]]>
          <![CDATA[<211>  362]]>
          <![CDATA[<212>  PRT]]>
          <![CDATA[<213>  人工序列]]>
          <![CDATA[<220>]]>
          <![CDATA[<223>  合成：野生型IL-2-xELL杵Fc]]>
          <![CDATA[<400>  32]]>
          Ala Pro Thr Ser Ser Ser Thr Lys Lys Thr Gln Leu Gln Leu Glu His 
          1               5                   10                  15      
          Leu Leu Leu Asp Leu Gln Met Ile Leu Asn Gly Ile Asn Asn Tyr Lys 
                      20                  25                  30          
          Asn Pro Lys Leu Thr Arg Met Leu Thr Phe Lys Phe Tyr Met Pro Lys 
                  35                  40                  45              
          Lys Ala Thr Glu Leu Lys His Leu Gln Cys Leu Glu Glu Glu Leu Lys 
              50                  55                  60                  
          Pro Leu Glu Glu Val Leu Asn Leu Ala Gln Ser Lys Asn Phe His Leu 
          65                  70                  75                  80  
          Arg Pro Arg Asp Leu Ile Ser Asn Ile Asn Val Ile Val Leu Glu Leu 
                          85                  90                  95      
          Lys Gly Ser Glu Thr Thr Phe Met Cys Glu Tyr Ala Asp Glu Thr Ala 
                      100                 105                 110         
          Thr Ile Val Glu Phe Leu Asn Arg Trp Ile Thr Phe Cys Gln Ser Ile 
                  115                 120                 125             
          Ile Ser Thr Leu Thr Pro Gly Gly Gly Gly Asp Lys Thr His Thr Cys 
              130                 135                 140                 
          Pro Pro Cys Pro Ala Pro Gly Gly Pro Ser Val Phe Leu Phe Pro Pro 
          145                 150                 155                 160 
          Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys 
                          165                 170                 175     
          Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp 
                      180                 185                 190         
          Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu 
                  195                 200                 205             
          Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu 
              210                 215                 220                 
          His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn 
          225                 230                 235                 240 
          Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly 
                          245                 250                 255     
          Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Cys Arg Asp Glu 
                      260                 265                 270         
          Leu Thr Lys Asn Gln Val Ser Leu Trp Cys Leu Val Lys Gly Phe Tyr 
                  275                 280                 285             
          Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn 
              290                 295                 300                 
          Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe 
          305                 310                 315                 320 
          Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn 
                          325                 330                 335     
          Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr 
                      340                 345                 350         
          Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys 
                  355                 360         
          <![CDATA[<210>  33]]>
          <![CDATA[<211>  362]]>
          <![CDATA[<212>  PRT]]>
          <![CDATA[<213>  人工序列]]>
          <![CDATA[<220>]]>
          <![CDATA[<223>  合成：IL-2-F42K-xELL杵Fc]]>
          <![CDATA[<400>  33]]>
          Ala Pro Thr Ser Ser Ser Thr Lys Lys Thr Gln Leu Gln Leu Glu His 
          1               5                   10                  15      
          Leu Leu Leu Asp Leu Gln Met Ile Leu Asn Gly Ile Asn Asn Tyr Lys 
                      20                  25                  30          
          Asn Pro Lys Leu Thr Arg Met Leu Thr Lys Lys Phe Tyr Met Pro Lys 
                  35                  40                  45              
          Lys Ala Thr Glu Leu Lys His Leu Gln Cys Leu Glu Glu Glu Leu Lys 
              50                  55                  60                  
          Pro Leu Glu Glu Val Leu Asn Leu Ala Gln Ser Lys Asn Phe His Leu 
          65                  70                  75                  80  
          Arg Pro Arg Asp Leu Ile Ser Asn Ile Asn Val Ile Val Leu Glu Leu 
                          85                  90                  95      
          Lys Gly Ser Glu Thr Thr Phe Met Cys Glu Tyr Ala Asp Glu Thr Ala 
                      100                 105                 110         
          Thr Ile Val Glu Phe Leu Asn Arg Trp Ile Thr Phe Cys Gln Ser Ile 
                  115                 120                 125             
          Ile Ser Thr Leu Thr Pro Gly Gly Gly Gly Asp Lys Thr His Thr Cys 
              130                 135                 140                 
          Pro Pro Cys Pro Ala Pro Gly Gly Pro Ser Val Phe Leu Phe Pro Pro 
          145                 150                 155                 160 
          Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys 
                          165                 170                 175     
          Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp 
                      180                 185                 190         
          Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu 
                  195                 200                 205             
          Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu 
              210                 215                 220                 
          His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn 
          225                 230                 235                 240 
          Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly 
                          245                 250                 255     
          Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Cys Arg Asp Glu 
                      260                 265                 270         
          Leu Thr Lys Asn Gln Val Ser Leu Trp Cys Leu Val Lys Gly Phe Tyr 
                  275                 280                 285             
          Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn 
              290                 295                 300                 
          Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe 
          305                 310                 315                 320 
          Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn 
                          325                 330                 335     
          Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr 
                      340                 345                 350         
          Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys 
                  355                 360         
          <![CDATA[<210>  34]]>
          <![CDATA[<211>  362]]>
          <![CDATA[<212>  PRT]]>
          <![CDATA[<213>  人工序列]]>
          <![CDATA[<220>]]>
          <![CDATA[<223>  合成：IL-2-P65E-xELL杵Fc]]>
          <![CDATA[<400>  34]]>
          Ala Pro Thr Ser Ser Ser Thr Lys Lys Thr Gln Leu Gln Leu Glu His 
          1               5                   10                  15      
          Leu Leu Leu Asp Leu Gln Met Ile Leu Asn Gly Ile Asn Asn Tyr Lys 
                      20                  25                  30          
          Asn Pro Lys Leu Thr Arg Met Leu Thr Phe Lys Phe Tyr Met Pro Lys 
                  35                  40                  45              
          Lys Ala Thr Glu Leu Lys His Leu Gln Cys Leu Glu Glu Glu Leu Lys 
              50                  55                  60                  
          Glu Leu Glu Glu Val Leu Asn Leu Ala Gln Ser Lys Asn Phe His Leu 
          65                  70                  75                  80  
          Arg Pro Arg Asp Leu Ile Ser Asn Ile Asn Val Ile Val Leu Glu Leu 
                          85                  90                  95      
          Lys Gly Ser Glu Thr Thr Phe Met Cys Glu Tyr Ala Asp Glu Thr Ala 
                      100                 105                 110         
          Thr Ile Val Glu Phe Leu Asn Arg Trp Ile Thr Phe Cys Gln Ser Ile 
                  115                 120                 125             
          Ile Ser Thr Leu Thr Pro Gly Gly Gly Gly Asp Lys Thr His Thr Cys 
              130                 135                 140                 
          Pro Pro Cys Pro Ala Pro Gly Gly Pro Ser Val Phe Leu Phe Pro Pro 
          145                 150                 155                 160 
          Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys 
                          165                 170                 175     
          Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp 
                      180                 185                 190         
          Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu 
                  195                 200                 205             
          Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu 
              210                 215                 220                 
          His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn 
          225                 230                 235                 240 
          Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly 
                          245                 250                 255     
          Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Cys Arg Asp Glu 
                      260                 265                 270         
          Leu Thr Lys Asn Gln Val Ser Leu Trp Cys Leu Val Lys Gly Phe Tyr 
                  275                 280                 285             
          Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn 
              290                 295                 300                 
          Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe 
          305                 310                 315                 320 
          Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn 
                          325                 330                 335     
          Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr 
                      340                 345                 350         
          Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys 
                  355                 360         
          <![CDATA[<210>  35]]>
          <![CDATA[<211>  362]]>
          <![CDATA[<212>  PRT]]>
          <![CDATA[<213>  人工序列]]>
          <![CDATA[<220>]]>
          <![CDATA[<223>  合成：IL-2-P65R-xELL杵Fc]]>
          <![CDATA[<400>  35]]>
          Ala Pro Thr Ser Ser Ser Thr Lys Lys Thr Gln Leu Gln Leu Glu His 
          1               5                   10                  15      
          Leu Leu Leu Asp Leu Gln Met Ile Leu Asn Gly Ile Asn Asn Tyr Lys 
                      20                  25                  30          
          Asn Pro Lys Leu Thr Arg Met Leu Thr Phe Lys Phe Tyr Met Pro Lys 
                  35                  40                  45              
          Lys Ala Thr Glu Leu Lys His Leu Gln Cys Leu Glu Glu Glu Leu Lys 
              50                  55                  60                  
          Arg Leu Glu Glu Val Leu Asn Leu Ala Gln Ser Lys Asn Phe His Leu 
          65                  70                  75                  80  
          Arg Pro Arg Asp Leu Ile Ser Asn Ile Asn Val Ile Val Leu Glu Leu 
                          85                  90                  95      
          Lys Gly Ser Glu Thr Thr Phe Met Cys Glu Tyr Ala Asp Glu Thr Ala 
                      100                 105                 110         
          Thr Ile Val Glu Phe Leu Asn Arg Trp Ile Thr Phe Cys Gln Ser Ile 
                  115                 120                 125             
          Ile Ser Thr Leu Thr Pro Gly Gly Gly Gly Asp Lys Thr His Thr Cys 
              130                 135                 140                 
          Pro Pro Cys Pro Ala Pro Gly Gly Pro Ser Val Phe Leu Phe Pro Pro 
          145                 150                 155                 160 
          Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys 
                          165                 170                 175     
          Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp 
                      180                 185                 190         
          Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu 
                  195                 200                 205             
          Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu 
              210                 215                 220                 
          His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn 
          225                 230                 235                 240 
          Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly 
                          245                 250                 255     
          Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Cys Arg Asp Glu 
                      260                 265                 270         
          Leu Thr Lys Asn Gln Val Ser Leu Trp Cys Leu Val Lys Gly Phe Tyr 
                  275                 280                 285             
          Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn 
              290                 295                 300                 
          Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe 
          305                 310                 315                 320 
          Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn 
                          325                 330                 335     
          Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr 
                      340                 345                 350         
          Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys 
                  355                 360         
          <![CDATA[<210>  36]]>
          <![CDATA[<211>  362]]>
          <![CDATA[<212>  PRT]]>
          <![CDATA[<213>  人工序列]]>
          <![CDATA[<220>]]>
          <![CDATA[<223>  合成：IL-2-F42K-D84S-xELL杵Fc]]>
          <![CDATA[<400>  36]]>
          Ala Pro Thr Ser Ser Ser Thr Lys Lys Thr Gln Leu Gln Leu Glu His 
          1               5                   10                  15      
          Leu Leu Leu Asp Leu Gln Met Ile Leu Asn Gly Ile Asn Asn Tyr Lys 
                      20                  25                  30          
          Asn Pro Lys Leu Thr Arg Met Leu Thr Lys Lys Phe Tyr Met Pro Lys 
                  35                  40                  45              
          Lys Ala Thr Glu Leu Lys His Leu Gln Cys Leu Glu Glu Glu Leu Lys 
              50                  55                  60                  
          Pro Leu Glu Glu Val Leu Asn Leu Ala Gln Ser Lys Asn Phe His Leu 
          65                  70                  75                  80  
          Arg Pro Arg Ser Leu Ile Ser Asn Ile Asn Val Ile Val Leu Glu Leu 
                          85                  90                  95      
          Lys Gly Ser Glu Thr Thr Phe Met Cys Glu Tyr Ala Asp Glu Thr Ala 
                      100                 105                 110         
          Thr Ile Val Glu Phe Leu Asn Arg Trp Ile Thr Phe Cys Gln Ser Ile 
                  115                 120                 125             
          Ile Ser Thr Leu Thr Pro Gly Gly Gly Gly Asp Lys Thr His Thr Cys 
              130                 135                 140                 
          Pro Pro Cys Pro Ala Pro Gly Gly Pro Ser Val Phe Leu Phe Pro Pro 
          145                 150                 155                 160 
          Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys 
                          165                 170                 175     
          Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp 
                      180                 185                 190         
          Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu 
                  195                 200                 205             
          Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu 
              210                 215                 220                 
          His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn 
          225                 230                 235                 240 
          Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly 
                          245                 250                 255     
          Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Cys Arg Asp Glu 
                      260                 265                 270         
          Leu Thr Lys Asn Gln Val Ser Leu Trp Cys Leu Val Lys Gly Phe Tyr 
                  275                 280                 285             
          Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn 
              290                 295                 300                 
          Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe 
          305                 310                 315                 320 
          Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn 
                          325                 330                 335     
          Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr 
                      340                 345                 350         
          Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys 
                  355                 360         
          <![CDATA[<210>  37]]>
          <![CDATA[<211>  362]]>
          <![CDATA[<212>  PRT]]>
          <![CDATA[<213>  人工序列]]>
          <![CDATA[<220>]]>
          <![CDATA[<223>  合成：IL-2-F42K-E95Q-xELL杵Fc]]>
          <![CDATA[<400>  37]]>
          Ala Pro Thr Ser Ser Ser Thr Lys Lys Thr Gln Leu Gln Leu Glu His 
          1               5                   10                  15      
          Leu Leu Leu Asp Leu Gln Met Ile Leu Asn Gly Ile Asn Asn Tyr Lys 
                      20                  25                  30          
          Asn Pro Lys Leu Thr Arg Met Leu Thr Lys Lys Phe Tyr Met Pro Lys 
                  35                  40                  45              
          Lys Ala Thr Glu Leu Lys His Leu Gln Cys Leu Glu Glu Glu Leu Lys 
              50                  55                  60                  
          Pro Leu Glu Glu Val Leu Asn Leu Ala Gln Ser Lys Asn Phe His Leu 
          65                  70                  75                  80  
          Arg Pro Arg Asp Leu Ile Ser Asn Ile Asn Val Ile Val Leu Gln Leu 
                          85                  90                  95      
          Lys Gly Ser Glu Thr Thr Phe Met Cys Glu Tyr Ala Asp Glu Thr Ala 
                      100                 105                 110         
          Thr Ile Val Glu Phe Leu Asn Arg Trp Ile Thr Phe Cys Gln Ser Ile 
                  115                 120                 125             
          Ile Ser Thr Leu Thr Pro Gly Gly Gly Gly Asp Lys Thr His Thr Cys 
              130                 135                 140                 
          Pro Pro Cys Pro Ala Pro Gly Gly Pro Ser Val Phe Leu Phe Pro Pro 
          145                 150                 155                 160 
          Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys 
                          165                 170                 175     
          Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp 
                      180                 185                 190         
          Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu 
                  195                 200                 205             
          Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu 
              210                 215                 220                 
          His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn 
          225                 230                 235                 240 
          Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly 
                          245                 250                 255     
          Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Cys Arg Asp Glu 
                      260                 265                 270         
          Leu Thr Lys Asn Gln Val Ser Leu Trp Cys Leu Val Lys Gly Phe Tyr 
                  275                 280                 285             
          Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn 
              290                 295                 300                 
          Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe 
          305                 310                 315                 320 
          Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn 
                          325                 330                 335     
          Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr 
                      340                 345                 350         
          Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys 
                  355                 360         
          <![CDATA[<210>  38]]>
          <![CDATA[<211>  362]]>
          <![CDATA[<212>  PRT]]>
          <![CDATA[<213>  人工序列]]>
          <![CDATA[<220>]]>
          <![CDATA[<223>  合成：IL-2-F42K-M23A-xELL杵Fc]]>
          <![CDATA[<400>  38]]>
          Ala Pro Thr Ser Ser Ser Thr Lys Lys Thr Gln Leu Gln Leu Glu His 
          1               5                   10                  15      
          Leu Leu Leu Asp Leu Gln Ala Ile Leu Asn Gly Ile Asn Asn Tyr Lys 
                      20                  25                  30          
          Asn Pro Lys Leu Thr Arg Met Leu Thr Lys Lys Phe Tyr Met Pro Lys 
                  35                  40                  45              
          Lys Ala Thr Glu Leu Lys His Leu Gln Cys Leu Glu Glu Glu Leu Lys 
              50                  55                  60                  
          Pro Leu Glu Glu Val Leu Asn Leu Ala Gln Ser Lys Asn Phe His Leu 
          65                  70                  75                  80  
          Arg Pro Arg Asp Leu Ile Ser Asn Ile Asn Val Ile Val Leu Glu Leu 
                          85                  90                  95      
          Lys Gly Ser Glu Thr Thr Phe Met Cys Glu Tyr Ala Asp Glu Thr Ala 
                      100                 105                 110         
          Thr Ile Val Glu Phe Leu Asn Arg Trp Ile Thr Phe Cys Gln Ser Ile 
                  115                 120                 125             
          Ile Ser Thr Leu Thr Pro Gly Gly Gly Gly Asp Lys Thr His Thr Cys 
              130                 135                 140                 
          Pro Pro Cys Pro Ala Pro Gly Gly Pro Ser Val Phe Leu Phe Pro Pro 
          145                 150                 155                 160 
          Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys 
                          165                 170                 175     
          Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp 
                      180                 185                 190         
          Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu 
                  195                 200                 205             
          Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu 
              210                 215                 220                 
          His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn 
          225                 230                 235                 240 
          Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly 
                          245                 250                 255     
          Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Cys Arg Asp Glu 
                      260                 265                 270         
          Leu Thr Lys Asn Gln Val Ser Leu Trp Cys Leu Val Lys Gly Phe Tyr 
                  275                 280                 285             
          Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn 
              290                 295                 300                 
          Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe 
          305                 310                 315                 320 
          Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn 
                          325                 330                 335     
          Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr 
                      340                 345                 350         
          Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys 
                  355                 360         
          <![CDATA[<210>  39]]>
          <![CDATA[<211>  362]]>
          <![CDATA[<212>  PRT]]>
          <![CDATA[<213>  人工序列]]>
          <![CDATA[<220>]]>
          <![CDATA[<223>  合成：IL-2-H16A-F42K-xELL杵Fc]]>
          <![CDATA[<400>  39]]>
          Ala Pro Thr Ser Ser Ser Thr Lys Lys Thr Gln Leu Gln Leu Glu Ala 
          1               5                   10                  15      
          Leu Leu Leu Asp Leu Gln Met Ile Leu Asn Gly Ile Asn Asn Tyr Lys 
                      20                  25                  30          
          Asn Pro Lys Leu Thr Arg Met Leu Thr Lys Lys Phe Tyr Met Pro Lys 
                  35                  40                  45              
          Lys Ala Thr Glu Leu Lys His Leu Gln Cys Leu Glu Glu Glu Leu Lys 
              50                  55                  60                  
          Pro Leu Glu Glu Val Leu Asn Leu Ala Gln Ser Lys Asn Phe His Leu 
          65                  70                  75                  80  
          Arg Pro Arg Asp Leu Ile Ser Asn Ile Asn Val Ile Val Leu Glu Leu 
                          85                  90                  95      
          Lys Gly Ser Glu Thr Thr Phe Met Cys Glu Tyr Ala Asp Glu Thr Ala 
                      100                 105                 110         
          Thr Ile Val Glu Phe Leu Asn Arg Trp Ile Thr Phe Cys Gln Ser Ile 
                  115                 120                 125             
          Ile Ser Thr Leu Thr Pro Gly Gly Gly Gly Asp Lys Thr His Thr Cys 
              130                 135                 140                 
          Pro Pro Cys Pro Ala Pro Gly Gly Pro Ser Val Phe Leu Phe Pro Pro 
          145                 150                 155                 160 
          Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys 
                          165                 170                 175     
          Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp 
                      180                 185                 190         
          Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu 
                  195                 200                 205             
          Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu 
              210                 215                 220                 
          His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn 
          225                 230                 235                 240 
          Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly 
                          245                 250                 255     
          Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Cys Arg Asp Glu 
                      260                 265                 270         
          Leu Thr Lys Asn Gln Val Ser Leu Trp Cys Leu Val Lys Gly Phe Tyr 
                  275                 280                 285             
          Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn 
              290                 295                 300                 
          Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe 
          305                 310                 315                 320 
          Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn 
                          325                 330                 335     
          Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr 
                      340                 345                 350         
          Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys 
                  355                 360         
          <![CDATA[<210>  40]]>
          <![CDATA[<211>  362]]>
          <![CDATA[<212>  PRT]]>
          <![CDATA[<213>  人工序列]]>
          <![CDATA[<220>]]>
          <![CDATA[<223>  合成：IL-2-H16A-xELL杵Fc]]>
          <![CDATA[<400>  40]]>
          Ala Pro Thr Ser Ser Ser Thr Lys Lys Thr Gln Leu Gln Leu Glu Ala 
          1               5                   10                  15      
          Leu Leu Leu Asp Leu Gln Met Ile Leu Asn Gly Ile Asn Asn Tyr Lys 
                      20                  25                  30          
          Asn Pro Lys Leu Thr Arg Met Leu Thr Phe Lys Phe Tyr Met Pro Lys 
                  35                  40                  45              
          Lys Ala Thr Glu Leu Lys His Leu Gln Cys Leu Glu Glu Glu Leu Lys 
              50                  55                  60                  
          Pro Leu Glu Glu Val Leu Asn Leu Ala Gln Ser Lys Asn Phe His Leu 
          65                  70                  75                  80  
          Arg Pro Arg Asp Leu Ile Ser Asn Ile Asn Val Ile Val Leu Glu Leu 
                          85                  90                  95      
          Lys Gly Ser Glu Thr Thr Phe Met Cys Glu Tyr Ala Asp Glu Thr Ala 
                      100                 105                 110         
          Thr Ile Val Glu Phe Leu Asn Arg Trp Ile Thr Phe Cys Gln Ser Ile 
                  115                 120                 125             
          Ile Ser Thr Leu Thr Pro Gly Gly Gly Gly Asp Lys Thr His Thr Cys 
              130                 135                 140                 
          Pro Pro Cys Pro Ala Pro Gly Gly Pro Ser Val Phe Leu Phe Pro Pro 
          145                 150                 155                 160 
          Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys 
                          165                 170                 175     
          Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp 
                      180                 185                 190         
          Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu 
                  195                 200                 205             
          Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu 
              210                 215                 220                 
          His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn 
          225                 230                 235                 240 
          Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly 
                          245                 250                 255     
          Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Cys Arg Asp Glu 
                      260                 265                 270         
          Leu Thr Lys Asn Gln Val Ser Leu Trp Cys Leu Val Lys Gly Phe Tyr 
                  275                 280                 285             
          Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn 
              290                 295                 300                 
          Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe 
          305                 310                 315                 320 
          Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn 
                          325                 330                 335     
          Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr 
                      340                 345                 350         
          Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys 
                  355                 360         
          <![CDATA[<210>  41]]>
          <![CDATA[<211>  362]]>
          <![CDATA[<212>  PRT]]>
          <![CDATA[<213>  人工序列]]>
          <![CDATA[<220>]]>
          <![CDATA[<223>  合成：IL-2-P65R-H16A-xELL杵Fc]]>
          <![CDATA[<400>  41]]>
          Ala Pro Thr Ser Ser Ser Thr Lys Lys Thr Gln Leu Gln Leu Glu Ala 
          1               5                   10                  15      
          Leu Leu Leu Asp Leu Gln Met Ile Leu Asn Gly Ile Asn Asn Tyr Lys 
                      20                  25                  30          
          Asn Pro Lys Leu Thr Arg Met Leu Thr Phe Lys Phe Tyr Met Pro Lys 
                  35                  40                  45              
          Lys Ala Thr Glu Leu Lys His Leu Gln Cys Leu Glu Glu Glu Leu Lys 
              50                  55                  60                  
          Arg Leu Glu Glu Val Leu Asn Leu Ala Gln Ser Lys Asn Phe His Leu 
          65                  70                  75                  80  
          Arg Pro Arg Asp Leu Ile Ser Asn Ile Asn Val Ile Val Leu Glu Leu 
                          85                  90                  95      
          Lys Gly Ser Glu Thr Thr Phe Met Cys Glu Tyr Ala Asp Glu Thr Ala 
                      100                 105                 110         
          Thr Ile Val Glu Phe Leu Asn Arg Trp Ile Thr Phe Cys Gln Ser Ile 
                  115                 120                 125             
          Ile Ser Thr Leu Thr Pro Gly Gly Gly Gly Asp Lys Thr His Thr Cys 
              130                 135                 140                 
          Pro Pro Cys Pro Ala Pro Gly Gly Pro Ser Val Phe Leu Phe Pro Pro 
          145                 150                 155                 160 
          Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys 
                          165                 170                 175     
          Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp 
                      180                 185                 190         
          Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu 
                  195                 200                 205             
          Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu 
              210                 215                 220                 
          His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn 
          225                 230                 235                 240 
          Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly 
                          245                 250                 255     
          Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Cys Arg Asp Glu 
                      260                 265                 270         
          Leu Thr Lys Asn Gln Val Ser Leu Trp Cys Leu Val Lys Gly Phe Tyr 
                  275                 280                 285             
          Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn 
              290                 295                 300                 
          Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe 
          305                 310                 315                 320 
          Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn 
                          325                 330                 335     
          Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr 
                      340                 345                 350         
          Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys 
                  355                 360         
          <![CDATA[<210>  42]]>
          <![CDATA[<211>  362]]>
          <![CDATA[<212>  PRT]]>
          <![CDATA[<213>  人工序列]]>
          <![CDATA[<220>]]>
          <![CDATA[<223>  合成：IL-2-P65R-D84S-xELL杵Fc]]>
          <![CDATA[<400>  42]]>
          Ala Pro Thr Ser Ser Ser Thr Lys Lys Thr Gln Leu Gln Leu Glu His 
          1               5                   10                  15      
          Leu Leu Leu Asp Leu Gln Met Ile Leu Asn Gly Ile Asn Asn Tyr Lys 
                      20                  25                  30          
          Asn Pro Lys Leu Thr Arg Met Leu Thr Phe Lys Phe Tyr Met Pro Lys 
                  35                  40                  45              
          Lys Ala Thr Glu Leu Lys His Leu Gln Cys Leu Glu Glu Glu Leu Lys 
              50                  55                  60                  
          Arg Leu Glu Glu Val Leu Asn Leu Ala Gln Ser Lys Asn Phe His Leu 
          65                  70                  75                  80  
          Arg Pro Arg Ser Leu Ile Ser Asn Ile Asn Val Ile Val Leu Glu Leu 
                          85                  90                  95      
          Lys Gly Ser Glu Thr Thr Phe Met Cys Glu Tyr Ala Asp Glu Thr Ala 
                      100                 105                 110         
          Thr Ile Val Glu Phe Leu Asn Arg Trp Ile Thr Phe Cys Gln Ser Ile 
                  115                 120                 125             
          Ile Ser Thr Leu Thr Pro Gly Gly Gly Gly Asp Lys Thr His Thr Cys 
              130                 135                 140                 
          Pro Pro Cys Pro Ala Pro Gly Gly Pro Ser Val Phe Leu Phe Pro Pro 
          145                 150                 155                 160 
          Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys 
                          165                 170                 175     
          Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp 
                      180                 185                 190         
          Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu 
                  195                 200                 205             
          Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu 
              210                 215                 220                 
          His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn 
          225                 230                 235                 240 
          Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly 
                          245                 250                 255     
          Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Cys Arg Asp Glu 
                      260                 265                 270         
          Leu Thr Lys Asn Gln Val Ser Leu Trp Cys Leu Val Lys Gly Phe Tyr 
                  275                 280                 285             
          Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn 
              290                 295                 300                 
          Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe 
          305                 310                 315                 320 
          Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn 
                          325                 330                 335     
          Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr 
                      340                 345                 350         
          Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys 
                  355                 360         
          <![CDATA[<210>  43]]>
          <![CDATA[<211>  362]]>
          <![CDATA[<212>  PRT]]>
          <![CDATA[<213>  人工序列]]>
          <![CDATA[<220>]]>
          <![CDATA[<223>  合成：IL-2-RAS-xELL杵Fc]]>
          <![CDATA[<400>  43]]>
          Ala Pro Thr Ser Ser Ser Thr Lys Lys Thr Gln Leu Gln Leu Glu Ala 
          1               5                   10                  15      
          Leu Leu Leu Asp Leu Gln Met Ile Leu Asn Gly Ile Asn Asn Tyr Lys 
                      20                  25                  30          
          Asn Pro Lys Leu Thr Arg Met Leu Thr Phe Lys Phe Tyr Met Pro Lys 
                  35                  40                  45              
          Lys Ala Thr Glu Leu Lys His Leu Gln Cys Leu Glu Glu Glu Leu Lys 
              50                  55                  60                  
          Arg Leu Glu Glu Val Leu Asn Leu Ala Gln Ser Lys Asn Phe His Leu 
          65                  70                  75                  80  
          Arg Pro Arg Ser Leu Ile Ser Asn Ile Asn Val Ile Val Leu Glu Leu 
                          85                  90                  95      
          Lys Gly Ser Glu Thr Thr Phe Met Cys Glu Tyr Ala Asp Glu Thr Ala 
                      100                 105                 110         
          Thr Ile Val Glu Phe Leu Asn Arg Trp Ile Thr Phe Cys Gln Ser Ile 
                  115                 120                 125             
          Ile Ser Thr Leu Thr Pro Gly Gly Gly Gly Asp Lys Thr His Thr Cys 
              130                 135                 140                 
          Pro Pro Cys Pro Ala Pro Gly Gly Pro Ser Val Phe Leu Phe Pro Pro 
          145                 150                 155                 160 
          Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys 
                          165                 170                 175     
          Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp 
                      180                 185                 190         
          Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu 
                  195                 200                 205             
          Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu 
              210                 215                 220                 
          His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn 
          225                 230                 235                 240 
          Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly 
                          245                 250                 255     
          Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Cys Arg Asp Glu 
                      260                 265                 270         
          Leu Thr Lys Asn Gln Val Ser Leu Trp Cys Leu Val Lys Gly Phe Tyr 
                  275                 280                 285             
          Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn 
              290                 295                 300                 
          Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe 
          305                 310                 315                 320 
          Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn 
                          325                 330                 335     
          Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr 
                      340                 345                 350         
          Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys 
                  355                 360         
          <![CDATA[<210>  44]]>
          <![CDATA[<211>  230]]>
          <![CDATA[<212>  PRT]]>
          <![CDATA[<213>  人工序列]]>
          <![CDATA[<220>]]>
          <![CDATA[<223>  合成：連接子-EVN xELL臼Fc]]>
          <![CDATA[<400>  44]]>
          Lys Pro Gly Gly Gly Gly Asp Lys Thr His Thr Cys Pro Pro Cys Pro 
          1               5                   10                  15      
          Ala Pro Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp 
                      20                  25                  30          
          Thr Leu Met Arg Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp 
                  35                  40                  45              
          Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly 
              50                  55                  60                  
          Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn 
          65                  70                  75                  80  
          Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp 
                          85                  90                  95      
          Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro 
                      100                 105                 110         
          Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu 
                  115                 120                 125             
          Pro Gln Val Cys Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn 
              130                 135                 140                 
          Gln Val Ser Leu Ser Cys Ala Val Lys Gly Phe Tyr Pro Ser Asp Ile 
          145                 150                 155                 160 
          Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr 
                          165                 170                 175     
          Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Val Ser Lys 
                      180                 185                 190         
          Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys 
                  195                 200                 205             
          Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu 
              210                 215                 220                 
          Ser Leu Ser Pro Gly Lys 
          225                 230 
          <![CDATA[<210>  45]]>
          <![CDATA[<211>  361]]>
          <![CDATA[<212>  PRT]]>
          <![CDATA[<213>  人工序列]]>
          <![CDATA[<220>]]>
          <![CDATA[<223>  合成：xELL杵Fc-IL-2-T3G-C125S]]>
          <![CDATA[<400>  45]]>
          Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Gly Gly Pro Ser 
          1               5                   10                  15      
          Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg 
                      20                  25                  30          
          Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro 
                  35                  40                  45              
          Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala 
              50                  55                  60                  
          Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val 
          65                  70                  75                  80  
          Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr 
                          85                  90                  95      
          Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr 
                      100                 105                 110         
          Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu 
                  115                 120                 125             
          Pro Pro Cys Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu Trp Cys 
              130                 135                 140                 
          Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser 
          145                 150                 155                 160 
          Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp 
                          165                 170                 175     
          Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser 
                      180                 185                 190         
          Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala 
                  195                 200                 205             
          Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Gly 
              210                 215                 220                 
          Ser Gly Gly Ser Ala Pro Gly Ser Ser Ser Thr Lys Lys Thr Gln Leu 
          225                 230                 235                 240 
          Gln Leu Glu His Leu Leu Leu Asp Leu Gln Met Ile Leu Asn Gly Ile 
                          245                 250                 255     
          Asn Asn Tyr Lys Asn Pro Lys Leu Thr Arg Met Leu Thr Phe Lys Phe 
                      260                 265                 270         
          Tyr Met Pro Lys Lys Ala Thr Glu Leu Lys His Leu Gln Cys Leu Glu 
                  275                 280                 285             
          Glu Glu Leu Lys Pro Leu Glu Glu Val Leu Asn Leu Ala Gln Ser Lys 
              290                 295                 300                 
          Asn Phe His Leu Arg Pro Arg Asp Leu Ile Ser Asn Ile Asn Val Ile 
          305                 310                 315                 320 
          Val Leu Glu Leu Lys Gly Ser Glu Thr Thr Phe Met Cys Glu Tyr Ala 
                          325                 330                 335     
          Asp Glu Thr Ala Thr Ile Val Glu Phe Leu Asn Arg Trp Ile Thr Phe 
                      340                 345                 350         
          Ser Gln Ser Ile Ile Ser Thr Leu Thr 
                  355                 360     
          <![CDATA[<210>  46]]>
          <![CDATA[<211>  361]]>
          <![CDATA[<212>  PRT]]>
          <![CDATA[<213>  人工序列]]>
          <![CDATA[<220>]]>
          <![CDATA[<223>  合成：xELL杵Fc-IL-2-RAS-T3G-C125S]]>
          <![CDATA[<400>  46]]>
          Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Gly Gly Pro Ser 
          1               5                   10                  15      
          Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg 
                      20                  25                  30          
          Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro 
                  35                  40                  45              
          Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala 
              50                  55                  60                  
          Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val 
          65                  70                  75                  80  
          Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr 
                          85                  90                  95      
          Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr 
                      100                 105                 110         
          Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu 
                  115                 120                 125             
          Pro Pro Cys Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu Trp Cys 
              130                 135                 140                 
          Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser 
          145                 150                 155                 160 
          Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp 
                          165                 170                 175     
          Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser 
                      180                 185                 190         
          Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala 
                  195                 200                 205             
          Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Gly 
              210                 215                 220                 
          Ser Gly Gly Ser Ala Pro Gly Ser Ser Ser Thr Lys Lys Thr Gln Leu 
          225                 230                 235                 240 
          Gln Leu Glu Ala Leu Leu Leu Asp Leu Gln Met Ile Leu Asn Gly Ile 
                          245                 250                 255     
          Asn Asn Tyr Lys Asn Pro Lys Leu Thr Arg Met Leu Thr Phe Lys Phe 
                      260                 265                 270         
          Tyr Met Pro Lys Lys Ala Thr Glu Leu Lys His Leu Gln Cys Leu Glu 
                  275                 280                 285             
          Glu Glu Leu Lys Arg Leu Glu Glu Val Leu Asn Leu Ala Gln Ser Lys 
              290                 295                 300                 
          Asn Phe His Leu Arg Pro Arg Ser Leu Ile Ser Asn Ile Asn Val Ile 
          305                 310                 315                 320 
          Val Leu Glu Leu Lys Gly Ser Glu Thr Thr Phe Met Cys Glu Tyr Ala 
                          325                 330                 335     
          Asp Glu Thr Ala Thr Ile Val Glu Phe Leu Asn Arg Trp Ile Thr Phe 
                      340                 345                 350         
          Ser Gln Ser Ile Ile Ser Thr Leu Thr 
                  355                 360     
          <![CDATA[<210>  47]]>
          <![CDATA[<211>  226]]>
          <![CDATA[<212>  PRT]]>
          <![CDATA[<213>  智人]]>
          <![CDATA[<220>]]>
          <![CDATA[<221>  SITE]]>
          <![CDATA[<222>  (1)..(226)]]>
          <![CDATA[<223>  Fc區1 (人類野生型IgG1)]]>
          <![CDATA[<400>  47]]>
          Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly 
          1               5                   10                  15      
          Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met 
                      20                  25                  30          
          Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His 
                  35                  40                  45              
          Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val 
              50                  55                  60                  
          His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr 
          65                  70                  75                  80  
          Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly 
                          85                  90                  95      
          Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile 
                      100                 105                 110         
          Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val 
                  115                 120                 125             
          Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser 
              130                 135                 140                 
          Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu 
          145                 150                 155                 160 
          Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro 
                          165                 170                 175     
          Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val 
                      180                 185                 190         
          Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met 
                  195                 200                 205             
          His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser 
              210                 215                 220                 
          Pro Gly 
          225     
          <![CDATA[<210>  48]]>
          <![CDATA[<211>  223]]>
          <![CDATA[<212>  PRT]]>
          <![CDATA[<213>  智人]]>
          <![CDATA[<220>]]>
          <![CDATA[<221>  SITE]]>
          <![CDATA[<222>  (1)..(223)]]>
          <![CDATA[<223>  Fc區2 (人類IgG1 xELL杵)]]>
          <![CDATA[<400>  48]]>
          Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Gly Gly Pro Ser 
          1               5                   10                  15      
          Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg 
                      20                  25                  30          
          Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro 
                  35                  40                  45              
          Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala 
              50                  55                  60                  
          Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val 
          65                  70                  75                  80  
          Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr 
                          85                  90                  95      
          Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr 
                      100                 105                 110         
          Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu 
                  115                 120                 125             
          Pro Pro Cys Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu Trp Cys 
              130                 135                 140                 
          Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser 
          145                 150                 155                 160 
          Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp 
                          165                 170                 175     
          Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser 
                      180                 185                 190         
          Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala 
                  195                 200                 205             
          Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly 
              210                 215                 220             
          <![CDATA[<210>  49]]>
          <![CDATA[<211>  223]]>
          <![CDATA[<212>  PRT]]>
          <![CDATA[<213>  智人]]>
          <![CDATA[<220>]]>
          <![CDATA[<221>  SITE]]>
          <![CDATA[<222>  (1)..(223)]]>
          <![CDATA[<223>  Fc區3 (人類IgG1 EVN xELL臼I253R)]]>
          <![CDATA[<400>  49]]>
          Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Gly Gly Pro Ser 
          1               5                   10                  15      
          Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Arg Ser Arg 
                      20                  25                  30          
          Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro 
                  35                  40                  45              
          Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala 
              50                  55                  60                  
          Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val 
          65                  70                  75                  80  
          Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr 
                          85                  90                  95      
          Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr 
                      100                 105                 110         
          Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Cys Thr Leu 
                  115                 120                 125             
          Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu Ser Cys 
              130                 135                 140                 
          Ala Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser 
          145                 150                 155                 160 
          Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp 
                          165                 170                 175     
          Ser Asp Gly Ser Phe Phe Leu Val Ser Lys Leu Thr Val Asp Lys Ser 
                      180                 185                 190         
          Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala 
                  195                 200                 205             
          Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly 
              210                 215                 220             
          <![CDATA[<210>  50]]>
          <![CDATA[<211>  226]]>
          <![CDATA[<212>  PRT]]>
          <![CDATA[<213>  人工序列]]>
          <![CDATA[<220>]]>
          <![CDATA[<223>  合成：Fc區]]>
          <![CDATA[<400>  50]]>
          Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly 
          1               5                   10                  15      
          Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met 
                      20                  25                  30          
          Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His 
                  35                  40                  45              
          Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val 
              50                  55                  60                  
          His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr 
          65                  70                  75                  80  
          Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly 
                          85                  90                  95      
          Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile 
                      100                 105                 110         
          Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val 
                  115                 120                 125             
          Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser 
              130                 135                 140                 
          Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu 
          145                 150                 155                 160 
          Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro 
                          165                 170                 175     
          Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val 
                      180                 185                 190         
          Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met 
                  195                 200                 205             
          His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser 
              210                 215                 220                 
          Pro Gly 
          225     
          <![CDATA[<210>  51]]>
          <![CDATA[<211>  223]]>
          <![CDATA[<212>  PRT]]>
          <![CDATA[<213>  人工序列]]>
          <![CDATA[<220>]]>
          <![CDATA[<223>  合成：Fc區xELL]]>
          <![CDATA[<400>  51]]>
          Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Gly Gly Pro Ser 
          1               5                   10                  15      
          Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg 
                      20                  25                  30          
          Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro 
                  35                  40                  45              
          Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala 
              50                  55                  60                  
          Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val 
          65                  70                  75                  80  
          Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr 
                          85                  90                  95      
          Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr 
                      100                 105                 110         
          Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu 
                  115                 120                 125             
          Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu Thr Cys 
              130                 135                 140                 
          Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser 
          145                 150                 155                 160 
          Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp 
                          165                 170                 175     
          Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser 
                      180                 185                 190         
          Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala 
                  195                 200                 205             
          Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly 
              210                 215                 220             
          <![CDATA[<210>  52]]>
          <![CDATA[<211>  222]]>
          <![CDATA[<212>  PRT]]>
          <![CDATA[<213>  人工序列]]>
          <![CDATA[<220>]]>
          <![CDATA[<223>  合成：Fc區xELL H435R]]>
          <![CDATA[<400>  52]]>
          Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Gly Gly Pro Ser 
          1               5                   10                  15      
          Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg 
                      20                  25                  30          
          Thr Pro Glu Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu 
                  35                  40                  45              
          Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys 
              50                  55                  60                  
          Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser 
          65                  70                  75                  80  
          Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys 
                          85                  90                  95      
          Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile 
                      100                 105                 110         
          Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro 
                  115                 120                 125             
          Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu Thr Cys Leu 
              130                 135                 140                 
          Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn 
          145                 150                 155                 160 
          Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser 
                          165                 170                 175     
          Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg 
                      180                 185                 190         
          Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu 
                  195                 200                 205             
          His Asn Arg Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly 
              210                 215                 220         
          <![CDATA[<210>  53]]>
          <![CDATA[<211>  223]]>
          <![CDATA[<212>  PRT]]>
          <![CDATA[<213>  人工序列]]>
          <![CDATA[<220>]]>
          <![CDATA[<223>  合成：Fc區xELL M252Y及M428V (YV)]]>
          <![CDATA[<400>  53]]>
          Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Gly Gly Pro Ser 
          1               5                   10                  15      
          Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Tyr Ile Ser Arg 
                      20                  25                  30          
          Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro 
                  35                  40                  45              
          Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala 
              50                  55                  60                  
          Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val 
          65                  70                  75                  80  
          Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr 
                          85                  90                  95      
          Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr 
                      100                 105                 110         
          Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu 
                  115                 120                 125             
          Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu Thr Cys 
              130                 135                 140                 
          Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser 
          145                 150                 155                 160 
          Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp 
                          165                 170                 175     
          Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser 
                      180                 185                 190         
          Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Val His Glu Ala 
                  195                 200                 205             
          Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly 
              210                 215                 220             
          <![CDATA[<210>  54]]>
          <![CDATA[<211>  223]]>
          <![CDATA[<212>  PRT]]>
          <![CDATA[<213>  人工序列]]>
          <![CDATA[<220>]]>
          <![CDATA[<223>  合成：Fc區xELL M252Y及M428L (YL)]]>
          <![CDATA[<400>  54]]>
          Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Gly Gly Pro Ser 
          1               5                   10                  15      
          Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Tyr Ile Ser Arg 
                      20                  25                  30          
          Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro 
                  35                  40                  45              
          Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala 
              50                  55                  60                  
          Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val 
          65                  70                  75                  80  
          Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr 
                          85                  90                  95      
          Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr 
                      100                 105                 110         
          Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu 
                  115                 120                 125             
          Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu Thr Cys 
              130                 135                 140                 
          Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser 
          145                 150                 155                 160 
          Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp 
                          165                 170                 175     
          Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser 
                      180                 185                 190         
          Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Leu His Glu Ala 
                  195                 200                 205             
          Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly 
              210                 215                 220             
          <![CDATA[<210>  55]]>
          <![CDATA[<211>  223]]>
          <![CDATA[<212>  PRT]]>
          <![CDATA[<213>  人工序列]]>
          <![CDATA[<220>]]>
          <![CDATA[<223>  合成：Fc區xELL M252Y, M428L, H435R (YLR)]]>
          <![CDATA[<400>  55]]>
          Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Gly Gly Pro Ser 
          1               5                   10                  15      
          Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Tyr Ile Ser Arg 
                      20                  25                  30          
          Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro 
                  35                  40                  45              
          Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala 
              50                  55                  60                  
          Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val 
          65                  70                  75                  80  
          Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr 
                          85                  90                  95      
          Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr 
                      100                 105                 110         
          Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu 
                  115                 120                 125             
          Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu Thr Cys 
              130                 135                 140                 
          Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser 
          145                 150                 155                 160 
          Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp 
                          165                 170                 175     
          Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser 
                      180                 185                 190         
          Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Leu His Glu Ala 
                  195                 200                 205             
          Leu His Asn Arg Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly 
              210                 215                 220             
          <![CDATA[<210>  56]]>
          <![CDATA[<211>  223]]>
          <![CDATA[<212>  PRT]]>
          <![CDATA[<213>  人工序列]]>
          <![CDATA[<220>]]>
          <![CDATA[<223>  合成：Fc區xELL M252Y, M428V, H435R (YVR)]]>
          <![CDATA[<400>  56]]>
          Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Gly Gly Pro Ser 
          1               5                   10                  15      
          Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Tyr Ile Ser Arg 
                      20                  25                  30          
          Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro 
                  35                  40                  45              
          Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala 
              50                  55                  60                  
          Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val 
          65                  70                  75                  80  
          Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr 
                          85                  90                  95      
          Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr 
                      100                 105                 110         
          Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu 
                  115                 120                 125             
          Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu Thr Cys 
              130                 135                 140                 
          Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser 
          145                 150                 155                 160 
          Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp 
                          165                 170                 175     
          Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser 
                      180                 185                 190         
          Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Val His Glu Ala 
                  195                 200                 205             
          Leu His Asn Arg Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly 
              210                 215                 220             
          <![CDATA[<210>  57]]>
          <![CDATA[<211>  223]]>
          <![CDATA[<212>  PRT]]>
          <![CDATA[<213>  人工序列]]>
          <![CDATA[<220>]]>
          <![CDATA[<223>  合成：Fc區xELL S354C T366W杵]]>
          <![CDATA[<400>  57]]>
          Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Gly Gly Pro Ser 
          1               5                   10                  15      
          Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg 
                      20                  25                  30          
          Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro 
                  35                  40                  45              
          Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala 
              50                  55                  60                  
          Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val 
          65                  70                  75                  80  
          Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr 
                          85                  90                  95      
          Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr 
                      100                 105                 110         
          Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu 
                  115                 120                 125             
          Pro Pro Cys Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu Trp Cys 
              130                 135                 140                 
          Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser 
          145                 150                 155                 160 
          Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp 
                          165                 170                 175     
          Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser 
                      180                 185                 190         
          Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala 
                  195                 200                 205             
          Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly 
              210                 215                 220             
          <![CDATA[<210>  58]]>
          <![CDATA[<211>  223]]>
          <![CDATA[<212>  PRT]]>
          <![CDATA[<213>  人工序列]]>
          <![CDATA[<220>]]>
          <![CDATA[<223>  合成：Fc區xELL H435R S354C T366W杵]]>
          <![CDATA[<400>  58]]>
          Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Gly Gly Pro Ser 
          1               5                   10                  15      
          Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg 
                      20                  25                  30          
          Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro 
                  35                  40                  45              
          Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala 
              50                  55                  60                  
          Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val 
          65                  70                  75                  80  
          Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr 
                          85                  90                  95      
          Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr 
                      100                 105                 110         
          Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu 
                  115                 120                 125             
          Pro Pro Cys Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu Trp Cys 
              130                 135                 140                 
          Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser 
          145                 150                 155                 160 
          Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp 
                          165                 170                 175     
          Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser 
                      180                 185                 190         
          Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala 
                  195                 200                 205             
          Leu His Asn Arg Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly 
              210                 215                 220             
          <![CDATA[<210>  59]]>
          <![CDATA[<211>  223]]>
          <![CDATA[<212>  PRT]]>
          <![CDATA[<213>  人工序列]]>
          <![CDATA[<220>]]>
          <![CDATA[<223>  合成：Fc區xELL M252Y及M428V (YV) S354C T366W杵]]>
          <![CDATA[<400>  59]]>
          Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Gly Gly Pro Ser 
          1               5                   10                  15      
          Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Tyr Ile Ser Arg 
                      20                  25                  30          
          Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro 
                  35                  40                  45              
          Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala 
              50                  55                  60                  
          Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val 
          65                  70                  75                  80  
          Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr 
                          85                  90                  95      
          Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr 
                      100                 105                 110         
          Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu 
                  115                 120                 125             
          Pro Pro Cys Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu Trp Cys 
              130                 135                 140                 
          Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser 
          145                 150                 155                 160 
          Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp 
                          165                 170                 175     
          Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser 
                      180                 185                 190         
          Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Val His Glu Ala 
                  195                 200                 205             
          Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly 
              210                 215                 220             
          <![CDATA[<210>  60]]>
          <![CDATA[<211>  223]]>
          <![CDATA[<212>  PRT]]>
          <![CDATA[<213>  人工序列]]>
          <![CDATA[<220>]]>
          <![CDATA[<223>  合成：Fc區xELL M252Y及M428L (YL) S354C T366W杵]]>
          <![CDATA[<400>  60]]>
          Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Gly Gly Pro Ser 
          1               5                   10                  15      
          Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Tyr Ile Ser Arg 
                      20                  25                  30          
          Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro 
                  35                  40                  45              
          Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala 
              50                  55                  60                  
          Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val 
          65                  70                  75                  80  
          Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr 
                          85                  90                  95      
          Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr 
                      100                 105                 110         
          Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu 
                  115                 120                 125             
          Pro Pro Cys Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu Trp Cys 
              130                 135                 140                 
          Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser 
          145                 150                 155                 160 
          Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp 
                          165                 170                 175     
          Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser 
                      180                 185                 190         
          Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Leu His Glu Ala 
                  195                 200                 205             
          Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly 
              210                 215                 220             
          <![CDATA[<210>  61]]>
          <![CDATA[<211>  223]]>
          <![CDATA[<212>  PRT]]>
          <![CDATA[<213>  人工序列]]>
          <![CDATA[<220>]]>
          <![CDATA[<223>  合成：Fc區xELL M252Y, M428L, H435R (YLR) S354C T366W杵]]>
          <![CDATA[<400>  61]]>
          Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Gly Gly Pro Ser 
          1               5                   10                  15      
          Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Tyr Ile Ser Arg 
                      20                  25                  30          
          Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro 
                  35                  40                  45              
          Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala 
              50                  55                  60                  
          Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val 
          65                  70                  75                  80  
          Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr 
                          85                  90                  95      
          Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr 
                      100                 105                 110         
          Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu 
                  115                 120                 125             
          Pro Pro Cys Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu Trp Cys 
              130                 135                 140                 
          Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser 
          145                 150                 155                 160 
          Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp 
                          165                 170                 175     
          Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser 
                      180                 185                 190         
          Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Leu His Glu Ala 
                  195                 200                 205             
          Leu His Asn Arg Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly 
              210                 215                 220             
          <![CDATA[<210>  62]]>
          <![CDATA[<211>  223]]>
          <![CDATA[<212>  PRT]]>
          <![CDATA[<213>  人工序列]]>
          <![CDATA[<220>]]>
          <![CDATA[<223>  合成：Fc區xELL M252Y, M428V, H435R (YVR) S354C T366W杵]]>
          <![CDATA[<400>  62]]>
          Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Gly Gly Pro Ser 
          1               5                   10                  15      
          Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Tyr Ile Ser Arg 
                      20                  25                  30          
          Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro 
                  35                  40                  45              
          Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala 
              50                  55                  60                  
          Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val 
          65                  70                  75                  80  
          Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr 
                          85                  90                  95      
          Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr 
                      100                 105                 110         
          Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu 
                  115                 120                 125             
          Pro Pro Cys Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu Trp Cys 
              130                 135                 140                 
          Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser 
          145                 150                 155                 160 
          Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp 
                          165                 170                 175     
          Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser 
                      180                 185                 190         
          Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Val His Glu Ala 
                  195                 200                 205             
          Leu His Asn Arg Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly 
              210                 215                 220             
          <![CDATA[<210>  63]]>
          <![CDATA[<211>  223]]>
          <![CDATA[<212>  PRT]]>
          <![CDATA[<213>  人工序列]]>
          <![CDATA[<220>]]>
          <![CDATA[<223>  合成：Fc區xELL T366S, L368A, Y407V臼]]>
          <![CDATA[<400>  63]]>
          Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Gly Gly Pro Ser 
          1               5                   10                  15      
          Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg 
                      20                  25                  30          
          Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro 
                  35                  40                  45              
          Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala 
              50                  55                  60                  
          Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val 
          65                  70                  75                  80  
          Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr 
                          85                  90                  95      
          Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr 
                      100                 105                 110         
          Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Cys Thr Leu 
                  115                 120                 125             
          Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu Ser Cys 
              130                 135                 140                 
          Ala Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser 
          145                 150                 155                 160 
          Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp 
                          165                 170                 175     
          Ser Asp Gly Ser Phe Phe Leu Val Ser Lys Leu Thr Val Asp Lys Ser 
                      180                 185                 190         
          Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala 
                  195                 200                 205             
          Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly 
              210                 215                 220             
          <![CDATA[<210>  64]]>
          <![CDATA[<211>  223]]>
          <![CDATA[<212>  PRT]]>
          <![CDATA[<213>  人工序列]]>
          <![CDATA[<220>]]>
          <![CDATA[<223>  合成：Fc區xELL H435R, T366S, L368A, Y407V臼]]>
          <![CDATA[<400>  64]]>
          Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Gly Gly Pro Ser 
          1               5                   10                  15      
          Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg 
                      20                  25                  30          
          Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro 
                  35                  40                  45              
          Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala 
              50                  55                  60                  
          Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val 
          65                  70                  75                  80  
          Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr 
                          85                  90                  95      
          Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr 
                      100                 105                 110         
          Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Cys Thr Leu 
                  115                 120                 125             
          Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu Ser Cys 
              130                 135                 140                 
          Ala Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser 
          145                 150                 155                 160 
          Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp 
                          165                 170                 175     
          Ser Asp Gly Ser Phe Phe Leu Val Ser Lys Leu Thr Val Asp Lys Ser 
                      180                 185                 190         
          Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala 
                  195                 200                 205             
          Leu His Asn Arg Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly 
              210                 215                 220             
          <![CDATA[<210>  65]]>
          <![CDATA[<211>  223]]>
          <![CDATA[<212>  PRT]]>
          <![CDATA[<213>  人工序列]]>
          <![CDATA[<220>]]>
          <![CDATA[<223>  合成：Fc區xELL M252Y及M428V (YV) T366S, L368A, ]]>
                 Y407V臼
          <![CDATA[<400>  65]]>
          Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Gly Gly Pro Ser 
          1               5                   10                  15      
          Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Tyr Ile Ser Arg 
                      20                  25                  30          
          Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro 
                  35                  40                  45              
          Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala 
              50                  55                  60                  
          Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val 
          65                  70                  75                  80  
          Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr 
                          85                  90                  95      
          Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr 
                      100                 105                 110         
          Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Cys Thr Leu 
                  115                 120                 125             
          Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu Ser Cys 
              130                 135                 140                 
          Ala Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser 
          145                 150                 155                 160 
          Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp 
                          165                 170                 175     
          Ser Asp Gly Ser Phe Phe Leu Val Ser Lys Leu Thr Val Asp Lys Ser 
                      180                 185                 190         
          Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Val His Glu Ala 
                  195                 200                 205             
          Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly 
              210                 215                 220             
          <![CDATA[<210>  66]]>
          <![CDATA[<211>  223]]>
          <![CDATA[<212>  PRT]]>
          <![CDATA[<213>  人工序列]]>
          <![CDATA[<220>]]>
          <![CDATA[<223>  合成：Fc區xELL M252Y及M428L (YL) T366S, L368A, ]]>
                 Y407V臼
          <![CDATA[<400>  66]]>
          Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Gly Gly Pro Ser 
          1               5                   10                  15      
          Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Tyr Ile Ser Arg 
                      20                  25                  30          
          Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro 
                  35                  40                  45              
          Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala 
              50                  55                  60                  
          Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val 
          65                  70                  75                  80  
          Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr 
                          85                  90                  95      
          Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr 
                      100                 105                 110         
          Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Cys Thr Leu 
                  115                 120                 125             
          Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu Ser Cys 
              130                 135                 140                 
          Ala Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser 
          145                 150                 155                 160 
          Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp 
                          165                 170                 175     
          Ser Asp Gly Ser Phe Phe Leu Val Ser Lys Leu Thr Val Asp Lys Ser 
                      180                 185                 190         
          Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Leu His Glu Ala 
                  195                 200                 205             
          Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly 
              210                 215                 220             
          <![CDATA[<210>  67]]>
          <![CDATA[<211>  223]]>
          <![CDATA[<212>  PRT]]>
          <![CDATA[<213>  人工序列]]>
          <![CDATA[<220>]]>
          <![CDATA[<223>  合成：Fc區xELL M252Y, M428L, H435R (YLR) T366S, L368A,]]>
                 Y407V臼
          <![CDATA[<400>  67]]>
          Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Gly Gly Pro Ser 
          1               5                   10                  15      
          Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Tyr Ile Ser Arg 
                      20                  25                  30          
          Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro 
                  35                  40                  45              
          Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala 
              50                  55                  60                  
          Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val 
          65                  70                  75                  80  
          Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr 
                          85                  90                  95      
          Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr 
                      100                 105                 110         
          Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Cys Thr Leu 
                  115                 120                 125             
          Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu Ser Cys 
              130                 135                 140                 
          Ala Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser 
          145                 150                 155                 160 
          Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp 
                          165                 170                 175     
          Ser Asp Gly Ser Phe Phe Leu Val Ser Lys Leu Thr Val Asp Lys Ser 
                      180                 185                 190         
          Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Leu His Glu Ala 
                  195                 200                 205             
          Leu His Asn Arg Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly 
              210                 215                 220             
          <![CDATA[<210>  68]]>
          <![CDATA[<211>  223]]>
          <![CDATA[<212>  PRT]]>
          <![CDATA[<213>  人工序列]]>
          <![CDATA[<220>]]>
          <![CDATA[<223>  合成：Fc區xELL M252Y, M428V, H435R (YVR) T366S, L368A,]]>
                 Y407V臼
          <![CDATA[<400>  68]]>
          Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Gly Gly Pro Ser 
          1               5                   10                  15      
          Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Tyr Ile Ser Arg 
                      20                  25                  30          
          Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro 
                  35                  40                  45              
          Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala 
              50                  55                  60                  
          Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val 
          65                  70                  75                  80  
          Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr 
                          85                  90                  95      
          Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr 
                      100                 105                 110         
          Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Cys Thr Leu 
                  115                 120                 125             
          Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu Ser Cys 
              130                 135                 140                 
          Ala Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser 
          145                 150                 155                 160 
          Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp 
                          165                 170                 175     
          Ser Asp Gly Ser Phe Phe Leu Val Ser Lys Leu Thr Val Asp Lys Ser 
                      180                 185                 190         
          Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Val His Glu Ala 
                  195                 200                 205             
          Leu His Asn Arg Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly 
              210                 215                 220             
          <![CDATA[<210>  69]]>
          <![CDATA[<211>  226]]>
          <![CDATA[<212>  PRT]]>
          <![CDATA[<213>  人工序列]]>
          <![CDATA[<220>]]>
          <![CDATA[<223>  合成：Fc區H435R]]>
          <![CDATA[<400>  69]]>
          Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly 
          1               5                   10                  15      
          Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met 
                      20                  25                  30          
          Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His 
                  35                  40                  45              
          Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val 
              50                  55                  60                  
          His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr 
          65                  70                  75                  80  
          Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly 
                          85                  90                  95      
          Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile 
                      100                 105                 110         
          Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val 
                  115                 120                 125             
          Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser 
              130                 135                 140                 
          Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu 
          145                 150                 155                 160 
          Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro 
                          165                 170                 175     
          Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val 
                      180                 185                 190         
          Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met 
                  195                 200                 205             
          His Glu Ala Leu His Asn Arg Tyr Thr Gln Lys Ser Leu Ser Leu Ser 
              210                 215                 220                 
          Pro Gly 
          225     
          <![CDATA[<210>  70]]>
          <![CDATA[<211>  226]]>
          <![CDATA[<212>  PRT]]>
          <![CDATA[<213>  人工序列]]>
          <![CDATA[<220>]]>
          <![CDATA[<223>  合成：Fc區M252Y及M428V (YV)]]>
          <![CDATA[<400>  70]]>
          Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly 
          1               5                   10                  15      
          Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Tyr 
                      20                  25                  30          
          Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His 
                  35                  40                  45              
          Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val 
              50                  55                  60                  
          His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr 
          65                  70                  75                  80  
          Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly 
                          85                  90                  95      
          Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile 
                      100                 105                 110         
          Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val 
                  115                 120                 125             
          Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser 
              130                 135                 140                 
          Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu 
          145                 150                 155                 160 
          Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro 
                          165                 170                 175     
          Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val 
                      180                 185                 190         
          Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Val 
                  195                 200                 205             
          His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser 
              210                 215                 220                 
          Pro Gly 
          225     
          <![CDATA[<210>  71]]>
          <![CDATA[<211>  226]]>
          <![CDATA[<212>  PRT]]>
          <![CDATA[<213>  人工序列]]>
          <![CDATA[<220>]]>
          <![CDATA[<223>  合成：Fc區M252Y及M428L (YL)]]>
          <![CDATA[<400>  71]]>
          Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly 
          1               5                   10                  15      
          Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Tyr 
                      20                  25                  30          
          Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His 
                  35                  40                  45              
          Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val 
              50                  55                  60                  
          His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr 
          65                  70                  75                  80  
          Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly 
                          85                  90                  95      
          Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile 
                      100                 105                 110         
          Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val 
                  115                 120                 125             
          Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser 
              130                 135                 140                 
          Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu 
          145                 150                 155                 160 
          Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro 
                          165                 170                 175     
          Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val 
                      180                 185                 190         
          Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Leu 
                  195                 200                 205             
          His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser 
              210                 215                 220                 
          Pro Gly 
          225     
          <![CDATA[<210>  72]]>
          <![CDATA[<211>  226]]>
          <![CDATA[<212>  PRT]]>
          <![CDATA[<213>  人工序列]]>
          <![CDATA[<220>]]>
          <![CDATA[<223>  合成：Fc區M252Y, M428L, H435R (YLR)]]>
          <![CDATA[<400>  72]]>
          Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly 
          1               5                   10                  15      
          Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Tyr 
                      20                  25                  30          
          Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His 
                  35                  40                  45              
          Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val 
              50                  55                  60                  
          His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr 
          65                  70                  75                  80  
          Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly 
                          85                  90                  95      
          Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile 
                      100                 105                 110         
          Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val 
                  115                 120                 125             
          Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser 
              130                 135                 140                 
          Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu 
          145                 150                 155                 160 
          Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro 
                          165                 170                 175     
          Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val 
                      180                 185                 190         
          Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Leu 
                  195                 200                 205             
          His Glu Ala Leu His Asn Arg Tyr Thr Gln Lys Ser Leu Ser Leu Ser 
              210                 215                 220                 
          Pro Gly 
          225     
          <![CDATA[<210>  73]]>
          <![CDATA[<211>  226]]>
          <![CDATA[<212>  PRT]]>
          <![CDATA[<213>  人工序列]]>
          <![CDATA[<220>]]>
          <![CDATA[<223>  合成：Fc區M252Y, M428V, H435R (YVR)]]>
          <![CDATA[<400>  73]]>
          Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly 
          1               5                   10                  15      
          Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Tyr 
                      20                  25                  30          
          Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His 
                  35                  40                  45              
          Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val 
              50                  55                  60                  
          His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr 
          65                  70                  75                  80  
          Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly 
                          85                  90                  95      
          Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile 
                      100                 105                 110         
          Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val 
                  115                 120                 125             
          Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser 
              130                 135                 140                 
          Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu 
          145                 150                 155                 160 
          Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro 
                          165                 170                 175     
          Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val 
                      180                 185                 190         
          Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Val 
                  195                 200                 205             
          His Glu Ala Leu His Asn Arg Tyr Thr Gln Lys Ser Leu Ser Leu Ser 
              210                 215                 220                 
          Pro Gly 
          225     
          <![CDATA[<210>  74]]>
          <![CDATA[<211>  226]]>
          <![CDATA[<212>  PRT]]>
          <![CDATA[<213>  人工序列]]>
          <![CDATA[<220>]]>
          <![CDATA[<223>  合成：Fc區S354C T366W杵]]>
          <![CDATA[<400>  74]]>
          Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly 
          1               5                   10                  15      
          Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met 
                      20                  25                  30          
          Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His 
                  35                  40                  45              
          Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val 
              50                  55                  60                  
          His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr 
          65                  70                  75                  80  
          Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly 
                          85                  90                  95      
          Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile 
                      100                 105                 110         
          Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val 
                  115                 120                 125             
          Tyr Thr Leu Pro Pro Cys Arg Asp Glu Leu Thr Lys Asn Gln Val Ser 
              130                 135                 140                 
          Leu Trp Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu 
          145                 150                 155                 160 
          Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro 
                          165                 170                 175     
          Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val 
                      180                 185                 190         
          Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met 
                  195                 200                 205             
          His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser 
              210                 215                 220                 
          Pro Gly 
          225     
          <![CDATA[<210>  75]]>
          <![CDATA[<211>  226]]>
          <![CDATA[<212>  PRT]]>
          <![CDATA[<213>  人工序列]]>
          <![CDATA[<220>]]>
          <![CDATA[<223>  合成：Fc區H435R S354C T366W杵]]>
          <![CDATA[<400>  75]]>
          Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly 
          1               5                   10                  15      
          Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met 
                      20                  25                  30          
          Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His 
                  35                  40                  45              
          Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val 
              50                  55                  60                  
          His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr 
          65                  70                  75                  80  
          Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly 
                          85                  90                  95      
          Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile 
                      100                 105                 110         
          Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val 
                  115                 120                 125             
          Tyr Thr Leu Pro Pro Cys Arg Asp Glu Leu Thr Lys Asn Gln Val Ser 
              130                 135                 140                 
          Leu Trp Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu 
          145                 150                 155                 160 
          Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro 
                          165                 170                 175     
          Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val 
                      180                 185                 190         
          Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met 
                  195                 200                 205             
          His Glu Ala Leu His Asn Arg Tyr Thr Gln Lys Ser Leu Ser Leu Ser 
              210                 215                 220                 
          Pro Gly 
          225     
          <![CDATA[<210>  76]]>
          <![CDATA[<211>  226]]>
          <![CDATA[<212>  PRT]]>
          <![CDATA[<213>  人工序列]]>
          <![CDATA[<220>]]>
          <![CDATA[<223>  合成：Fc區M252Y及M428L (YL) S354C T366W杵]]>
          <![CDATA[<400>  76]]>
          Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly 
          1               5                   10                  15      
          Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Tyr 
                      20                  25                  30          
          Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His 
                  35                  40                  45              
          Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val 
              50                  55                  60                  
          His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr 
          65                  70                  75                  80  
          Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly 
                          85                  90                  95      
          Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile 
                      100                 105                 110         
          Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val 
                  115                 120                 125             
          Tyr Thr Leu Pro Pro Cys Arg Asp Glu Leu Thr Lys Asn Gln Val Ser 
              130                 135                 140                 
          Leu Trp Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu 
          145                 150                 155                 160 
          Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro 
                          165                 170                 175     
          Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val 
                      180                 185                 190         
          Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Leu 
                  195                 200                 205             
          His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser 
              210                 215                 220                 
          Pro Gly 
          225     
          <![CDATA[<210>  77]]>
          <![CDATA[<211>  226]]>
          <![CDATA[<212>  PRT]]>
          <![CDATA[<213>  人工序列]]>
          <![CDATA[<220>]]>
          <![CDATA[<223>  合成：Fc區M252Y, M428L, H435R (YLR) S354C T366W杵]]>
          <![CDATA[<400>  77]]>
          Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly 
          1               5                   10                  15      
          Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Tyr 
                      20                  25                  30          
          Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His 
                  35                  40                  45              
          Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val 
              50                  55                  60                  
          His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr 
          65                  70                  75                  80  
          Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly 
                          85                  90                  95      
          Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile 
                      100                 105                 110         
          Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val 
                  115                 120                 125             
          Tyr Thr Leu Pro Pro Cys Arg Asp Glu Leu Thr Lys Asn Gln Val Ser 
              130                 135                 140                 
          Leu Trp Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu 
          145                 150                 155                 160 
          Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro 
                          165                 170                 175     
          Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val 
                      180                 185                 190         
          Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Leu 
                  195                 200                 205             
          His Glu Ala Leu His Asn Arg Tyr Thr Gln Lys Ser Leu Ser Leu Ser 
              210                 215                 220                 
          Pro Gly 
          225     
          <![CDATA[<210>  78]]>
          <![CDATA[<211>  226]]>
          <![CDATA[<212>  PRT]]>
          <![CDATA[<213>  人工序列]]>
          <![CDATA[<220>]]>
          <![CDATA[<223>  合成：Fc區M252Y, M428V, H435R (YVR) S354C T366W杵]]>
          <![CDATA[<400>  78]]>
          Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly 
          1               5                   10                  15      
          Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Tyr 
                      20                  25                  30          
          Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His 
                  35                  40                  45              
          Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val 
              50                  55                  60                  
          His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr 
          65                  70                  75                  80  
          Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly 
                          85                  90                  95      
          Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile 
                      100                 105                 110         
          Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val 
                  115                 120                 125             
          Tyr Thr Leu Pro Pro Cys Arg Asp Glu Leu Thr Lys Asn Gln Val Ser 
              130                 135                 140                 
          Leu Trp Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu 
          145                 150                 155                 160 
          Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro 
                          165                 170                 175     
          Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val 
                      180                 185                 190         
          Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Val 
                  195                 200                 205             
          His Glu Ala Leu His Asn Arg Tyr Thr Gln Lys Ser Leu Ser Leu Ser 
              210                 215                 220                 
          Pro Gly 
          225     
          <![CDATA[<210>  79]]>
          <![CDATA[<211>  226]]>
          <![CDATA[<212>  PRT]]>
          <![CDATA[<213>  人工序列]]>
          <![CDATA[<220>]]>
          <![CDATA[<223>  合成：Fc區T366S, L368A, Y407V臼]]>
          <![CDATA[<400>  79]]>
          Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly 
          1               5                   10                  15      
          Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met 
                      20                  25                  30          
          Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His 
                  35                  40                  45              
          Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val 
              50                  55                  60                  
          His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr 
          65                  70                  75                  80  
          Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly 
                          85                  90                  95      
          Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile 
                      100                 105                 110         
          Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val 
                  115                 120                 125             
          Cys Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser 
              130                 135                 140                 
          Leu Ser Cys Ala Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu 
          145                 150                 155                 160 
          Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro 
                          165                 170                 175     
          Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Val Ser Lys Leu Thr Val 
                      180                 185                 190         
          Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met 
                  195                 200                 205             
          His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser 
              210                 215                 220                 
          Pro Gly 
          225     
          <![CDATA[<210>  80]]>
          <![CDATA[<211>  226]]>
          <![CDATA[<212>  PRT]]>
          <![CDATA[<213>  人工序列]]>
          <![CDATA[<220>]]>
          <![CDATA[<223>  合成：Fc區H435R, T366S, L368A, Y407V臼]]>
          <![CDATA[<400>  80]]>
          Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly 
          1               5                   10                  15      
          Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met 
                      20                  25                  30          
          Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His 
                  35                  40                  45              
          Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val 
              50                  55                  60                  
          His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr 
          65                  70                  75                  80  
          Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly 
                          85                  90                  95      
          Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile 
                      100                 105                 110         
          Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val 
                  115                 120                 125             
          Cys Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser 
              130                 135                 140                 
          Leu Ser Cys Ala Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu 
          145                 150                 155                 160 
          Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro 
                          165                 170                 175     
          Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Val Ser Lys Leu Thr Val 
                      180                 185                 190         
          Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met 
                  195                 200                 205             
          His Glu Ala Leu His Asn Arg Tyr Thr Gln Lys Ser Leu Ser Leu Ser 
              210                 215                 220                 
          Pro Gly 
          225     
          <![CDATA[<210>  81]]>
          <![CDATA[<211>  226]]>
          <![CDATA[<212>  PRT]]>
          <![CDATA[<213>  人工序列]]>
          <![CDATA[<220>]]>
          <![CDATA[<223>  合成：Fc區M252Y及M428V (YV) T366S, L368A, Y407V臼]]>
          <![CDATA[<400>  81]]>
          Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly 
          1               5                   10                  15      
          Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Tyr 
                      20                  25                  30          
          Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His 
                  35                  40                  45              
          Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val 
              50                  55                  60                  
          His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr 
          65                  70                  75                  80  
          Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly 
                          85                  90                  95      
          Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile 
                      100                 105                 110         
          Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val 
                  115                 120                 125             
          Cys Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser 
              130                 135                 140                 
          Leu Ser Cys Ala Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu 
          145                 150                 155                 160 
          Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro 
                          165                 170                 175     
          Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Val Ser Lys Leu Thr Val 
                      180                 185                 190         
          Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Val 
                  195                 200                 205             
          His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser 
              210                 215                 220                 
          Pro Gly 
          225     
          <![CDATA[<210>  82]]>
          <![CDATA[<211>  226]]>
          <![CDATA[<212>  PRT]]>
          <![CDATA[<213>  人工序列]]>
          <![CDATA[<220>]]>
          <![CDATA[<223>  合成：Fc區M252Y及M428L (YL) T366S, L368A, Y407V臼]]>
          <![CDATA[<400>  82]]>
          Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly 
          1               5                   10                  15      
          Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Tyr 
                      20                  25                  30          
          Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His 
                  35                  40                  45              
          Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val 
              50                  55                  60                  
          His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr 
          65                  70                  75                  80  
          Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly 
                          85                  90                  95      
          Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile 
                      100                 105                 110         
          Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val 
                  115                 120                 125             
          Cys Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser 
              130                 135                 140                 
          Leu Ser Cys Ala Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu 
          145                 150                 155                 160 
          Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro 
                          165                 170                 175     
          Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Val Ser Lys Leu Thr Val 
                      180                 185                 190         
          Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Leu 
                  195                 200                 205             
          His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser 
              210                 215                 220                 
          Pro Gly 
          225     
          <![CDATA[<210>  83]]>
          <![CDATA[<211>  226]]>
          <![CDATA[<212>  PRT]]>
          <![CDATA[<213>  人工序列]]>
          <![CDATA[<220>]]>
          <![CDATA[<223>  合成：Fc區M252Y, M428L, H435R (YLR) T366S, L368A, ]]>
                 Y407V臼
          <![CDATA[<400>  83]]>
          Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly 
          1               5                   10                  15      
          Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Tyr 
                      20                  25                  30          
          Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His 
                  35                  40                  45              
          Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val 
              50                  55                  60                  
          His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr 
          65                  70                  75                  80  
          Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly 
                          85                  90                  95      
          Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile 
                      100                 105                 110         
          Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val 
                  115                 120                 125             
          Cys Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser 
              130                 135                 140                 
          Leu Ser Cys Ala Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu 
          145                 150                 155                 160 
          Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro 
                          165                 170                 175     
          Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Val Ser Lys Leu Thr Val 
                      180                 185                 190         
          Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Leu 
                  195                 200                 205             
          His Glu Ala Leu His Asn Arg Tyr Thr Gln Lys Ser Leu Ser Leu Ser 
              210                 215                 220                 
          Pro Gly 
          225     
          <![CDATA[<210>  84]]>
          <![CDATA[<211>  119]]>
          <![CDATA[<212>  PRT]]>
          <![CDATA[<213>  智人]]>
          <![CDATA[<220>]]>
          <![CDATA[<221>  SITE]]>
          <![CDATA[<222>  (1)..(119)]]>
          <![CDATA[<223>  截短野生型人類IL-2]]>
          <![CDATA[<400>  84]]>
          Gln Leu Gln Leu Glu His Leu Leu Leu Asp Leu Gln Met Ile Leu Asn 
          1               5                   10                  15      
          Gly Ile Asn Asn Tyr Lys Asn Pro Lys Leu Thr Arg Met Leu Thr Phe 
                      20                  25                  30          
          Lys Phe Tyr Met Pro Lys Lys Ala Thr Glu Leu Lys His Leu Gln Cys 
                  35                  40                  45              
          Leu Glu Glu Glu Leu Lys Pro Leu Glu Glu Val Leu Asn Leu Ala Gln 
              50                  55                  60                  
          Ser Lys Asn Phe His Leu Arg Pro Arg Asp Leu Ile Ser Asn Ile Asn 
          65                  70                  75                  80  
          Val Ile Val Leu Glu Leu Lys Gly Ser Glu Thr Thr Phe Met Cys Glu 
                          85                  90                  95      
          Tyr Ala Asp Glu Thr Ala Thr Ile Val Glu Phe Leu Asn Arg Trp Ile 
                      100                 105                 110         
          Thr Phe Cys Gln Ser Ile Ile 
                  115                 
          <![CDATA[<210>  85]]>
          <![CDATA[<211>  362]]>
          <![CDATA[<212>  PRT]]>
          <![CDATA[<213>  人工序列]]>
          <![CDATA[<220>]]>
          <![CDATA[<223>  合成：IL-2-F42K-E15S-xELL杵Fc]]>
          <![CDATA[<400>  85]]>
          Ala Pro Thr Ser Ser Ser Thr Lys Lys Thr Gln Leu Gln Leu Ser His 
          1               5                   10                  15      
          Leu Leu Leu Asp Leu Gln Met Ile Leu Asn Gly Ile Asn Asn Tyr Lys 
                      20                  25                  30          
          Asn Pro Lys Leu Thr Arg Met Leu Thr Lys Lys Phe Tyr Met Pro Lys 
                  35                  40                  45              
          Lys Ala Thr Glu Leu Lys His Leu Gln Cys Leu Glu Glu Glu Leu Lys 
              50                  55                  60                  
          Pro Leu Glu Glu Val Leu Asn Leu Ala Gln Ser Lys Asn Phe His Leu 
          65                  70                  75                  80  
          Arg Pro Arg Asp Leu Ile Ser Asn Ile Asn Val Ile Val Leu Glu Leu 
                          85                  90                  95      
          Lys Gly Ser Glu Thr Thr Phe Met Cys Glu Tyr Ala Asp Glu Thr Ala 
                      100                 105                 110         
          Thr Ile Val Glu Phe Leu Asn Arg Trp Ile Thr Phe Cys Gln Ser Ile 
                  115                 120                 125             
          Ile Ser Thr Leu Thr Pro Gly Gly Gly Gly Asp Lys Thr His Thr Cys 
              130                 135                 140                 
          Pro Pro Cys Pro Ala Pro Gly Gly Pro Ser Val Phe Leu Phe Pro Pro 
          145                 150                 155                 160 
          Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys 
                          165                 170                 175     
          Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp 
                      180                 185                 190         
          Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu 
                  195                 200                 205             
          Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu 
              210                 215                 220                 
          His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn 
          225                 230                 235                 240 
          Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly 
                          245                 250                 255     
          Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Cys Arg Asp Glu 
                      260                 265                 270         
          Leu Thr Lys Asn Gln Val Ser Leu Trp Cys Leu Val Lys Gly Phe Tyr 
                  275                 280                 285             
          Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn 
              290                 295                 300                 
          Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe 
          305                 310                 315                 320 
          Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn 
                          325                 330                 335     
          Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr 
                      340                 345                 350         
          Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys 
                  355                 360         
          <![CDATA[<210>  86]]>
          <![CDATA[<211>  361]]>
          <![CDATA[<212>  PRT]]>
          <![CDATA[<213>  人工序列]]>
          <![CDATA[<220>]]>
          <![CDATA[<223>  合成：xELL-杵Fc-IL-2-T3A, C125S]]>
          <![CDATA[<400>  86]]>
          Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Gly Gly Pro Ser 
          1               5                   10                  15      
          Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg 
                      20                  25                  30          
          Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro 
                  35                  40                  45              
          Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala 
              50                  55                  60                  
          Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val 
          65                  70                  75                  80  
          Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr 
                          85                  90                  95      
          Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr 
                      100                 105                 110         
          Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu 
                  115                 120                 125             
          Pro Pro Cys Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu Trp Cys 
              130                 135                 140                 
          Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser 
          145                 150                 155                 160 
          Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp 
                          165                 170                 175     
          Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser 
                      180                 185                 190         
          Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala 
                  195                 200                 205             
          Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Gly 
              210                 215                 220                 
          Ser Gly Gly Ser Ala Pro Ala Ser Ser Ser Thr Lys Lys Thr Gln Leu 
          225                 230                 235                 240 
          Gln Leu Glu His Leu Leu Leu Asp Leu Gln Met Ile Leu Asn Gly Ile 
                          245                 250                 255     
          Asn Asn Tyr Lys Asn Pro Lys Leu Thr Arg Met Leu Thr Phe Lys Phe 
                      260                 265                 270         
          Tyr Met Pro Lys Lys Ala Thr Glu Leu Lys His Leu Gln Cys Leu Glu 
                  275                 280                 285             
          Glu Glu Leu Lys Pro Leu Glu Glu Val Leu Asn Leu Ala Gln Ser Lys 
              290                 295                 300                 
          Asn Phe His Leu Arg Pro Arg Asp Leu Ile Ser Asn Ile Asn Val Ile 
          305                 310                 315                 320 
          Val Leu Glu Leu Lys Gly Ser Glu Thr Thr Phe Met Cys Glu Tyr Ala 
                          325                 330                 335     
          Asp Glu Thr Ala Thr Ile Val Glu Phe Leu Asn Arg Trp Ile Thr Phe 
                      340                 345                 350         
          Ser Gln Ser Ile Ile Ser Thr Leu Thr 
                  355                 360     
          <![CDATA[<210>  87]]>
          <![CDATA[<211>  361]]>
          <![CDATA[<212>  PRT]]>
          <![CDATA[<213>  人工序列]]>
          <![CDATA[<220>]]>
          <![CDATA[<223>  合成：xELL-杵Fc-IL-2-RAS-T3A, C125S]]>
          <![CDATA[<400>  87]]>
          Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Gly Gly Pro Ser 
          1               5                   10                  15      
          Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg 
                      20                  25                  30          
          Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro 
                  35                  40                  45              
          Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala 
              50                  55                  60                  
          Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val 
          65                  70                  75                  80  
          Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr 
                          85                  90                  95      
          Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr 
                      100                 105                 110         
          Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu 
                  115                 120                 125             
          Pro Pro Cys Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu Trp Cys 
              130                 135                 140                 
          Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser 
          145                 150                 155                 160 
          Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp 
                          165                 170                 175     
          Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser 
                      180                 185                 190         
          Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala 
                  195                 200                 205             
          Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Gly 
              210                 215                 220                 
          Ser Gly Gly Ser Ala Pro Ala Ser Ser Ser Thr Lys Lys Thr Gln Leu 
          225                 230                 235                 240 
          Gln Leu Glu Ala Leu Leu Leu Asp Leu Gln Met Ile Leu Asn Gly Ile 
                          245                 250                 255     
          Asn Asn Tyr Lys Asn Pro Lys Leu Thr Arg Met Leu Thr Phe Lys Phe 
                      260                 265                 270         
          Tyr Met Pro Lys Lys Ala Thr Glu Leu Lys His Leu Gln Cys Leu Glu 
                  275                 280                 285             
          Glu Glu Leu Lys Arg Leu Glu Glu Val Leu Asn Leu Ala Gln Ser Lys 
              290                 295                 300                 
          Asn Phe His Leu Arg Pro Arg Ser Leu Ile Ser Asn Ile Asn Val Ile 
          305                 310                 315                 320 
          Val Leu Glu Leu Lys Gly Ser Glu Thr Thr Phe Met Cys Glu Tyr Ala 
                          325                 330                 335     
          Asp Glu Thr Ala Thr Ile Val Glu Phe Leu Asn Arg Trp Ile Thr Phe 
                      340                 345                 350         
          Ser Gln Ser Ile Ile Ser Thr Leu Thr 
                  355                 360     
          <![CDATA[<210>  88]]>
          <![CDATA[<211>  584]]>
          <![CDATA[<212>  PRT]]>
          <![CDATA[<213>  人工序列]]>
          <![CDATA[<220>]]>
          <![CDATA[<223>  合成：派立珠單抗類似物杵Fc-IL-2-RAS-T3A, C125S]]>
          <![CDATA[<400>  88]]>
          Gln Val Gln Leu Val Gln Ser Gly Val 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          
          Tyr Met Tyr Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met 
                  35                  40                  45              
          Gly Gly Ile Asn Pro Ser Asn Gly Gly Thr Asn Phe Asn Glu Lys Phe 
              50                  55                  60                  
          Lys Asn Arg Val Thr Leu Thr Thr Asp Ser Ser Thr Thr Thr Ala Tyr 
          65                  70                  75                  80  
          Met Glu Leu Lys Ser Leu Gln Phe Asp Asp Thr Ala Val Tyr Tyr Cys 
                          85                  90                  95      
          Ala Arg Arg Asp Tyr Arg Phe Asp Met Gly Phe Asp Tyr Trp Gly Gln 
                      100                 105                 110         
          Gly Thr Thr Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val 
                  115                 120                 125             
          Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala 
              130                 135                 140                 
          Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser 
          145                 150                 155                 160 
          Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val 
                          165                 170                 175     
          Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro 
                      180                 185                 190         
          Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys 
                  195                 200                 205             
          Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys Asp 
              210                 215                 220                 
          Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Gly Gly Pro Ser Val 
          225                 230                 235                 240 
          Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr 
                          245                 250                 255     
          Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu 
                      260                 265                 270         
          Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys 
                  275                 280                 285             
          Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser 
              290                 295                 300                 
          Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys 
          305                 310                 315                 320 
          Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile 
                          325                 330                 335     
          Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro 
                      340                 345                 350         
          Pro Cys Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu Trp Cys Leu 
                  355                 360                 365             
          Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn 
              370                 375                 380                 
          Gly Gln Pro Glu Asn Asn Tyr Asp Thr Thr Pro Pro Val Leu Asp Ser 
          385                 390                 395                 400 
          Asp Gly Ser Phe Phe Leu Tyr Ser Asp Leu Thr Val Asp Lys Ser Arg 
                          405                 410                 415     
          Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu 
                      420                 425                 430         
          His Asn Arg Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Gly Ser 
                  435                 440                 445             
          Gly Gly Ser Ala Pro Ala Ser Ser Ser Thr Lys Lys Thr Gln Leu Gln 
              450                 455                 460                 
          Leu Glu Ala Leu Leu Leu Asp Leu Gln Met Ile Leu Asn Gly Ile Asn 
          465                 470                 475                 480 
          Asn Tyr Lys Asn Pro Lys Leu Thr Arg Met Leu Thr Phe Lys Phe Tyr 
                          485                 490                 495     
          Met Pro Lys Lys Ala Thr Glu Leu Lys His Leu Gln Cys Leu Glu Glu 
                      500                 505                 510         
          Glu Leu Lys Arg Leu Glu Glu Val Leu Asn Leu Ala Gln Ser Lys Asn 
                  515                 520                 525             
          Phe His Leu Arg Pro Arg Ser Leu Ile Ser Asn Ile Asn Val Ile Val 
              530                 535                 540                 
          Leu Glu Leu Lys Gly Ser Glu Thr Thr Phe Met Cys Glu Tyr Ala Asp 
          545                 550                 555                 560 
          Glu Thr Ala Thr Ile Val Glu Phe Leu Asn Arg Trp Ile Thr Phe Ser 
                          565                 570                 575     
          Gln Ser Ile Ile Ser Thr Leu Thr 
                      580                 
          <![CDATA[<210>  89]]>
          <![CDATA[<211>  447]]>
          <![CDATA[<212>  PRT]]>
          <![CDATA[<213>  人工序列]]>
          <![CDATA[<220>]]>
          <![CDATA[<223>  合成：派立珠單抗類似物臼Fc]]>
          <![CDATA[<400>  89]]>
          Gln Val Gln Leu Val Gln Ser Gly Val 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          
          Tyr Met Tyr Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met 
                  35                  40                  45              
          Gly Gly Ile Asn Pro Ser Asn Gly Gly Thr Asn Phe Asn Glu Lys Phe 
              50                  55                  60                  
          Lys Asn Arg Val Thr Leu Thr Thr Asp Ser Ser Thr Thr Thr Ala Tyr 
          65                  70                  75                  80  
          Met Glu Leu Lys Ser Leu Gln Phe Asp Asp Thr Ala Val Tyr Tyr Cys 
                          85                  90                  95      
          Ala Arg Arg Asp Tyr Arg Phe Asp Met Gly Phe Asp Tyr Trp Gly Gln 
                      100                 105                 110         
          Gly Thr Thr Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val 
                  115                 120                 125             
          Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala 
              130                 135                 140                 
          Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser 
          145                 150                 155                 160 
          Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val 
                          165                 170                 175     
          Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro 
                      180                 185                 190         
          Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys 
                  195                 200                 205             
          Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys Asp 
              210                 215                 220                 
          Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Gly Gly Pro Ser Val 
          225                 230                 235                 240 
          Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr 
                          245                 250                 255     
          Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu 
                      260                 265                 270         
          Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys 
                  275                 280                 285             
          Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser 
              290                 295                 300                 
          Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys 
          305                 310                 315                 320 
          Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile 
                          325                 330                 335     
          Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Cys Thr Leu Pro 
                      340                 345                 350         
          Pro Ser Arg Asp Lys Leu Thr Lys Asn Gln Val Ser Leu Ser Cys Ala 
                  355                 360                 365             
          Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Lys Ser Asn 
              370                 375                 380                 
          Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser 
          385                 390                 395                 400 
          Lys Gly Ser Phe Phe Leu Val Ser Lys Leu Thr Val Asp Lys Ser Arg 
                          405                 410                 415     
          Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu 
                      420                 425                 430         
          His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys 
                  435                 440                 445         
          <![CDATA[<210>  90]]>
          <![CDATA[<211>  218]]>
          <![CDATA[<212>  PRT]]>
          <![CDATA[<213>  人工序列]]>
          <![CDATA[<220>]]>
          <![CDATA[<223>  合成：派立珠單抗輕鏈類似物]]>
          <![CDATA[<400>  90]]>
          Glu Ile Val Leu Thr Gln Ser Pro Ala Thr Leu Ser Leu Ser Pro Gly 
          1               5                   10                  15      
          Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Lys Gly Val Ser Thr Ser 
                      20                  25                  30          
          Gly Tyr Ser Tyr Leu His Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro 
                  35                  40                  45              
          Arg Leu Leu Ile Tyr Leu Ala Ser Tyr Leu Glu Ser Gly Val Pro Ala 
              50                  55                  60                  
          Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser 
          65                  70                  75                  80  
          Ser Leu Glu Pro Glu Asp Phe Ala Val Tyr Tyr Cys Gln His Ser Arg 
                          85                  90                  95      
          Asp Leu Pro Leu Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys Arg 
                      100                 105                 110         
          Thr Val Ala Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln 
                  115                 120                 125             
          Leu Lys Ser Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr 
              130                 135                 140                 
          Pro Arg Glu Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser 
          145                 150                 155                 160 
          Gly Asn Ser Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr 
                          165                 170                 175     
          Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys 
                      180                 185                 190         
          His Lys Val Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro 
                  195                 200                 205             
          Val Thr Lys Ser Phe Asn Arg Gly Glu Cys 
              210                 215             
          <![CDATA[<210>  91]]>
          <![CDATA[<211>  584]]>
          <![CDATA[<212>  PRT]]>
          <![CDATA[<213>  人工序列]]>
          <![CDATA[<220>]]>
          <![CDATA[<223>  合成：派立珠單抗類似物IL-2-RAS-T3G, C125S]]>
          <![CDATA[<400>  91]]>
          Gln Val Gln Leu Val Gln Ser Gly Val 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          
          Tyr Met Tyr Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met 
                  35                  40                  45              
          Gly Gly Ile Asn Pro Ser Asn Gly Gly Thr Asn Phe Asn Glu Lys Phe 
              50                  55                  60                  
          Lys Asn Arg Val Thr Leu Thr Thr Asp Ser Ser Thr Thr Thr Ala Tyr 
          65                  70                  75                  80  
          Met Glu Leu Lys Ser Leu Gln Phe Asp Asp Thr Ala Val Tyr Tyr Cys 
                          85                  90                  95      
          Ala Arg Arg Asp Tyr Arg Phe Asp Met Gly Phe Asp Tyr Trp Gly Gln 
                      100                 105                 110         
          Gly Thr Thr Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val 
                  115                 120                 125             
          Phe Pro Leu Ala Pro Cys Ser Arg Ser Thr Ser Glu Ser Thr Ala Ala 
              130                 135                 140                 
          Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser 
          145                 150                 155                 160 
          Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val 
                          165                 170                 175     
          Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro 
                      180                 185                 190         
          Ser Ser Ser Leu Gly Thr Lys Thr Tyr Thr Cys Asn Val Asp His Lys 
                  195                 200                 205             
          Pro Ser Asn Thr Lys Val Asp Lys Arg Val Glu Ser Lys Tyr Gly Pro 
              210                 215                 220                 
          Pro Cys Pro Pro Cys Pro Ala Pro Glu Phe Leu Gly Gly Pro Ser Val 
          225                 230                 235                 240 
          Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr 
                          245                 250                 255     
          Pro Glu Val Thr Cys Val Val Val Asp Val Ser Gln Glu Asp Pro Glu 
                      260                 265                 270         
          Val Gln Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys 
                  275                 280                 285             
          Thr Lys Pro Arg Glu Glu Gln Phe Asn Ser Thr Tyr Arg Val Val Ser 
              290                 295                 300                 
          Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys 
          305                 310                 315                 320 
          Cys Lys Val Ser Asn Lys Gly Leu Pro Ser Ser Ile Glu Lys Thr Ile 
                          325                 330                 335     
          Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro 
                      340                 345                 350         
          Pro Ser Gln Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu 
                  355                 360                 365             
          Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn 
              370                 375                 380                 
          Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser 
          385                 390                 395                 400 
          Asp Gly Ser Phe Phe Leu Tyr Ser Arg Leu Thr Val Asp Lys Ser Arg 
                          405                 410                 415     
          Trp Gln Glu Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu 
                      420                 425                 430         
          His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Leu Gly Gly Ser 
                  435                 440                 445             
          Gly Gly Ser Ala Pro Gly Ser Ser Ser Thr Lys Lys Thr Gln Leu Gln 
              450                 455                 460                 
          Leu Glu Ala Leu Leu Leu Asp Leu Gln Met Ile Leu Asn Gly Ile Asn 
          465                 470                 475                 480 
          Asn Tyr Lys Asn Pro Lys Leu Thr Arg Met Leu Thr Phe Lys Phe Tyr 
                          485                 490                 495     
          Met Pro Lys Lys Ala Thr Glu Leu Lys His Leu Gln Cys Leu Glu Glu 
                      500                 505                 510         
          Glu Leu Lys Arg Leu Glu Glu Val Leu Asn Leu Ala Gln Ser Lys Asn 
                  515                 520                 525             
          Phe His Leu Arg Pro Arg Ser Leu Ile Ser Asn Ile Asn Val Ile Val 
              530                 535                 540                 
          Leu Glu Leu Lys Gly Ser Glu Thr Thr Phe Met Cys Glu Tyr Ala Asp 
          545                 550                 555                 560 
          Glu Thr Ala Thr Ile Val Glu Phe Leu Asn Arg Trp Ile Thr Phe Ser 
                          565                 570                 575     
          Gln Ser Ile Ile Ser Thr Leu Thr 
                      580                 
          <![CDATA[<210>  92]]>
          <![CDATA[<211>  611]]>
          <![CDATA[<212>  PRT]]>
          <![CDATA[<213>  人工序列]]>
          <![CDATA[<220>]]>
          <![CDATA[<223>  合成：NKp46-scFv xELL-杵Fc-IL-2-RAS-T3A, C125S]]>
          <![CDATA[<400>  92]]>
          Gln Val Gln Leu Gln Gln Ser Gly Pro Glu Leu Val Lys Pro Gly Ala 
          1               5                   10                  15      
          Ser Val Lys Met Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Asp Tyr 
                      20                  25                  30          
          Val Ile Asn Trp Gly Lys Gln Arg Ser Gly Gln Gly Leu Glu Trp Ile 
                  35                  40                  45              
          Gly Glu Ile Tyr Pro Gly Ser Gly Thr Asn Tyr Tyr Asn Glu Lys Phe 
              50                  55                  60                  
          Lys Ala Lys Ala Thr Leu Thr Ala Asp Lys Ser Ser Asn Ile Ala Tyr 
          65                  70                  75                  80  
          Met Gln Leu Ser Ser Leu Thr Ser Glu Asp Ser Ala Val Tyr Phe Cys 
                          85                  90                  95      
          Ala Arg Arg Gly Arg Tyr Gly Leu Tyr Ala Met Asp Tyr Trp Gly Gln 
                      100                 105                 110         
          Gly Thr Ser Val Thr Val Ser Ser Val Glu Gly Gly Ser Gly Gly Ser 
                  115                 120                 125             
          Gly Gly Ser Gly Gly Ser Gly Gly Val Asp Asp Ile Gln Met Thr Gln 
              130                 135                 140                 
          Thr Thr Ser Ser Leu Ser Ala Ser Leu Gly Asp Arg Val Thr Ile Ser 
          145                 150                 155                 160 
          Cys Arg Ala Ser Gln Asp Ile Ser Asn Tyr Leu Asn Trp Tyr Gln Gln 
                          165                 170                 175     
          Lys Pro Asp Gly Thr Val Lys Leu Leu Ile Tyr Tyr Thr Ser Arg Leu 
                      180                 185                 190         
          His Ser Gly Val Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp 
                  195                 200                 205             
          Tyr Ser Leu Thr Ile Asn Asn Leu Glu Gln Glu Asp Ile Ala Thr Tyr 
              210                 215                 220                 
          Phe Cys Gln Gln Gly Asn Thr Arg Pro Trp Thr Phe Gly Gly Gly Thr 
          225                 230                 235                 240 
          Lys Leu Glu Ile Lys Pro Gly Gly Gly Gly Asp Lys Thr His Thr Cys 
                          245                 250                 255     
          Pro Pro Cys Pro Ala Pro Gly Gly Pro Ser Val Phe Leu Phe Pro Pro 
                      260                 265                 270         
          Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys 
                  275                 280                 285             
          Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp 
              290                 295                 300                 
          Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu 
          305                 310                 315                 320 
          Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu 
                          325                 330                 335     
          His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn 
                      340                 345                 350         
          Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly 
                  355                 360                 365             
          Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Cys Arg Asp Glu 
              370                 375                 380                 
          Leu Thr Lys Asn Gln Val Ser Leu Trp Cys Leu Val Lys Gly Phe Tyr 
          385                 390                 395                 400 
          Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn 
                          405                 410                 415     
          Asn Tyr Asp Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe 
                      420                 425                 430         
          Leu Tyr Ser Asp Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn 
                  435                 440                 445             
          Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn Arg Tyr Thr 
              450                 455                 460                 
          Gln Lys Ser Leu Ser Leu Ser Pro Gly Gly Ser Gly Gly Ser Ala Pro 
          465                 470                 475                 480 
          Ala Ser Ser Ser Thr Lys Lys Thr Gln Leu Gln Leu Glu Ala Leu Leu 
                          485                 490                 495     
          Leu Asp Leu Gln Met Ile Leu Asn Gly Ile Asn Asn Tyr Lys Asn Pro 
                      500                 505                 510         
          Lys Leu Thr Arg Met Leu Thr Phe Lys Phe Tyr Met Pro Lys Lys Ala 
                  515                 520                 525             
          Thr Glu Leu Lys His Leu Gln Cys Leu Glu Glu Glu Leu Lys Arg Leu 
              530                 535                 540                 
          Glu Glu Val Leu Asn Leu Ala Gln Ser Lys Asn Phe His Leu Arg Pro 
          545                 550                 555                 560 
          Arg Ser Leu Ile Ser Asn Ile Asn Val Ile Val Leu Glu Leu Lys Gly 
                          565                 570                 575     
          Ser Glu Thr Thr Phe Met Cys Glu Tyr Ala Asp Glu Thr Ala Thr Ile 
                      580                 585                 590         
          Val Glu Phe Leu Asn Arg Trp Ile Thr Phe Ser Gln Ser Ile Ile Ser 
                  595                 600                 605             
          Thr Leu Thr 
              610     
          <![CDATA[<210>  93]]>
          <![CDATA[<211>  474]]>
          <![CDATA[<212>  PRT]]>
          <![CDATA[<213>  人工序列]]>
          <![CDATA[<220>]]>
          <![CDATA[<223>  合成：NKp46-scFv xELL-臼Fc]]>
          <![CDATA[<400>  93]]>
          Gln Val Gln Leu Gln Gln Ser Gly Pro Glu Leu Val Lys Pro Gly Ala 
          1               5                   10                  15      
          Ser Val Lys Met Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Asp Tyr 
                      20                  25                  30          
          Val Ile Asn Trp Gly Lys Gln Arg Ser Gly Gln Gly Leu Glu Trp Ile 
                  35                  40                  45              
          Gly Glu Ile Tyr Pro Gly Ser Gly Thr Asn Tyr Tyr Asn Glu Lys Phe 
              50                  55                  60                  
          Lys Ala Lys Ala Thr Leu Thr Ala Asp Lys Ser Ser Asn Ile Ala Tyr 
          65                  70                  75                  80  
          Met Gln Leu Ser Ser Leu Thr Ser Glu Asp Ser Ala Val Tyr Phe Cys 
                          85                  90                  95      
          Ala Arg Arg Gly Arg Tyr Gly Leu Tyr Ala Met Asp Tyr Trp Gly Gln 
                      100                 105                 110         
          Gly Thr Ser Val Thr Val Ser Ser Val Glu Gly Gly Ser Gly Gly Ser 
                  115                 120                 125             
          Gly Gly Ser Gly Gly Ser Gly Gly Val Asp Asp Ile Gln Met Thr Gln 
              130                 135                 140                 
          Thr Thr Ser Ser Leu Ser Ala Ser Leu Gly Asp Arg Val Thr Ile Ser 
          145                 150                 155                 160 
          Cys Arg Ala Ser Gln Asp Ile Ser Asn Tyr Leu Asn Trp Tyr Gln Gln 
                          165                 170                 175     
          Lys Pro Asp Gly Thr Val Lys Leu Leu Ile Tyr Tyr Thr Ser Arg Leu 
                      180                 185                 190         
          His Ser Gly Val Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp 
                  195                 200                 205             
          Tyr Ser Leu Thr Ile Asn Asn Leu Glu Gln Glu Asp Ile Ala Thr Tyr 
              210                 215                 220                 
          Phe Cys Gln Gln Gly Asn Thr Arg Pro Trp Thr Phe Gly Gly Gly Thr 
          225                 230                 235                 240 
          Lys Leu Glu Ile Lys Pro Gly Gly Gly Gly Asp Lys Thr His Thr Cys 
                          245                 250                 255     
          Pro Pro Cys Pro Ala Pro Gly Gly Pro Ser Val Phe Leu Phe Pro Pro 
                      260                 265                 270         
          Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys 
                  275                 280                 285             
          Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp 
              290                 295                 300                 
          Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu 
          305                 310                 315                 320 
          Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu 
                          325                 330                 335     
          His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn 
                      340                 345                 350         
          Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly 
                  355                 360                 365             
          Gln Pro Arg Glu Pro Gln Val Cys Thr Leu Pro Pro Ser Arg Asp Lys 
              370                 375                 380                 
          Leu Thr Lys Asn Gln Val Ser Leu Ser Cys Ala Val Lys Gly Phe Tyr 
          385                 390                 395                 400 
          Pro Ser Asp Ile Ala Val Glu Trp Lys Ser Asn Gly Gln Pro Glu Asn 
                          405                 410                 415     
          Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Lys Gly Ser Phe Phe 
                      420                 425                 430         
          Leu Val Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn 
                  435                 440                 445             
          Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr 
              450                 455                 460                 
          Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys 
          465                 470                 
          <![CDATA[<210>  94]]>
          <![CDATA[<211>  477]]>
          <![CDATA[<212>  PRT]]>
          <![CDATA[<213>  人工序列]]>
          <![CDATA[<220>]]>
          <![CDATA[<223>  合成：NKp46-scFv xELL-Fc]]>
          <![CDATA[<400>  94]]>
          Gln Val Gln Leu Gln Gln Ser Gly Pro Glu Leu Val Lys Pro Gly Ala 
          1               5                   10                  15      
          Ser Val Lys Met Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Asp Tyr 
                      20                  25                  30          
          Val Ile Asn Trp Gly Lys Gln Arg Ser Gly Gln Gly Leu Glu Trp Ile 
                  35                  40                  45              
          Gly Glu Ile Tyr Pro Gly Ser Gly Thr Asn Tyr Tyr Asn Glu Lys Phe 
              50                  55                  60                  
          Lys Ala Lys Ala Thr Leu Thr Ala Asp Lys Ser Ser Asn Ile Ala Tyr 
          65                  70                  75                  80  
          Met Gln Leu Ser Ser Leu Thr Ser Glu Asp Ser Ala Val Tyr Phe Cys 
                          85                  90                  95      
          Ala Arg Arg Gly Arg Tyr Gly Leu Tyr Ala Met Asp Tyr Trp Gly Gln 
                      100                 105                 110         
          Gly Thr Ser Val Thr Val Ser Ser Val Glu Gly Gly Ser Gly Gly Ser 
                  115                 120                 125             
          Gly Gly Ser Gly Gly Ser Gly Gly Val Asp Asp Ile Gln Met Thr Gln 
              130                 135                 140                 
          Thr Thr Ser Ser Leu Ser Ala Ser Leu Gly Asp Arg Val Thr Ile Ser 
          145                 150                 155                 160 
          Cys Arg Ala Ser Gln Asp Ile Ser Asn Tyr Leu Asn Trp Tyr Gln Gln 
                          165                 170                 175     
          Lys Pro Asp Gly Thr Val Lys Leu Leu Ile Tyr Tyr Thr Ser Arg Leu 
                      180                 185                 190         
          His Ser Gly Val Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp 
                  195                 200                 205             
          Tyr Ser Leu Thr Ile Asn Asn Leu Glu Gln Glu Asp Ile Ala Thr Tyr 
              210                 215                 220                 
          Phe Cys Gln Gln Gly Asn Thr Arg Pro Trp Thr Phe Gly Gly Gly Thr 
          225                 230                 235                 240 
          Lys Leu Glu Ile Lys Pro Gly Gly Gly Gly Asp Lys Thr His Thr Cys 
                          245                 250                 255     
          Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu 
                      260                 265                 270         
          Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu 
                  275                 280                 285             
          Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys 
              290                 295                 300                 
          Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys 
          305                 310                 315                 320 
          Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu 
                          325                 330                 335     
          Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys 
                      340                 345                 350         
          Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys 
                  355                 360                 365             
          Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser 
              370                 375                 380                 
          Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys 
          385                 390                 395                 400 
          Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln 
                          405                 410                 415     
          Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly 
                      420                 425                 430         
          Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln 
                  435                 440                 445             
          Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn 
              450                 455                 460                 
          His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys 
          465                 470                 475         
          <![CDATA[<210>  95]]>
          <![CDATA[<211>  587]]>
          <![CDATA[<212>  PRT]]>
          <![CDATA[<213>  人工序列]]>
          <![CDATA[<220>]]>
          <![CDATA[<223>  合成：LAG3-MAb xELL-杵Fc-IL-2-RAS-TGCS]]>
          <![CDATA[<400>  95]]>
          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          
          Tyr Met His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met 
                  35                  40                  45              
          Gly Trp Ile Asn Ala Asn Ser Gly Gly Thr Asn Tyr Ala Gln Lys Phe 
              50                  55                  60                  
          Gln Gly Arg Val Thr Met Thr Arg Asp Thr Ser Ile Ser Thr Ala Tyr 
          65                  70                  75                  80  
          Met Glu Leu Ser Arg Leu Arg Ser Asp Asp Thr Ala Val Tyr Tyr Cys 
                          85                  90                  95      
          Ala Arg Asp Ile Tyr Asp Ser Ser Asp Gln Leu Asn Val Trp Gly Gln 
                      100                 105                 110         
          Gly Thr Met Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val 
                  115                 120                 125             
          Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala 
              130                 135                 140                 
          Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser 
          145                 150                 155                 160 
          Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val 
                          165                 170                 175     
          Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro 
                      180                 185                 190         
          Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys 
                  195                 200                 205             
          Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys Asp 
              210                 215                 220                 
          Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly 
          225                 230                 235                 240 
          Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile 
                          245                 250                 255     
          Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu 
                      260                 265                 270         
          Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His 
                  275                 280                 285             
          Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg 
              290                 295                 300                 
          Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys 
          305                 310                 315                 320 
          Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu 
                          325                 330                 335     
          Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr 
                      340                 345                 350         
          Thr Leu Pro Pro Cys Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu 
                  355                 360                 365             
          Trp 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 Gly Ser Gly Gly Ser Ala Pro Gly Ser Ser Ser Thr Lys Lys Thr 
              450                 455                 460                 
          Gln Leu Gln Leu Glu Ala Leu Leu Leu Asp Leu Gln Met Ile Leu Asn 
          465                 470                 475                 480 
          Gly Ile Asn Asn Tyr Lys Asn Pro Lys Leu Thr Arg Met Leu Thr Phe 
                          485                 490                 495     
          Lys Phe Tyr Met Pro Lys Lys Ala Thr Glu Leu Lys His Leu Gln Cys 
                      500                 505                 510         
          Leu Glu Glu Glu Leu Lys Arg Leu Glu Glu Val Leu Asn Leu Ala Gln 
                  515                 520                 525             
          Ser Lys Asn Phe His Leu Arg Pro Arg Ser Leu Ile Ser Asn Ile Asn 
              530                 535                 540                 
          Val Ile Val Leu Glu Leu Lys Gly Ser Glu Thr Thr Phe Met Cys Glu 
          545                 550                 555                 560 
          Tyr Ala Asp Glu Thr Ala Thr Ile Val Glu Phe Leu Asn Arg Trp Ile 
                          565                 570                 575     
          Thr Phe Ser Gln Ser Ile Ile Ser Thr Leu Thr 
                      580                 585         
          <![CDATA[<210>  96]]>
          <![CDATA[<211>  447]]>
          <![CDATA[<212>  PRT]]>
          <![CDATA[<213>  人工序列]]>
          <![CDATA[<220>]]>
          <![CDATA[<223>  合成：LAG3-MAb xELL-臼Fc]]>
          <![CDATA[<400>  96]]>
          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          
          Tyr Met His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met 
                  35                  40                  45              
          Gly Trp Ile Asn Ala Asn Ser Gly Gly Thr Asn Tyr Ala Gln Lys Phe 
              50                  55                  60                  
          Gln Gly Arg Val Thr Met Thr Arg Asp Thr Ser Ile Ser Thr Ala Tyr 
          65                  70                  75                  80  
          Met Glu Leu Ser Arg Leu Arg Ser Asp Asp Thr Ala Val Tyr Tyr Cys 
                          85                  90                  95      
          Ala Arg Asp Ile Tyr Asp Ser Ser Asp Gln Leu Asn Val Trp Gly Gln 
                      100                 105                 110         
          Gly Thr Met Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val 
                  115                 120                 125             
          Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala 
              130                 135                 140                 
          Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser 
          145                 150                 155                 160 
          Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val 
                          165                 170                 175     
          Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro 
                      180                 185                 190         
          Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys 
                  195                 200                 205             
          Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys Asp 
              210                 215                 220                 
          Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Gly Gly Pro Ser Val 
          225                 230                 235                 240 
          Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Arg Ser Arg Thr 
                          245                 250                 255     
          Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu 
                      260                 265                 270         
          Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys 
                  275                 280                 285             
          Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser 
              290                 295                 300                 
          Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys 
          305                 310                 315                 320 
          Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile 
                          325                 330                 335     
          Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Cys Thr Leu Pro 
                      340                 345                 350         
          Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu Ser Cys Ala 
                  355                 360                 365             
          Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn 
              370                 375                 380                 
          Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser 
          385                 390                 395                 400 
          Asp Gly Ser Phe Phe Leu Val Ser Lys Leu Thr Val Asp Lys Ser Arg 
                          405                 410                 415     
          Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu 
                      420                 425                 430         
          His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys 
                  435                 440                 445         
          <![CDATA[<210>  97]]>
          <![CDATA[<211>  214]]>
          <![CDATA[<212>  PRT]]>
          <![CDATA[<213>  人工序列]]>
          <![CDATA[<220>]]>
          <![CDATA[<223>  合成：LAG3-MAb輕鏈]]>
          <![CDATA[<400>  97]]>
          Glu Ile Val Leu Thr Gln Ser Pro Ala Thr Leu Ser Leu Ser Pro Gly 
          1               5                   10                  15      
          Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Val Ser Ser Tyr 
                      20                  25                  30          
          Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu Ile 
                  35                  40                  45              
          Tyr Asp Ala Ser Asn Arg Ala Thr Gly Ile Pro Ala Arg Phe Ser Gly 
              50                  55                  60                  
          Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Glu Pro 
          65                  70                  75                  80  
          Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Ala Ser Ile Trp Pro Leu 
                          85                  90                  95      
          Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys Arg Thr Val Ala Ala 
                      100                 105                 110         
          Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly 
                  115                 120                 125             
          Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala 
              130                 135                 140                 
          Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln 
          145                 150                 155                 160 
          Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser 
                          165                 170                 175     
          Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr 
                      180                 185                 190         
          Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser 
                  195                 200                 205             
          Phe Asn Arg Gly Glu Cys 
              210                 
          <![CDATA[<210>  98]]>
          <![CDATA[<211>  450]]>
          <![CDATA[<212>  PRT]]>
          <![CDATA[<213>  人工序列]]>
          <![CDATA[<220>]]>
          <![CDATA[<223>  合成：LAG3-MAb IgG1]]>
          <![CDATA[<400>  98]]>
          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          
          Tyr Met His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met 
                  35                  40                  45              
          Gly Trp Ile Asn Ala Asn Ser Gly Gly Thr Asn Tyr Ala Gln Lys Phe 
              50                  55                  60                  
          Gln Gly Arg Val Thr Met Thr Arg Asp Thr Ser Ile Ser Thr Ala Tyr 
          65                  70                  75                  80  
          Met Glu Leu Ser Arg Leu Arg Ser Asp Asp Thr Ala Val Tyr Tyr Cys 
                          85                  90                  95      
          Ala Arg Asp Ile Tyr Asp Ser Ser Asp Gln Leu Asn Val Trp Gly Gln 
                      100                 105                 110         
          Gly Thr Met Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val 
                  115                 120                 125             
          Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala 
              130                 135                 140                 
          Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser 
          145                 150                 155                 160 
          Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val 
                          165                 170                 175     
          Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro 
                      180                 185                 190         
          Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys 
                  195                 200                 205             
          Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys Asp 
              210                 215                 220                 
          Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly 
          225                 230                 235                 240 
          Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile 
                          245                 250                 255     
          Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu 
                      260                 265                 270         
          Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His 
                  275                 280                 285             
          Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg 
              290                 295                 300                 
          Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys 
          305                 310                 315                 320 
          Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu 
                          325                 330                 335     
          Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr 
                      340                 345                 350         
          Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu 
                  355                 360                 365             
          Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp 
              370                 375                 380                 
          Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val 
          385                 390                 395                 400 
          Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp 
                          405                 410                 415     
          Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His 
                      420                 425                 430         
          Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro 
                  435                 440                 445             
          Gly Lys 
              450 
          <![CDATA[<210>  99]]>
          <![CDATA[<211>  492]]>
          <![CDATA[<212>  PRT]]>
          <![CDATA[<213>  人工序列]]>
          <![CDATA[<220>]]>
          <![CDATA[<223>  合成：LAG3-VHH xELL-杵Fc-IL-2-RAS-TGCS]]>
          <![CDATA[<400>  99]]>
          Glu Val Gln Leu Val Glu Ser Gly Gly Gly Trp Gln Pro Gly Gly Ser 
          1               5                   10                  15      
          Leu Arg Leu Ser Cys Ala Ala Ser Gly Arg Thr Phe Ser Asp Tyr Val 
                      20                  25                  30          
          Met Gly Trp Phe Arg Gln Ala Pro Gly Lys Glu Arg Glu Phe Val Ala 
                  35                  40                  45              
          Ala Ile Ser Glu Ser Gly Gly Arg Thr His Tyr Ala Asp Ser Val Lys 
              50                  55                  60                  
          Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr Leu 
          65                  70                  75                  80  
          Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Leu Tyr Tyr Cys Ala 
                          85                  90                  95      
          Thr Thr Leu Leu Trp Trp Thr Ser Glu Tyr Ala Pro Ile Lys Ala Asn 
                      100                 105                 110         
          Asp Tyr Asp Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Lys Pro Gly 
                  115                 120                 125             
          Gly Gly Gly Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Gly 
              130                 135                 140                 
          Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met 
          145                 150                 155                 160 
          Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His 
                          165                 170                 175     
          Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val 
                      180                 185                 190         
          His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr 
                  195                 200                 205             
          Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly 
              210                 215                 220                 
          Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile 
          225                 230                 235                 240 
          Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val 
                          245                 250                 255     
          Tyr Thr Leu Pro Pro Cys Arg Asp Glu Leu Thr Lys Asn Gln Val Ser 
                      260                 265                 270         
          Leu Trp Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu 
                  275                 280                 285             
          Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro 
              290                 295                 300                 
          Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val 
          305                 310                 315                 320 
          Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met 
                          325                 330                 335     
          His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser 
                      340                 345                 350         
          Pro Gly Gly Ser Gly Gly Ser Ala Pro Gly Ser Ser Ser Thr Lys Lys 
                  355                 360                 365             
          Thr Gln Leu Gln Leu Glu Ala Leu Leu Leu Asp Leu Gln Met Ile Leu 
              370                 375                 380                 
          Asn Gly Ile Asn Asn Tyr Lys Asn Pro Lys Leu Thr Arg Met Leu Thr 
          385                 390                 395                 400 
          Phe Lys Phe Tyr Met Pro Lys Lys Ala Thr Glu Leu Lys His Leu Gln 
                          405                 410                 415     
          Cys Leu Glu Glu Glu Leu Lys Arg Leu Glu Glu Val Leu Asn Leu Ala 
                      420                 425                 430         
          Gln Ser Lys Asn Phe His Leu Arg Pro Arg Ser Leu Ile Ser Asn Ile 
                  435                 440                 445             
          Asn Val Ile Val Leu Glu Leu Lys Gly Ser Glu Thr Thr Phe Met Cys 
              450                 455                 460                 
          Glu Tyr Ala Asp Glu Thr Ala Thr Ile Val Glu Phe Leu Asn Arg Trp 
          465                 470                 475                 480 
          Ile Thr Phe Ser Gln Ser Ile Ile Ser Thr Leu Thr 
                          485                 490         
          <![CDATA[<210>  100]]>
          <![CDATA[<211>  355]]>
          <![CDATA[<212>  PRT]]>
          <![CDATA[<213>  人工序列]]>
          <![CDATA[<220>]]>
          <![CDATA[<223>  合成：LAG3-VHH xELL-臼T366S, L368A, Y407V, H435R Fc]]>
          <![CDATA[<400>  100]]>
          Glu Val Gln Leu Val Glu Ser Gly Gly Gly Trp Gln Pro Gly Gly Ser 
          1               5                   10                  15      
          Leu Arg Leu Ser Cys Ala Ala Ser Gly Arg Thr Phe Ser Asp Tyr Val 
                      20                  25                  30          
          Met Gly Trp Phe Arg Gln Ala Pro Gly Lys Glu Arg Glu Phe Val Ala 
                  35                  40                  45              
          Ala Ile Ser Glu Ser Gly Gly Arg Thr His Tyr Ala Asp Ser Val Lys 
              50                  55                  60                  
          Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr Leu 
          65                  70                  75                  80  
          Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Leu Tyr Tyr Cys Ala 
                          85                  90                  95      
          Thr Thr Leu Leu Trp Trp Thr Ser Glu Tyr Ala Pro Ile Lys Ala Asn 
                      100                 105                 110         
          Asp Tyr Asp Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Lys Pro Gly 
                  115                 120                 125             
          Gly Gly Gly Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Gly 
              130                 135                 140                 
          Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met 
          145                 150                 155                 160 
          Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His 
                          165                 170                 175     
          Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val 
                      180                 185                 190         
          His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr 
                  195                 200                 205             
          Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly 
              210                 215                 220                 
          Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile 
          225                 230                 235                 240 
          Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val 
                          245                 250                 255     
          Cys Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser 
                      260                 265                 270         
          Leu Ser Cys Ala Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu 
                  275                 280                 285             
          Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro 
              290                 295                 300                 
          Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Val Ser Lys Leu Thr Val 
          305                 310                 315                 320 
          Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met 
                          325                 330                 335     
          His Glu Ala Leu His Asn Arg Tyr Thr Gln Lys Ser Leu Ser Leu Ser 
                      340                 345                 350         
          Pro Gly Lys 
                  355 
          <![CDATA[<210>  101]]>
          <![CDATA[<211>  355]]>
          <![CDATA[<212>  PRT]]>
          <![CDATA[<213>  人工序列]]>
          <![CDATA[<220>]]>
          <![CDATA[<223>  合成：LAG3-VHH xELL-杵Fc]]>
          <![CDATA[<400>  101]]>
          Glu Val Gln Leu Val Glu Ser Gly Gly Gly Trp Gln Pro Gly Gly Ser 
          1               5                   10                  15      
          Leu Arg Leu Ser Cys Ala Ala Ser Gly Arg Thr Phe Ser Asp Tyr Val 
                      20                  25                  30          
          Met Gly Trp Phe Arg Gln Ala Pro Gly Lys Glu Arg Glu Phe Val Ala 
                  35                  40                  45              
          Ala Ile Ser Glu Ser Gly Gly Arg Thr His Tyr Ala Asp Ser Val Lys 
              50                  55                  60                  
          Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr Leu 
          65                  70                  75                  80  
          Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Leu Tyr Tyr Cys Ala 
                          85                  90                  95      
          Thr Thr Leu Leu Trp Trp Thr Ser Glu Tyr Ala Pro Ile Lys Ala Asn 
                      100                 105                 110         
          Asp Tyr Asp Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Lys Pro Gly 
                  115                 120                 125             
          Gly Gly Gly Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Gly 
              130                 135                 140                 
          Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met 
          145                 150                 155                 160 
          Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His 
                          165                 170                 175     
          Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val 
                      180                 185                 190         
          His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr 
                  195                 200                 205             
          Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly 
              210                 215                 220                 
          Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile 
          225                 230                 235                 240 
          Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val 
                          245                 250                 255     
          Tyr Thr Leu Pro Pro Cys Arg Asp Glu Leu Thr Lys Asn Gln Val Ser 
                      260                 265                 270         
          Leu Trp Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu 
                  275                 280                 285             
          Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro 
              290                 295                 300                 
          Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val 
          305                 310                 315                 320 
          Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met 
                          325                 330                 335     
          His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser 
                      340                 345                 350         
          Pro Gly Lys 
                  355 
          <![CDATA[<210>  102]]>
          <![CDATA[<211>  361]]>
          <![CDATA[<212>  PRT]]>
          <![CDATA[<213>  人工序列]]>
          <![CDATA[<220>]]>
          <![CDATA[<223>  合成：xELL-杵Fc-IL-2-RAS-M23A-T3A, C125S]]>
          <![CDATA[<400>  102]]>
          Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Gly Gly Pro Ser 
          1               5                   10                  15      
          Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Tyr Ile Ser Arg 
                      20                  25                  30          
          Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro 
                  35                  40                  45              
          Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala 
              50                  55                  60                  
          Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val 
          65                  70                  75                  80  
          Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr 
                          85                  90                  95      
          Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr 
                      100                 105                 110         
          Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu 
                  115                 120                 125             
          Pro Pro Cys Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu Trp Cys 
              130                 135                 140                 
          Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser 
          145                 150                 155                 160 
          Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp 
                          165                 170                 175     
          Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser 
                      180                 185                 190         
          Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Val His Glu Ala 
                  195                 200                 205             
          Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Gly 
              210                 215                 220                 
          Ser Gly Gly Ser Ala Pro Ala Ser Ser Ser Thr Lys Lys Thr Gln Leu 
          225                 230                 235                 240 
          Gln Leu Glu Ala Leu Leu Leu Asp Leu Gln Ala Ile Leu Asn Gly Ile 
                          245                 250                 255     
          Asn Asn Tyr Lys Asn Pro Lys Leu Thr Arg Met Leu Thr Phe Lys Phe 
                      260                 265                 270         
          Tyr Met Pro Lys Lys Ala Thr Glu Leu Lys His Leu Gln Cys Leu Glu 
                  275                 280                 285             
          Glu Glu Leu Lys Arg Leu Glu Glu Val Leu Asn Leu Ala Gln Ser Lys 
              290                 295                 300                 
          Asn Phe His Leu Arg Pro Arg Ser Leu Ile Ser Asn Ile Asn Val Ile 
          305                 310                 315                 320 
          Val Leu Glu Leu Lys Gly Ser Glu Thr Thr Phe Met Cys Glu Tyr Ala 
                          325                 330                 335     
          Asp Glu Thr Ala Thr Ile Val Glu Phe Leu Asn Arg Trp Ile Thr Phe 
                      340                 345                 350         
          Ser Gln Ser Ile Ile Ser Thr Leu Thr 
                  355                 360     
          <![CDATA[<210>  103]]>
          <![CDATA[<211>  361]]>
          <![CDATA[<212>  PRT]]>
          <![CDATA[<213>  人工序列]]>
          <![CDATA[<220>]]>
          <![CDATA[<223>  合成：xELL-杵Fc-IL-2-RAS-E95Q-T3A, C125S]]>
          <![CDATA[<400>  103]]>
          Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Gly Gly Pro Ser 
          1               5                   10                  15      
          Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Tyr Ile Ser Arg 
                      20                  25                  30          
          Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro 
                  35                  40                  45              
          Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala 
              50                  55                  60                  
          Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val 
          65                  70                  75                  80  
          Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr 
                          85                  90                  95      
          Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr 
                      100                 105                 110         
          Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu 
                  115                 120                 125             
          Pro Pro Cys Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu Trp Cys 
              130                 135                 140                 
          Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser 
          145                 150                 155                 160 
          Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp 
                          165                 170                 175     
          Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser 
                      180                 185                 190         
          Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Val His Glu Ala 
                  195                 200                 205             
          Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Gly 
              210                 215                 220                 
          Ser Gly Gly Ser Ala Pro Ala Ser Ser Ser Thr Lys Lys Thr Gln Leu 
          225                 230                 235                 240 
          Gln Leu Glu Ala Leu Leu Leu Asp Leu Gln Met Ile Leu Asn Gly Ile 
                          245                 250                 255     
          Asn Asn Tyr Lys Asn Pro Lys Leu Thr Arg Met Leu Thr Phe Lys Phe 
                      260                 265                 270         
          Tyr Met Pro Lys Lys Ala Thr Glu Leu Lys His Leu Gln Cys Leu Glu 
                  275                 280                 285             
          Glu Glu Leu Lys Arg Leu Glu Glu Val Leu Asn Leu Ala Gln Ser Lys 
              290                 295                 300                 
          Asn Phe His Leu Arg Pro Arg Ser Leu Ile Ser Asn Ile Asn Val Ile 
          305                 310                 315                 320 
          Val Leu Gln Leu Lys Gly Ser Glu Thr Thr Phe Met Cys Glu Tyr Ala 
                          325                 330                 335     
          Asp Glu Thr Ala Thr Ile Val Glu Phe Leu Asn Arg Trp Ile Thr Phe 
                      340                 345                 350         
          Ser Gln Ser Ile Ile Ser Thr Leu Thr 
                  355                 360     
          <![CDATA[<210>  104]]>
          <![CDATA[<211>  361]]>
          <![CDATA[<212>  PRT]]>
          <![CDATA[<213>  人工序列]]>
          <![CDATA[<220>]]>
          <![CDATA[<223>  合成：xELL-杵Fc-IL-2-RAS-M23A-E95Q-T3A, C125S]]>
          <![CDATA[<400>  104]]>
          Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Gly Gly Pro Ser 
          1               5                   10                  15      
          Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Tyr Ile Ser Arg 
                      20                  25                  30          
          Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro 
                  35                  40                  45              
          Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala 
              50                  55                  60                  
          Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val 
          65                  70                  75                  80  
          Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr 
                          85                  90                  95      
          Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr 
                      100                 105                 110         
          Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu 
                  115                 120                 125             
          Pro Pro Cys Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu Trp Cys 
              130                 135                 140                 
          Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser 
          145                 150                 155                 160 
          Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp 
                          165                 170                 175     
          Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser 
                      180                 185                 190         
          Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Val His Glu Ala 
                  195                 200                 205             
          Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Gly 
              210                 215                 220                 
          Ser Gly Gly Ser Ala Pro Ala Ser Ser Ser Thr Lys Lys Thr Gln Leu 
          225                 230                 235                 240 
          Gln Leu Glu Ala Leu Leu Leu Asp Leu Gln Ala Ile Leu Asn Gly Ile 
                          245                 250                 255     
          Asn Asn Tyr Lys Asn Pro Lys Leu Thr Arg Met Leu Thr Phe Lys Phe 
                      260                 265                 270         
          Tyr Met Pro Lys Lys Ala Thr Glu Leu Lys His Leu Gln Cys Leu Glu 
                  275                 280                 285             
          Glu Glu Leu Lys Arg Leu Glu Glu Val Leu Asn Leu Ala Gln Ser Lys 
              290                 295                 300                 
          Asn Phe His Leu Arg Pro Arg Ser Leu Ile Ser Asn Ile Asn Val Ile 
          305                 310                 315                 320 
          Val Leu Gln Leu Lys Gly Ser Glu Thr Thr Phe Met Cys Glu Tyr Ala 
                          325                 330                 335     
          Asp Glu Thr Ala Thr Ile Val Glu Phe Leu Asn Arg Trp Ile Thr Phe 
                      340                 345                 350         
          Ser Gln Ser Ile Ile Ser Thr Leu Thr 
                  355                 360     
          <![CDATA[<210>  105]]>
          <![CDATA[<211>  133]]>
          <![CDATA[<212>  PRT]]>
          <![CDATA[<213>  人工序列]]>
          <![CDATA[<220>]]>
          <![CDATA[<223>  合成：IL-2-T3G-C125S]]>
          <![CDATA[<400>  105]]>
          Ala Pro Gly Ser Ser Ser Thr Lys Lys Thr Gln Leu Gln Leu Glu His 
          1               5                   10                  15      
          Leu Leu Leu Asp Leu Gln Met Ile Leu Asn Gly Ile Asn Asn Tyr Lys 
                      20                  25                  30          
          Asn Pro Lys Leu Thr Arg Met Leu Thr Phe Lys Phe Tyr Met Pro Lys 
                  35                  40                  45              
          Lys Ala Thr Glu Leu Lys His Leu Gln Cys Leu Glu Glu Glu Leu Lys 
              50                  55                  60                  
          Pro Leu Glu Glu Val Leu Asn Leu Ala Gln Ser Lys Asn Phe His Leu 
          65                  70                  75                  80  
          Arg Pro Arg Asp Leu Ile Ser Asn Ile Asn Val Ile Val Leu Glu Leu 
                          85                  90                  95      
          Lys Gly Ser Glu Thr Thr Phe Met Cys Glu Tyr Ala Asp Glu Thr Ala 
                      100                 105                 110         
          Thr Ile Val Glu Phe Leu Asn Arg Trp Ile Thr Phe Ser Gln Ser Ile 
                  115                 120                 125             
          Ile Ser Thr Leu Thr 
              130             
          <![CDATA[<210>  106]]>
          <![CDATA[<211>  133]]>
          <![CDATA[<212>  PRT]]>
          <![CDATA[<213>  人工序列]]>
          <![CDATA[<220>]]>
          <![CDATA[<223>  合成：IL-2-T3A-E61R-P65R-C125S]]>
          <![CDATA[<400>  106]]>
          Ala Pro Ala Ser Ser Ser Thr Lys Lys Thr Gln Leu Gln Leu Glu His 
          1               5                   10                  15      
          Leu Leu Leu Asp Leu Gln Met Ile Leu Asn Gly Ile Asn Asn Tyr Lys 
                      20                  25                  30          
          Asn Pro Lys Leu Thr Arg Met Leu Thr Phe Lys Phe Tyr Met Pro Lys 
                  35                  40                  45              
          Lys Ala Thr Glu Leu Lys His Leu Gln Cys Leu Glu Arg Glu Leu Lys 
              50                  55                  60                  
          Arg Leu Glu Glu Val Leu Asn Leu Ala Gln Ser Lys Asn Phe His Leu 
          65                  70                  75                  80  
          Arg Pro Arg Asp Leu Ile Ser Asn Ile Asn Val Ile Val Leu Glu Leu 
                          85                  90                  95      
          Lys Gly Ser Glu Thr Thr Phe Met Cys Glu Tyr Ala Asp Glu Thr Ala 
                      100                 105                 110         
          Thr Ile Val Glu Phe Leu Asn Arg Trp Ile Thr Phe Ser Gln Ser Ile 
                  115                 120                 125             
          Ile Ser Thr Leu Thr 
              130             
          <![CDATA[<210>  107]]>
          <![CDATA[<211>  133]]>
          <![CDATA[<212>  PRT]]>
          <![CDATA[<213>  人工序列]]>
          <![CDATA[<220>]]>
          <![CDATA[<223>  合成：IL-2-T3A-R38A-P65R-C125S]]>
          <![CDATA[<400>  107]]>
          Ala Pro Ala Ser Ser Ser Thr Lys Lys Thr Gln Leu Gln Leu Glu His 
          1               5                   10                  15      
          Leu Leu Leu Asp Leu Gln Met Ile Leu Asn Gly Ile Asn Asn Tyr Lys 
                      20                  25                  30          
          Asn Pro Lys Leu Thr Ala Met Leu Thr Phe Lys Phe Tyr Met Pro Lys 
                  35                  40                  45              
          Lys Ala Thr Glu Leu Lys His Leu Gln Cys Leu Glu Glu Glu Leu Lys 
              50                  55                  60                  
          Arg Leu Glu Glu Val Leu Asn Leu Ala Gln Ser Lys Asn Phe His Leu 
          65                  70                  75                  80  
          Arg Pro Arg Asp Leu Ile Ser Asn Ile Asn Val Ile Val Leu Glu Leu 
                          85                  90                  95      
          Lys Gly Ser Glu Thr Thr Phe Met Cys Glu Tyr Ala Asp Glu Thr Ala 
                      100                 105                 110         
          Thr Ile Val Glu Phe Leu Asn Arg Trp Ile Thr Phe Ser Gln Ser Ile 
                  115                 120                 125             
          Ile Ser Thr Leu Thr 
              130             
          <![CDATA[<210>  108]]>
          <![CDATA[<211>  133]]>
          <![CDATA[<212>  PRT]]>
          <![CDATA[<213>  人工序列]]>
          <![CDATA[<220>]]>
          <![CDATA[<223>  合成：IL-2-T3A-H16A-E61R-P65R-D84S-C125S]]>
          <![CDATA[<400>  108]]>
          Ala Pro Ala Ser Ser Ser Thr Lys Lys Thr Gln Leu Gln Leu Glu Ala 
          1               5                   10                  15      
          Leu Leu Leu Asp Leu Gln Met Ile Leu Asn Gly Ile Asn Asn Tyr Lys 
                      20                  25                  30          
          Asn Pro Lys Leu Thr Arg Met Leu Thr Phe Lys Phe Tyr Met Pro Lys 
                  35                  40                  45              
          Lys Ala Thr Glu Leu Lys His Leu Gln Cys Leu Glu Arg Glu Leu Lys 
              50                  55                  60                  
          Arg Leu Glu Glu Val Leu Asn Leu Ala Gln Ser Lys Asn Phe His Leu 
          65                  70                  75                  80  
          Arg Pro Arg Ser Leu Ile Ser Asn Ile Asn Val Ile Val Leu Glu Leu 
                          85                  90                  95      
          Lys Gly Ser Glu Thr Thr Phe Met Cys Glu Tyr Ala Asp Glu Thr Ala 
                      100                 105                 110         
          Thr Ile Val Glu Phe Leu Asn Arg Trp Ile Thr Phe Ser Gln Ser Ile 
                  115                 120                 125             
          Ile Ser Thr Leu Thr 
              130             
          <![CDATA[<210>  109]]>
          <![CDATA[<211>  133]]>
          <![CDATA[<212>  PRT]]>
          <![CDATA[<213>  人工序列]]>
          <![CDATA[<220>]]>
          <![CDATA[<223>  合成：IL-2-T3A-H16A-R38A-P65R-D84S-C125S]]>
          <![CDATA[<400>  109]]>
          Ala Pro Ala Ser Ser Ser Thr Lys Lys Thr Gln Leu Gln Leu Glu Ala 
          1               5                   10                  15      
          Leu Leu Leu Asp Leu Gln Met Ile Leu Asn Gly Ile Asn Asn Tyr Lys 
                      20                  25                  30          
          Asn Pro Lys Leu Thr Ala Met Leu Thr Phe Lys Phe Tyr Met Pro Lys 
                  35                  40                  45              
          Lys Ala Thr Glu Leu Lys His Leu Gln Cys Leu Glu Glu Glu Leu Lys 
              50                  55                  60                  
          Arg Leu Glu Glu Val Leu Asn Leu Ala Gln Ser Lys Asn Phe His Leu 
          65                  70                  75                  80  
          Arg Pro Arg Ser Leu Ile Ser Asn Ile Asn Val Ile Val Leu Glu Leu 
                          85                  90                  95      
          Lys Gly Ser Glu Thr Thr Phe Met Cys Glu Tyr Ala Asp Glu Thr Ala 
                      100                 105                 110         
          Thr Ile Val Glu Phe Leu Asn Arg Trp Ile Thr Phe Ser Gln Ser Ile 
                  115                 120                 125             
          Ile Ser Thr Leu Thr 
              130             
          <![CDATA[<210>  110]]>
          <![CDATA[<211>  133]]>
          <![CDATA[<212>  PRT]]>
          <![CDATA[<213>  人工序列]]>
          <![CDATA[<220>]]>
          <![CDATA[<223>  合成：IL-2-T3A-H16A-L19A-P65R-D84S-C125S]]>
          <![CDATA[<400>  110]]>
          Ala Pro Ala Ser Ser Ser Thr Lys Lys Thr Gln Leu Gln Leu Glu Ala 
          1               5                   10                  15      
          Leu Leu Leu Ala Leu Gln Met Ile Leu Asn Gly Ile Asn Asn Tyr Lys 
                      20                  25                  30          
          Asn Pro Lys Leu Thr Arg Met Leu Thr Phe Lys Phe Tyr Met Pro Lys 
                  35                  40                  45              
          Lys Ala Thr Glu Leu Lys His Leu Gln Cys Leu Glu Glu Glu Leu Lys 
              50                  55                  60                  
          Arg Leu Glu Glu Val Leu Asn Leu Ala Gln Ser Lys Asn Phe His Leu 
          65                  70                  75                  80  
          Arg Pro Arg Ser Leu Ile Ser Asn Ile Asn Val Ile Val Leu Glu Leu 
                          85                  90                  95      
          Lys Gly Ser Glu Thr Thr Phe Met Cys Glu Tyr Ala Asp Glu Thr Ala 
                      100                 105                 110         
          Thr Ile Val Glu Phe Leu Asn Arg Trp Ile Thr Phe Ser Gln Ser Ile 
                  115                 120                 125             
          Ile Ser Thr Leu Thr 
              130             
          <![CDATA[<210>  111]]>
          <![CDATA[<211>  133]]>
          <![CDATA[<212>  PRT]]>
          <![CDATA[<213>  人工序列]]>
          <![CDATA[<220>]]>
          <![CDATA[<223>  合成：IL-2-T3A-H16A-P65R-D84S-N88S-C125S]]>
          <![CDATA[<400>  111]]>
          Ala Pro Ala Ser Ser Ser Thr Lys Lys Thr Gln Leu Gln Leu Glu Ala 
          1               5                   10                  15      
          Leu Leu Leu Asp Leu Gln Met Ile Leu Asn Gly Ile Asn Asn Tyr Lys 
                      20                  25                  30          
          Asn Pro Lys Leu Thr Arg Met Leu Thr Phe Lys Phe Tyr Met Pro Lys 
                  35                  40                  45              
          Lys Ala Thr Glu Leu Lys His Leu Gln Cys Leu Glu Glu Glu Leu Lys 
              50                  55                  60                  
          Arg Leu Glu Glu Val Leu Asn Leu Ala Gln Ser Lys Asn Phe His Leu 
          65                  70                  75                  80  
          Arg Pro Arg Ser Leu Ile Ser Ser Ile Asn Val Ile Val Leu Glu Leu 
                          85                  90                  95      
          Lys Gly Ser Glu Thr Thr Phe Met Cys Glu Tyr Ala Asp Glu Thr Ala 
                      100                 105                 110         
          Thr Ile Val Glu Phe Leu Asn Arg Trp Ile Thr Phe Ser Gln Ser Ile 
                  115                 120                 125             
          Ile Ser Thr Leu Thr 
              130             
          <![CDATA[<210>  112]]>
          <![CDATA[<211>  133]]>
          <![CDATA[<212>  PRT]]>
          <![CDATA[<213>  人工序列]]>
          <![CDATA[<220>]]>
          <![CDATA[<223>  合成：IL-2-T3A-H16A-P65R-D84S-E95Q-C125S]]>
          <![CDATA[<400>  112]]>
          Ala Pro Ala Ser Ser Ser Thr Lys Lys Thr Gln Leu Gln Leu Glu Ala 
          1               5                   10                  15      
          Leu Leu Leu Asp Leu Gln Met Ile Leu Asn Gly Ile Asn Asn Tyr Lys 
                      20                  25                  30          
          Asn Pro Lys Leu Thr Arg Met Leu Thr Phe Lys Phe Tyr Met Pro Lys 
                  35                  40                  45              
          Lys Ala Thr Glu Leu Lys His Leu Gln Cys Leu Glu Glu Glu Leu Lys 
              50                  55                  60                  
          Arg Leu Glu Glu Val Leu Asn Leu Ala Gln Ser Lys Asn Phe His Leu 
          65                  70                  75                  80  
          Arg Pro Arg Ser Leu Ile Ser Asn Ile Asn Val Ile Val Leu Gln Leu 
                          85                  90                  95      
          Lys Gly Ser Glu Thr Thr Phe Met Cys Glu Tyr Ala Asp Glu Thr Ala 
                      100                 105                 110         
          Thr Ile Val Glu Phe Leu Asn Arg Trp Ile Thr Phe Ser Gln Ser Ile 
                  115                 120                 125             
          Ile Ser Thr Leu Thr 
              130             
          <![CDATA[<210>  113]]>
          <![CDATA[<211>  133]]>
          <![CDATA[<212>  PRT]]>
          <![CDATA[<213>  人工序列]]>
          <![CDATA[<220>]]>
          <![CDATA[<223>  合成：IL-2-T3A-H16A-M23A-P65R-D84S-C125S]]>
          <![CDATA[<400>  113]]>
          Ala Pro Ala Ser Ser Ser Thr Lys Lys Thr Gln Leu Gln Leu Glu Ala 
          1               5                   10                  15      
          Leu Leu Leu Asp Leu Gln Ala Ile Leu Asn Gly Ile Asn Asn Tyr Lys 
                      20                  25                  30          
          Asn Pro Lys Leu Thr Arg Met Leu Thr Phe Lys Phe Tyr Met Pro Lys 
                  35                  40                  45              
          Lys Ala Thr Glu Leu Lys His Leu Gln Cys Leu Glu Glu Glu Leu Lys 
              50                  55                  60                  
          Arg Leu Glu Glu Val Leu Asn Leu Ala Gln Ser Lys Asn Phe His Leu 
          65                  70                  75                  80  
          Arg Pro Arg Ser Leu Ile Ser Asn Ile Asn Val Ile Val Leu Glu Leu 
                          85                  90                  95      
          Lys Gly Ser Glu Thr Thr Phe Met Cys Glu Tyr Ala Asp Glu Thr Ala 
                      100                 105                 110         
          Thr Ile Val Glu Phe Leu Asn Arg Trp Ile Thr Phe Ser Gln Ser Ile 
                  115                 120                 125             
          Ile Ser Thr Leu Thr 
              130             
          <![CDATA[<210>  114]]>
          <![CDATA[<211>  133]]>
          <![CDATA[<212>  PRT]]>
          <![CDATA[<213>  人工序列]]>
          <![CDATA[<220>]]>
          <![CDATA[<223>  合成：IL-2-T3A-H16A-M23A-P65R-D84S-E95Q-C125S]]>
          <![CDATA[<400>  114]]>
          Ala Pro Ala Ser Ser Ser Thr Lys Lys Thr Gln Leu Gln Leu Glu Ala 
          1               5                   10                  15      
          Leu Leu Leu Asp Leu Gln Ala Ile Leu Asn Gly Ile Asn Asn Tyr Lys 
                      20                  25                  30          
          Asn Pro Lys Leu Thr Arg Met Leu Thr Phe Lys Phe Tyr Met Pro Lys 
                  35                  40                  45              
          Lys Ala Thr Glu Leu Lys His Leu Gln Cys Leu Glu Glu Glu Leu Lys 
              50                  55                  60                  
          Arg Leu Glu Glu Val Leu Asn Leu Ala Gln Ser Lys Asn Phe His Leu 
          65                  70                  75                  80  
          Arg Pro Arg Ser Leu Ile Ser Asn Ile Asn Val Ile Val Leu Gln Leu 
                          85                  90                  95      
          Lys Gly Ser Glu Thr Thr Phe Met Cys Glu Tyr Ala Asp Glu Thr Ala 
                      100                 105                 110         
          Thr Ile Val Glu Phe Leu Asn Arg Trp Ile Thr Phe Ser Gln Ser Ile 
                  115                 120                 125             
          Ile Ser Thr Leu Thr 
              130             
          <![CDATA[<210>  115]]>
          <![CDATA[<211>  133]]>
          <![CDATA[<212>  PRT]]>
          <![CDATA[<213>  人工序列]]>
          <![CDATA[<220>]]>
          <![CDATA[<223>  合成：IL-2-T3A-H16A-L19A-E61R-P65R-D84S-C125S]]>
          <![CDATA[<400>  115]]>
          Ala Pro Ala Ser Ser Ser Thr Lys Lys Thr Gln Leu Gln Leu Glu Ala 
          1               5                   10                  15      
          Leu Leu Ala Asp Leu Gln Met Ile Leu Asn Gly Ile Asn Asn Tyr Lys 
                      20                  25                  30          
          Asn Pro Lys Leu Thr Arg Met Leu Thr Phe Lys Phe Tyr Met Pro Lys 
                  35                  40                  45              
          Lys Ala Thr Glu Leu Lys His Leu Gln Cys Leu Glu Arg Glu Leu Lys 
              50                  55                  60                  
          Arg Leu Glu Glu Val Leu Asn Leu Ala Gln Ser Lys Asn Phe His Leu 
          65                  70                  75                  80  
          Arg Pro Arg Ser Leu Ile Ser Asn Ile Asn Val Ile Val Leu Glu Leu 
                          85                  90                  95      
          Lys Gly Ser Glu Thr Thr Phe Met Cys Glu Tyr Ala Asp Glu Thr Ala 
                      100                 105                 110         
          Thr Ile Val Glu Phe Leu Asn Arg Trp Ile Thr Phe Ser Gln Ser Ile 
                  115                 120                 125             
          Ile Ser Thr Leu Thr 
              130             
          <![CDATA[<210>  116]]>
          <![CDATA[<211>  133]]>
          <![CDATA[<212>  PRT]]>
          <![CDATA[<213>  人工序列]]>
          <![CDATA[<220>]]>
          <![CDATA[<223>  合成：IL-2-T3A-H16A-M23A-E61R-P65R-D84S-E95Q-C125S]]>
          <![CDATA[<400>  116]]>
          Ala Pro Ala Ser Ser Ser Thr Lys Lys Thr Gln Leu Gln Leu Glu Ala 
          1               5                   10                  15      
          Leu Leu Leu Asp Leu Gln Ala Ile Leu Asn Gly Ile Asn Asn Tyr Lys 
                      20                  25                  30          
          Asn Pro Lys Leu Thr Arg Met Leu Thr Phe Lys Phe Tyr Met Pro Lys 
                  35                  40                  45              
          Lys Ala Thr Glu Leu Lys His Leu Gln Cys Leu Glu Arg Glu Leu Lys 
              50                  55                  60                  
          Arg Leu Glu Glu Val Leu Asn Leu Ala Gln Ser Lys Asn Phe His Leu 
          65                  70                  75                  80  
          Arg Pro Arg Ser Leu Ile Ser Asn Ile Asn Val Ile Val Leu Gln Leu 
                          85                  90                  95      
          Lys Gly Ser Glu Thr Thr Phe Met Cys Glu Tyr Ala Asp Glu Thr Ala 
                      100                 105                 110         
          Thr Ile Val Glu Phe Leu Asn Arg Trp Ile Thr Phe Ser Gln Ser Ile 
                  115                 120                 125             
          Ile Ser Thr Leu Thr 
              130             
          <![CDATA[<210>  117]]>
          <![CDATA[<211>  133]]>
          <![CDATA[<212>  PRT]]>
          <![CDATA[<213>  人工序列]]>
          <![CDATA[<220>]]>
          <![CDATA[<223>  合成：IL-2-T3A-H16A-M23A-E61R-P65R-D84S-N88S-C125S]]>
          <![CDATA[<400>  117]]>
          Ala Pro Ala Ser Ser Ser Thr Lys Lys Thr Gln Leu Gln Leu Glu Ala 
          1               5                   10                  15      
          Leu Leu Leu Asp Leu Gln Ala Ile Leu Asn Gly Ile Asn Asn Tyr Lys 
                      20                  25                  30          
          Asn Pro Lys Leu Thr Arg Met Leu Thr Phe Lys Phe Tyr Met Pro Lys 
                  35                  40                  45              
          Lys Ala Thr Glu Leu Lys His Leu Gln Cys Leu Glu Arg Glu Leu Lys 
              50                  55                  60                  
          Arg Leu Glu Glu Val Leu Asn Leu Ala Gln Ser Lys Asn Phe His Leu 
          65                  70                  75                  80  
          Arg Pro Arg Ser Leu Ile Ser Ser Ile Asn Val Ile Val Leu Glu Leu 
                          85                  90                  95      
          Lys Gly Ser Glu Thr Thr Phe Met Cys Glu Tyr Ala Asp Glu Thr Ala 
                      100                 105                 110         
          Thr Ile Val Glu Phe Leu Asn Arg Trp Ile Thr Phe Ser Gln Ser Ile 
                  115                 120                 125             
          Ile Ser Thr Leu Thr 
              130             
          <![CDATA[<210>  118]]>
          <![CDATA[<211>  133]]>
          <![CDATA[<212>  PRT]]>
          <![CDATA[<213>  人工序列]]>
          <![CDATA[<220>]]>
          <![CDATA[<223>  合成：IL-2-T3A-H16A-E61R-P65R-D84S-N88S-E95Q-C125S]]>
          <![CDATA[<400>  118]]>
          Ala Pro Ala Ser Ser Ser Thr Lys Lys Thr Gln Leu Gln Leu Glu Ala 
          1               5                   10                  15      
          Leu Leu Leu Asp Leu Gln Met Ile Leu Asn Gly Ile Asn Asn Tyr Lys 
                      20                  25                  30          
          Asn Pro Lys Leu Thr Arg Met Leu Thr Phe Lys Phe Tyr Met Pro Lys 
                  35                  40                  45              
          Lys Ala Thr Glu Leu Lys His Leu Gln Cys Leu Glu Arg Glu Leu Lys 
              50                  55                  60                  
          Arg Leu Glu Glu Val Leu Asn Leu Ala Gln Ser Lys Asn Phe His Leu 
          65                  70                  75                  80  
          Arg Pro Arg Ser Leu Ile Ser Ser Ile Asn Val Ile Val Leu Gln Leu 
                          85                  90                  95      
          Lys Gly Ser Glu Thr Thr Phe Met Cys Glu Tyr Ala Asp Glu Thr Ala 
                      100                 105                 110         
          Thr Ile Val Glu Phe Leu Asn Arg Trp Ile Thr Phe Ser Gln Ser Ile 
                  115                 120                 125             
          Ile Ser Thr Leu Thr 
              130             
          <![CDATA[<210>  119]]>
          <![CDATA[<211>  133]]>
          <![CDATA[<212>  PRT]]>
          <![CDATA[<213>  人工序列]]>
          <![CDATA[<220>]]>
          <![CDATA[<223>  合成：IL-2-T3A-H16A-M23A-E61R-P65R-D84S-N88S-E95Q-C125S]]>
          <![CDATA[<400>  119]]>
          Ala Pro Ala Ser Ser Ser Thr Lys Lys Thr Gln Leu Gln Leu Glu Ala 
          1               5                   10                  15      
          Leu Leu Leu Asp Leu Gln Ala Ile Leu Asn Gly Ile Asn Asn Tyr Lys 
                      20                  25                  30          
          Asn Pro Lys Leu Thr Arg Met Leu Thr Phe Lys Phe Tyr Met Pro Lys 
                  35                  40                  45              
          Lys Ala Thr Glu Leu Lys His Leu Gln Cys Leu Glu Arg Glu Leu Lys 
              50                  55                  60                  
          Arg Leu Glu Glu Val Leu Asn Leu Ala Gln Ser Lys Asn Phe His Leu 
          65                  70                  75                  80  
          Arg Pro Arg Ser Leu Ile Ser Ser Ile Asn Val Ile Val Leu Gln Leu 
                          85                  90                  95      
          Lys Gly Ser Glu Thr Thr Phe Met Cys Glu Tyr Ala Asp Glu Thr Ala 
                      100                 105                 110         
          Thr Ile Val Glu Phe Leu Asn Arg Trp Ile Thr Phe Ser Gln Ser Ile 
                  115                 120                 125             
          Ile Ser Thr Leu Thr 
              130             
          <![CDATA[<210>  120]]>
          <![CDATA[<211>  133]]>
          <![CDATA[<212>  PRT]]>
          <![CDATA[<213>  人工序列]]>
          <![CDATA[<220>]]>
          <![CDATA[<223>  合成：IL-2-T3A-H16A-L19A-R38A-P65R-D84S-C125S]]>
          <![CDATA[<400>  120]]>
          Ala Pro Ala Ser Ser Ser Thr Lys Lys Thr Gln Leu Gln Leu Glu Ala 
          1               5                   10                  15      
          Leu Leu Ala Asp Leu Gln Met Ile Leu Asn Gly Ile Asn Asn Tyr Lys 
                      20                  25                  30          
          Asn Pro Lys Leu Thr Ala Met Leu Thr Phe Lys Phe Tyr Met Pro Lys 
                  35                  40                  45              
          Lys Ala Thr Glu Leu Lys His Leu Gln Cys Leu Glu Glu Glu Leu Lys 
              50                  55                  60                  
          Arg Leu Glu Glu Val Leu Asn Leu Ala Gln Ser Lys Asn Phe His Leu 
          65                  70                  75                  80  
          Arg Pro Arg Ser Leu Ile Ser Asn Ile Asn Val Ile Val Leu Glu Leu 
                          85                  90                  95      
          Lys Gly Ser Glu Thr Thr Phe Met Cys Glu Tyr Ala Asp Glu Thr Ala 
                      100                 105                 110         
          Thr Ile Val Glu Phe Leu Asn Arg Trp Ile Thr Phe Ser Gln Ser Ile 
                  115                 120                 125             
          Ile Ser Thr Leu Thr 
              130             
          <![CDATA[<210>  121]]>
          <![CDATA[<211>  133]]>
          <![CDATA[<212>  PRT]]>
          <![CDATA[<213>  人工序列]]>
          <![CDATA[<220>]]>
          <![CDATA[<223>  合成：IL-2-T3A-H16A-M23A-R38A-P65R-D84S-E95Q-C125S]]>
          <![CDATA[<400>  121]]>
          Ala Pro Ala Ser Ser Ser Thr Lys Lys Thr Gln Leu Gln Leu Glu Ala 
          1               5                   10                  15      
          Leu Leu Leu Asp Leu Gln Ala Ile Leu Asn Gly Ile Asn Asn Tyr Lys 
                      20                  25                  30          
          Asn Pro Lys Leu Thr Ala Met Leu Thr Phe Lys Phe Tyr Met Pro Lys 
                  35                  40                  45              
          Lys Ala Thr Glu Leu Lys His Leu Gln Cys Leu Glu Glu Glu Leu Lys 
              50                  55                  60                  
          Arg Leu Glu Glu Val Leu Asn Leu Ala Gln Ser Lys Asn Phe His Leu 
          65                  70                  75                  80  
          Arg Pro Arg Ser Leu Ile Ser Asn Ile Asn Val Ile Val Leu Gln Leu 
                          85                  90                  95      
          Lys Gly Ser Glu Thr Thr Phe Met Cys Glu Tyr Ala Asp Glu Thr Ala 
                      100                 105                 110         
          Thr Ile Val Glu Phe Leu Asn Arg Trp Ile Thr Phe Ser Gln Ser Ile 
                  115                 120                 125             
          Ile Ser Thr Leu Thr 
              130             
          <![CDATA[<210>  122]]>
          <![CDATA[<211>  133]]>
          <![CDATA[<212>  PRT]]>
          <![CDATA[<213>  人工序列]]>
          <![CDATA[<220>]]>
          <![CDATA[<223>  合成：IL-2-T3A-H16A-M23A-R38A-P65R-D84S-N88S-C125S]]>
          <![CDATA[<400>  122]]>
          Ala Pro Ala Ser Ser Ser Thr Lys Lys Thr Gln Leu Gln Leu Glu Ala 
          1               5                   10                  15      
          Leu Leu Leu Asp Leu Gln Ala Ile Leu Asn Gly Ile Asn Asn Tyr Lys 
                      20                  25                  30          
          Asn Pro Lys Leu Thr Ala Met Leu Thr Phe Lys Phe Tyr Met Pro Lys 
                  35                  40                  45              
          Lys Ala Thr Glu Leu Lys His Leu Gln Cys Leu Glu Glu Glu Leu Lys 
              50                  55                  60                  
          Arg Leu Glu Glu Val Leu Asn Leu Ala Gln Ser Lys Asn Phe His Leu 
          65                  70                  75                  80  
          Arg Pro Arg Ser Leu Ile Ser Ser Ile Asn Val Ile Val Leu Glu Leu 
                          85                  90                  95      
          Lys Gly Ser Glu Thr Thr Phe Met Cys Glu Tyr Ala Asp Glu Thr Ala 
                      100                 105                 110         
          Thr Ile Val Glu Phe Leu Asn Arg Trp Ile Thr Phe Ser Gln Ser Ile 
                  115                 120                 125             
          Ile Ser Thr Leu Thr 
              130             
          <![CDATA[<210>  123]]>
          <![CDATA[<211>  133]]>
          <![CDATA[<212>  PRT]]>
          <![CDATA[<213>  人工序列]]>
          <![CDATA[<220>]]>
          <![CDATA[<223>  合成：IL-2-T3A-H16A-R38A-P65R-D84S-N88S-E95Q-C125S]]>
          <![CDATA[<400>  123]]>
          Ala Pro Ala Ser Ser Ser Thr Lys Lys Thr Gln Leu Gln Leu Glu Ala 
          1               5                   10                  15      
          Leu Leu Leu Asp Leu Gln Met Ile Leu Asn Gly Ile Asn Asn Tyr Lys 
                      20                  25                  30          
          Asn Pro Lys Leu Thr Ala Met Leu Thr Phe Lys Phe Tyr Met Pro Lys 
                  35                  40                  45              
          Lys Ala Thr Glu Leu Lys His Leu Gln Cys Leu Glu Glu Glu Leu Lys 
              50                  55                  60                  
          Arg Leu Glu Glu Val Leu Asn Leu Ala Gln Ser Lys Asn Phe His Leu 
          65                  70                  75                  80  
          Arg Pro Arg Ser Leu Ile Ser Ser Ile Asn Val Ile Val Leu Gln Leu 
                          85                  90                  95      
          Lys Gly Ser Glu Thr Thr Phe Met Cys Glu Tyr Ala Asp Glu Thr Ala 
                      100                 105                 110         
          Thr Ile Val Glu Phe Leu Asn Arg Trp Ile Thr Phe Ser Gln Ser Ile 
                  115                 120                 125             
          Ile Ser Thr Leu Thr 
              130             
          <![CDATA[<210>  124]]>
          <![CDATA[<211>  133]]>
          <![CDATA[<212>  PRT]]>
          <![CDATA[<213>  人工序列]]>
          <![CDATA[<220>]]>
          <![CDATA[<223>  合成：IL-2-T3A-H16A-M23A-R38A-P65R-IL-2-D84S-N88S-E95Q-C125S]]>
          <![CDATA[<400>  124]]>
          Ala Pro Ala Ser Ser Ser Thr Lys Lys Thr Gln Leu Gln Leu Glu Ala 
          1               5                   10                  15      
          Leu Leu Leu Asp Leu Gln Ala Ile Leu Asn Gly Ile Asn Asn Tyr Lys 
                      20                  25                  30          
          Asn Pro Lys Leu Thr Ala Met Leu Thr Phe Lys Phe Tyr Met Pro Lys 
                  35                  40                  45              
          Lys Ala Thr Glu Leu Lys His Leu Gln Cys Leu Glu Glu Glu Leu Lys 
              50                  55                  60                  
          Arg Leu Glu Glu Val Leu Asn Leu Ala Gln Ser Lys Asn Phe His Leu 
          65                  70                  75                  80  
          Arg Pro Arg Ser Leu Ile Ser Ser Ile Asn Val Ile Val Leu Gln Leu 
                          85                  90                  95      
          Lys Gly Ser Glu Thr Thr Phe Met Cys Glu Tyr Ala Asp Glu Thr Ala 
                      100                 105                 110         
          Thr Ile Val Glu Phe Leu Asn Arg Trp Ile Thr Phe Ser Gln Ser Ile 
                  115                 120                 125             
          Ile Ser Thr Leu Thr 
              130             
          <![CDATA[<210>  125]]>
          <![CDATA[<211>  133]]>
          <![CDATA[<212>  PRT]]>
          <![CDATA[<213>  人工序列]]>
          <![CDATA[<220>]]>
          <![CDATA[<223>  合成：IL-2-T3A-H16A-L19N-P65R-D84S-C125S]]>
          <![CDATA[<400>  125]]>
          Ala Pro Ala Ser Ser Ser Thr Lys Lys Thr Gln Leu Gln Leu Glu Ala 
          1               5                   10                  15      
          Leu Leu Asn Asp Leu Gln Met Ile Leu Asn Gly Ile Asn Asn Tyr Lys 
                      20                  25                  30          
          Asn Pro Lys Leu Thr Arg Met Leu Thr Phe Lys Phe Tyr Met Pro Lys 
                  35                  40                  45              
          Lys Ala Thr Glu Leu Lys His Leu Gln Cys Leu Glu Glu Glu Leu Lys 
              50                  55                  60                  
          Arg Leu Glu Glu Val Leu Asn Leu Ala Gln Ser Lys Asn Phe His Leu 
          65                  70                  75                  80  
          Arg Pro Arg Ser Leu Ile Ser Asn Ile Asn Val Ile Val Leu Glu Leu 
                          85                  90                  95      
          Lys Gly Ser Glu Thr Thr Phe Met Cys Glu Tyr Ala Asp Glu Thr Ala 
                      100                 105                 110         
          Thr Ile Val Glu Phe Leu Asn Arg Trp Ile Thr Phe Ser Gln Ser Ile 
                  115                 120                 125             
          Ile Ser Thr Leu Thr 
              130             
          <![CDATA[<210>  126]]>
          <![CDATA[<211>  133]]>
          <![CDATA[<212>  PRT]]>
          <![CDATA[<213>  人工序列]]>
          <![CDATA[<220>]]>
          <![CDATA[<223>  合成：IL-2-T3A-H16A-L19S-P65R-D84S-C125S]]>
          <![CDATA[<400>  126]]>
          Ala Pro Ala Ser Ser Ser Thr Lys Lys Thr Gln Leu Gln Leu Glu Ala 
          1               5                   10                  15      
          Leu Leu Ser Asp Leu Gln Met Ile Leu Asn Gly Ile Asn Asn Tyr Lys 
                      20                  25                  30          
          Asn Pro Lys Leu Thr Arg Met Leu Thr Phe Lys Phe Tyr Met Pro Lys 
                  35                  40                  45              
          Lys Ala Thr Glu Leu Lys His Leu Gln Cys Leu Glu Glu Glu Leu Lys 
              50                  55                  60                  
          Arg Leu Glu Glu Val Leu Asn Leu Ala Gln Ser Lys Asn Phe His Leu 
          65                  70                  75                  80  
          Arg Pro Arg Ser Leu Ile Ser Asn Ile Asn Val Ile Val Leu Glu Leu 
                          85                  90                  95      
          Lys Gly Ser Glu Thr Thr Phe Met Cys Glu Tyr Ala Asp Glu Thr Ala 
                      100                 105                 110         
          Thr Ile Val Glu Phe Leu Asn Arg Trp Ile Thr Phe Ser Gln Ser Ile 
                  115                 120                 125             
          Ile Ser Thr Leu Thr 
              130             
          <![CDATA[<210>  127]]>
          <![CDATA[<211>  133]]>
          <![CDATA[<212>  PRT]]>
          <![CDATA[<213>  人工序列]]>
          <![CDATA[<220>]]>
          <![CDATA[<223>  合成：IL-2-T3A-H16A-L19T-P65R-D84S-C125S]]>
          <![CDATA[<400>  127]]>
          Ala Pro Ala Ser Ser Ser Thr Lys Lys Thr Gln Leu Gln Leu Glu Ala 
          1               5                   10                  15      
          Leu Leu Thr Asp Leu Gln Met Ile Leu Asn Gly Ile Asn Asn Tyr Lys 
                      20                  25                  30          
          Asn Pro Lys Leu Thr Arg Met Leu Thr Phe Lys Phe Tyr Met Pro Lys 
                  35                  40                  45              
          Lys Ala Thr Glu Leu Lys His Leu Gln Cys Leu Glu Glu Glu Leu Lys 
              50                  55                  60                  
          Arg Leu Glu Glu Val Leu Asn Leu Ala Gln Ser Lys Asn Phe His Leu 
          65                  70                  75                  80  
          Arg Pro Arg Ser Leu Ile Ser Asn Ile Asn Val Ile Val Leu Glu Leu 
                          85                  90                  95      
          Lys Gly Ser Glu Thr Thr Phe Met Cys Glu Tyr Ala Asp Glu Thr Ala 
                      100                 105                 110         
          Thr Ile Val Glu Phe Leu Asn Arg Trp Ile Thr Phe Ser Gln Ser Ile 
                  115                 120                 125             
          Ile Ser Thr Leu Thr 
              130             
          <![CDATA[<210>  128]]>
          <![CDATA[<211>  133]]>
          <![CDATA[<212>  PRT]]>
          <![CDATA[<213>  人工序列]]>
          <![CDATA[<220>]]>
          <![CDATA[<223>  合成：IL-2-T3A-H16A-L19V-P65R-D84S-C125S]]>
          <![CDATA[<400>  128]]>
          Ala Pro Ala Ser Ser Ser Thr Lys Lys Thr Gln Leu Gln Leu Glu Ala 
          1               5                   10                  15      
          Leu Leu Val Asp Leu Gln Met Ile Leu Asn Gly Ile Asn Asn Tyr Lys 
                      20                  25                  30          
          Asn Pro Lys Leu Thr Arg Met Leu Thr Phe Lys Phe Tyr Met Pro Lys 
                  35                  40                  45              
          Lys Ala Thr Glu Leu Lys His Leu Gln Cys Leu Glu Glu Glu Leu Lys 
              50                  55                  60                  
          Arg Leu Glu Glu Val Leu Asn Leu Ala Gln Ser Lys Asn Phe His Leu 
          65                  70                  75                  80  
          Arg Pro Arg Ser Leu Ile Ser Asn Ile Asn Val Ile Val Leu Glu Leu 
                          85                  90                  95      
          Lys Gly Ser Glu Thr Thr Phe Met Cys Glu Tyr Ala Asp Glu Thr Ala 
                      100                 105                 110         
          Thr Ile Val Glu Phe Leu Asn Arg Trp Ile Thr Phe Ser Gln Ser Ile 
                  115                 120                 125             
          Ile Ser Thr Leu Thr 
              130             
          <![CDATA[<210>  129]]>
          <![CDATA[<211>  133]]>
          <![CDATA[<212>  PRT]]>
          <![CDATA[<213>  人工序列]]>
          <![CDATA[<220>]]>
          <![CDATA[<223>  合成：IL-2-T3A-H16A-L19N-M23A-E61R-P65R-D84S-E95Q-C125S]]>
          <![CDATA[<400>  129]]>
          Ala Pro Ala Ser Ser Ser Thr Lys Lys Thr Gln Leu Gln Leu Glu Ala 
          1               5                   10                  15      
          Leu Leu Asn Asp Leu Gln Ala Ile Leu Asn Gly Ile Asn Asn Tyr Lys 
                      20                  25                  30          
          Asn Pro Lys Leu Thr Arg Met Leu Thr Phe Lys Phe Tyr Met Pro Lys 
                  35                  40                  45              
          Lys Ala Thr Glu Leu Lys His Leu Gln Cys Leu Glu Arg Glu Leu Lys 
              50                  55                  60                  
          Arg Leu Glu Glu Val Leu Asn Leu Ala Gln Ser Lys Asn Phe His Leu 
          65                  70                  75                  80  
          Arg Pro Arg Ser Leu Ile Ser Asn Ile Asn Val Ile Val Leu Glu Leu 
                          85                  90                  95      
          Gln Gly Ser Glu Thr Thr Phe Met Cys Glu Tyr Ala Asp Glu Thr Ala 
                      100                 105                 110         
          Thr Ile Val Glu Phe Leu Asn Arg Trp Ile Thr Phe Ser Gln Ser Ile 
                  115                 120                 125             
          Ile Ser Thr Leu Thr 
              130             
          <![CDATA[<210>  130]]>
          <![CDATA[<211>  133]]>
          <![CDATA[<212>  PRT]]>
          <![CDATA[<213>  人工序列]]>
          <![CDATA[<220>]]>
          <![CDATA[<223>  合成：IL-2-T3A-H16A-L19N-M23A-R38A-P65R-D84S-E95Q-C125S]]>
          <![CDATA[<400>  130]]>
          Ala Pro Ala Ser Ser Ser Thr Lys Lys Thr Gln Leu Gln Leu Glu Ala 
          1               5                   10                  15      
          Leu Leu Asn Asp Leu Gln Ala Ile Leu Asn Gly Ile Asn Asn Tyr Lys 
                      20                  25                  30          
          Asn Pro Lys Leu Thr Ala Met Leu Thr Phe Lys Phe Tyr Met Pro Lys 
                  35                  40                  45              
          Lys Ala Thr Glu Leu Lys His Leu Gln Cys Leu Glu Glu Glu Leu Lys 
              50                  55                  60                  
          Arg Leu Glu Glu Val Leu Asn Leu Ala Gln Ser Lys Asn Phe His Leu 
          65                  70                  75                  80  
          Arg Pro Arg Ser Leu Ile Ser Asn Ile Asn Val Ile Val Leu Gln Leu 
                          85                  90                  95      
          Lys Gly Ser Glu Thr Thr Phe Met Cys Glu Tyr Ala Asp Glu Thr Ala 
                      100                 105                 110         
          Thr Ile Val Glu Phe Leu Asn Arg Trp Ile Thr Phe Ser Gln Ser Ile 
                  115                 120                 125             
          Ile Ser Thr Leu Thr 
              130             
          <![CDATA[<210>  131]]>
          <![CDATA[<211>  133]]>
          <![CDATA[<212>  PRT]]>
          <![CDATA[<213>  人工序列]]>
          <![CDATA[<220>]]>
          <![CDATA[<223>  合成：IL-2-T3A-H16A-L19N-M23A-R38A-P65R-D84S-C125S]]>
          <![CDATA[<400>  131]]>
          Ala Pro Ala Ser Ser Ser Thr Lys Lys Thr Gln Leu Gln Leu Glu Ala 
          1               5                   10                  15      
          Leu Leu Asn Asp Leu Gln Ala Ile Leu Asn Gly Ile Asn Asn Tyr Lys 
                      20                  25                  30          
          Asn Pro Lys Leu Thr Ala Met Leu Thr Phe Lys Phe Tyr Met Pro Lys 
                  35                  40                  45              
          Lys Ala Thr Glu Leu Lys His Leu Gln Cys Leu Glu Glu Glu Leu Lys 
              50                  55                  60                  
          Arg Leu Glu Glu Val Leu Asn Leu Ala Gln Ser Lys Asn Phe His Leu 
          65                  70                  75                  80  
          Arg Pro Arg Ser Leu Ile Ser Asn Ile Asn Val Ile Val Leu Glu Leu 
                          85                  90                  95      
          Lys Gly Ser Glu Thr Thr Phe Met Cys Glu Tyr Ala Asp Glu Thr Ala 
                      100                 105                 110         
          Thr Ile Val Glu Phe Leu Asn Arg Trp Ile Thr Phe Ser Gln Ser Ile 
                  115                 120                 125             
          Ile Ser Thr Leu Thr 
              130             
          <![CDATA[<210>  132]]>
          <![CDATA[<211>  133]]>
          <![CDATA[<212>  PRT]]>
          <![CDATA[<213>  人工序列]]>
          <![CDATA[<220>]]>
          <![CDATA[<223>  合成：IL-2-T3A-H16A-L19N-R38A-P65R-D84S-E95Q-C125S]]>
          <![CDATA[<400>  132]]>
          Ala Pro Ala Ser Ser Ser Thr Lys Lys Thr Gln Leu Gln Leu Glu Ala 
          1               5                   10                  15      
          Leu Leu Asn Asp Leu Gln Met Ile Leu Asn Gly Ile Asn Asn Tyr Lys 
                      20                  25                  30          
          Asn Pro Lys Leu Thr Ala Met Leu Thr Phe Lys Phe Tyr Met Pro Lys 
                  35                  40                  45              
          Lys Ala Thr Glu Leu Lys His Leu Gln Cys Leu Glu Glu Glu Leu Lys 
              50                  55                  60                  
          Arg Leu Glu Glu Val Leu Asn Leu Ala Gln Ser Lys Asn Phe His Leu 
          65                  70                  75                  80  
          Arg Pro Arg Ser Leu Ile Ser Asn Ile Asn Val Ile Val Leu Gln Leu 
                          85                  90                  95      
          Lys Gly Ser Glu Thr Thr Phe Met Cys Glu Tyr Ala Asp Glu Thr Ala 
                      100                 105                 110         
          Thr Ile Val Glu Phe Leu Asn Arg Trp Ile Thr Phe Ser Gln Ser Ile 
                  115                 120                 125             
          Ile Ser Thr Leu Thr 
              130             
          <![CDATA[<210>  133]]>
          <![CDATA[<211>  133]]>
          <![CDATA[<212>  PRT]]>
          <![CDATA[<213>  人工序列]]>
          <![CDATA[<220>]]>
          <![CDATA[<223>  合成：IL-2-T3A-H16A-L19N-R38A-P65R-D84S-C125S]]>
          <![CDATA[<400>  133]]>
          Ala Pro Ala Ser Ser Ser Thr Lys Lys Thr Gln Leu Gln Leu Glu Ala 
          1               5                   10                  15      
          Leu Leu Asn Asp Leu Gln Met Ile Leu Asn Gly Ile Asn Asn Tyr Lys 
                      20                  25                  30          
          Asn Pro Lys Leu Thr Ala Met Leu Thr Phe Lys Phe Tyr Met Pro Lys 
                  35                  40                  45              
          Lys Ala Thr Glu Leu Lys His Leu Gln Cys Leu Glu Glu Glu Leu Lys 
              50                  55                  60                  
          Arg Leu Glu Glu Val Leu Asn Leu Ala Gln Ser Lys Asn Phe His Leu 
          65                  70                  75                  80  
          Arg Pro Arg Ser Leu Ile Ser Asn Ile Asn Val Ile Val Leu Glu Leu 
                          85                  90                  95      
          Lys Gly Ser Glu Thr Thr Phe Met Cys Glu Tyr Ala Asp Glu Thr Ala 
                      100                 105                 110         
          Thr Ile Val Glu Phe Leu Asn Arg Trp Ile Thr Phe Ser Gln Ser Ile 
                  115                 120                 125             
          Ile Ser Thr Leu Thr 
              130             
          <![CDATA[<210>  134]]>
          <![CDATA[<211>  133]]>
          <![CDATA[<212>  PRT]]>
          <![CDATA[<213>  人工序列]]>
          <![CDATA[<220>]]>
          <![CDATA[<223>  合成：IL-2-T3A-H16A-L19N-E61R-P65R-D84S-C125S]]>
          <![CDATA[<400>  134]]>
          Ala Pro Ala Ser Ser Ser Thr Lys Lys Thr Gln Leu Gln Leu Glu Ala 
          1               5                   10                  15      
          Leu Leu Asn Asp Leu Gln Met Ile Leu Asn Gly Ile Asn Asn Tyr Lys 
                      20                  25                  30          
          Asn Pro Lys Leu Thr Arg Met Leu Thr Phe Lys Phe Tyr Met Pro Lys 
                  35                  40                  45              
          Lys Ala Thr Glu Leu Lys His Leu Gln Cys Leu Glu Arg Glu Leu Lys 
              50                  55                  60                  
          Arg Leu Glu Glu Val Leu Asn Leu Ala Gln Ser Lys Asn Phe His Leu 
          65                  70                  75                  80  
          Arg Pro Arg Ser Leu Ile Ser Asn Ile Asn Val Ile Val Leu Glu Leu 
                          85                  90                  95      
          Lys Gly Ser Glu Thr Thr Phe Met Cys Glu Tyr Ala Asp Glu Thr Ala 
                      100                 105                 110         
          Thr Ile Val Glu Phe Leu Asn Arg Trp Ile Thr Phe Ser Gln Ser Ile 
                  115                 120                 125             
          Ile Ser Thr Leu Thr 
              130             
          <![CDATA[<210>  135]]>
          <![CDATA[<211>  133]]>
          <![CDATA[<212>  PRT]]>
          <![CDATA[<213>  人工序列]]>
          <![CDATA[<220>]]>
          <![CDATA[<223>  合成：IL-2-T3A-H16A-L19N-E61R-P65R-D84S-E95Q-C125S]]>
          <![CDATA[<400>  135]]>
          Ala Pro Ala Ser Ser Ser Thr Lys Lys Thr Gln Leu Gln Leu Glu Ala 
          1               5                   10                  15      
          Leu Leu Asn Asp Leu Gln Met Ile Leu Asn Gly Ile Asn Asn Tyr Lys 
                      20                  25                  30          
          Asn Pro Lys Leu Thr Arg Met Leu Thr Phe Lys Phe Tyr Met Pro Lys 
                  35                  40                  45              
          Lys Ala Thr Glu Leu Lys His Leu Gln Cys Leu Glu Arg Glu Leu Lys 
              50                  55                  60                  
          Arg Leu Glu Glu Val Leu Asn Leu Ala Gln Ser Lys Asn Phe His Leu 
          65                  70                  75                  80  
          Arg Pro Arg Ser Leu Ile Ser Asn Ile Asn Val Ile Val Leu Gln Leu 
                          85                  90                  95      
          Lys Gly Ser Glu Thr Thr Phe Met Cys Glu Tyr Ala Asp Glu Thr Ala 
                      100                 105                 110         
          Thr Ile Val Glu Phe Leu Asn Arg Trp Ile Thr Phe Ser Gln Ser Ile 
                  115                 120                 125             
          Ile Ser Thr Leu Thr 
              130             
          <![CDATA[<210>  136]]>
          <![CDATA[<211>  133]]>
          <![CDATA[<212>  PRT]]>
          <![CDATA[<213>  人工序列]]>
          <![CDATA[<220>]]>
          <![CDATA[<223>  合成：IL-2-T3A-H16A-L19N-M23A-E61R-P65R-D84S-C125S]]>
          <![CDATA[<400>  136]]>
          Ala Pro Ala Ser Ser Ser Thr Lys Lys Thr Gln Leu Gln Leu Glu Ala 
          1               5                   10                  15      
          Leu Leu Asn Asp Leu Gln Ala Ile Leu Asn Gly Ile Asn Asn Tyr Lys 
                      20                  25                  30          
          Asn Pro Lys Leu Thr Arg Met Leu Thr Phe Lys Phe Tyr Met Pro Lys 
                  35                  40                  45              
          Lys Ala Thr Glu Leu Lys His Leu Gln Cys Leu Glu Arg Glu Leu Lys 
              50                  55                  60                  
          Arg Leu Glu Glu Val Leu Asn Leu Ala Gln Ser Lys Asn Phe His Leu 
          65                  70                  75                  80  
          Arg Pro Arg Ser Leu Ile Ser Asn Ile Asn Val Ile Val Leu Glu Leu 
                          85                  90                  95      
          Lys Gly Ser Glu Thr Thr Phe Met Cys Glu Tyr Ala Asp Glu Thr Ala 
                      100                 105                 110         
          Thr Ile Val Glu Phe Leu Asn Arg Trp Ile Thr Phe Ser Gln Ser Ile 
                  115                 120                 125             
          Ile Ser Thr Leu Thr 
              130             
          <![CDATA[<210>  137]]>
          <![CDATA[<211>  133]]>
          <![CDATA[<212>  PRT]]>
          <![CDATA[<213>  人工序列]]>
          <![CDATA[<220>]]>
          <![CDATA[<223>  合成：IL-2-T3A-H16A-L19N-Q22A-E61R-P65R-D84S-C125S]]>
          <![CDATA[<400>  137]]>
          Ala Pro Ala Ser Ser Ser Thr Lys Lys Thr Gln Leu Gln Leu Glu Ala 
          1               5                   10                  15      
          Leu Leu Asn Asp Leu Ala Met Ile Leu Asn Gly Ile Asn Asn Tyr Lys 
                      20                  25                  30          
          Asn Pro Lys Leu Thr Arg Met Leu Thr Phe Lys Phe Tyr Met Pro Lys 
                  35                  40                  45              
          Lys Ala Thr Glu Leu Lys His Leu Gln Cys Leu Glu Arg Glu Leu Lys 
              50                  55                  60                  
          Arg Leu Glu Glu Val Leu Asn Leu Ala Gln Ser Lys Asn Phe His Leu 
          65                  70                  75                  80  
          Arg Pro Arg Ser Leu Ile Ser Asn Ile Asn Val Ile Val Leu Glu Leu 
                          85                  90                  95      
          Lys Gly Ser Glu Thr Thr Phe Met Cys Glu Tyr Ala Asp Glu Thr Ala 
                      100                 105                 110         
          Thr Ile Val Glu Phe Leu Asn Arg Trp Ile Thr Phe Ser Gln Ser Ile 
                  115                 120                 125             
          Ile Ser Thr Leu Thr 
              130             
          <![CDATA[<210>  138]]>
          <![CDATA[<211>  133]]>
          <![CDATA[<212>  PRT]]>
          <![CDATA[<213>  人工序列]]>
          <![CDATA[<220>]]>
          <![CDATA[<223>  合成：IL-2-T3A-H16A-L19N-E61R-P65R-D84S-R120A-C125S]]>
          <![CDATA[<400>  138]]>
          Ala Pro Ala Ser Ser Ser Thr Lys Lys Thr Gln Leu Gln Leu Glu Ala 
          1               5                   10                  15      
          Leu Leu Asn Asp Leu Gln Met Ile Leu Asn Gly Ile Asn Asn Tyr Lys 
                      20                  25                  30          
          Asn Pro Lys Leu Thr Arg Met Leu Thr Phe Lys Phe Tyr Met Pro Lys 
                  35                  40                  45              
          Lys Ala Thr Glu Leu Lys His Leu Gln Cys Leu Glu Arg Glu Leu Lys 
              50                  55                  60                  
          Arg Leu Glu Glu Val Leu Asn Leu Ala Gln Ser Lys Asn Phe His Leu 
          65                  70                  75                  80  
          Arg Pro Arg Ser Leu Ile Ser Asn Ile Asn Val Ile Val Leu Glu Leu 
                          85                  90                  95      
          Lys Gly Ser Glu Thr Thr Phe Met Cys Glu Tyr Ala Asp Glu Thr Ala 
                      100                 105                 110         
          Thr Ile Val Glu Phe Leu Asn Ala Trp Ile Thr Phe Ser Gln Ser Ile 
                  115                 120                 125             
          Ile Ser Thr Leu Thr 
              130             
          <![CDATA[<210>  139]]>
          <![CDATA[<211>  133]]>
          <![CDATA[<212>  PRT]]>
          <![CDATA[<213>  人工序列]]>
          <![CDATA[<220>]]>
          <![CDATA[<223>  合成：IL-2-T3A-H16A-L19N-E61R-P65R-D84S-C125S-Q126A]]>
          <![CDATA[<400>  139]]>
          Ala Pro Ala Ser Ser Ser Thr Lys Lys Thr Gln Leu Gln Leu Glu Ala 
          1               5                   10                  15      
          Leu Leu Asn Asp Leu Gln Met Ile Leu Asn Gly Ile Asn Asn Tyr Lys 
                      20                  25                  30          
          Asn Pro Lys Leu Thr Arg Met Leu Thr Phe Lys Phe Tyr Met Pro Lys 
                  35                  40                  45              
          Lys Ala Thr Glu Leu Lys His Leu Gln Cys Leu Glu Arg Glu Leu Lys 
              50                  55                  60                  
          Arg Leu Glu Glu Val Leu Asn Leu Ala Gln Ser Lys Asn Phe His Leu 
          65                  70                  75                  80  
          Arg Pro Arg Ser Leu Ile Ser Asn Ile Asn Val Ile Val Leu Glu Leu 
                          85                  90                  95      
          Lys Gly Ser Glu Thr Thr Phe Met Cys Glu Tyr Ala Asp Glu Thr Ala 
                      100                 105                 110         
          Thr Ile Val Glu Phe Leu Asn Arg Trp Ile Thr Phe Ser Ala Ser Ile 
                  115                 120                 125             
          Ile Ser Thr Leu Thr 
              130             
          <![CDATA[<210>  140]]>
          <![CDATA[<211>  133]]>
          <![CDATA[<212>  PRT]]>
          <![CDATA[<213>  人工序列]]>
          <![CDATA[<220>]]>
          <![CDATA[<223>  合成：IL-2-T3A-H16S-L19N-E61R-P65R-D84S-C125S]]>
          <![CDATA[<400>  140]]>
          Ala Pro Ala Ser Ser Ser Thr Lys Lys Thr Gln Leu Gln Leu Glu Ser 
          1               5                   10                  15      
          Leu Leu Asn Asp Leu Gln Met Ile Leu Asn Gly Ile Asn Asn Tyr Lys 
                      20                  25                  30          
          Asn Pro Lys Leu Thr Arg Met Leu Thr Phe Lys Phe Tyr Met Pro Lys 
                  35                  40                  45              
          Lys Ala Thr Glu Leu Lys His Leu Gln Cys Leu Glu Arg Glu Leu Lys 
              50                  55                  60                  
          Arg Leu Glu Glu Val Leu Asn Leu Ala Gln Ser Lys Asn Phe His Leu 
          65                  70                  75                  80  
          Arg Pro Arg Ser Leu Ile Ser Asn Ile Asn Val Ile Val Leu Glu Leu 
                          85                  90                  95      
          Lys Gly Ser Glu Thr Thr Phe Met Cys Glu Tyr Ala Asp Glu Thr Ala 
                      100                 105                 110         
          Thr Ile Val Glu Phe Leu Asn Arg Trp Ile Thr Phe Ser Gln Ser Ile 
                  115                 120                 125             
          Ile Ser Thr Leu Thr 
              130             
          <![CDATA[<210>  141]]>
          <![CDATA[<211>  133]]>
          <![CDATA[<212>  PRT]]>
          <![CDATA[<213>  人工序列]]>
          <![CDATA[<220>]]>
          <![CDATA[<223>  合成：IL-2-T3A-H16T-L19N-E61R-P65R-D84S-C125S]]>
          <![CDATA[<400>  141]]>
          Ala Pro Ala Ser Ser Ser Thr Lys Lys Thr Gln Leu Gln Leu Glu Thr 
          1               5                   10                  15      
          Leu Leu Asn Asp Leu Gln Met Ile Leu Asn Gly Ile Asn Asn Tyr Lys 
                      20                  25                  30          
          Asn Pro Lys Leu Thr Arg Met Leu Thr Phe Lys Phe Tyr Met Pro Lys 
                  35                  40                  45              
          Lys Ala Thr Glu Leu Lys His Leu Gln Cys Leu Glu Arg Glu Leu Lys 
              50                  55                  60                  
          Arg Leu Glu Glu Val Leu Asn Leu Ala Gln Ser Lys Asn Phe His Leu 
          65                  70                  75                  80  
          Arg Pro Arg Ser Leu Ile Ser Asn Ile Asn Val Ile Val Leu Glu Leu 
                          85                  90                  95      
          Lys Gly Ser Glu Thr Thr Phe Met Cys Glu Tyr Ala Asp Glu Thr Ala 
                      100                 105                 110         
          Thr Ile Val Glu Phe Leu Asn Arg Trp Ile Thr Phe Ser Gln Ser Ile 
                  115                 120                 125             
          Ile Ser Thr Leu Thr 
              130             
          <![CDATA[<210>  142]]>
          <![CDATA[<211>  133]]>
          <![CDATA[<212>  PRT]]>
          <![CDATA[<213>  人工序列]]>
          <![CDATA[<220>]]>
          <![CDATA[<223>  合成：IL-2-T3A-H16V-L19N-E61R-P65R-D84S-C125S]]>
          <![CDATA[<400>  142]]>
          Ala Pro Ala Ser Ser Ser Thr Lys Lys Thr Gln Leu Gln Leu Glu Val 
          1               5                   10                  15      
          Leu Leu Asn Asp Leu Gln Met Ile Leu Asn Gly Ile Asn Asn Tyr Lys 
                      20                  25                  30          
          Asn Pro Lys Leu Thr Arg Met Leu Thr Phe Lys Phe Tyr Met Pro Lys 
                  35                  40                  45              
          Lys Ala Thr Glu Leu Lys His Leu Gln Cys Leu Glu Arg Glu Leu Lys 
              50                  55                  60                  
          Arg Leu Glu Glu Val Leu Asn Leu Ala Gln Ser Lys Asn Phe His Leu 
          65                  70                  75                  80  
          Arg Pro Arg Ser Leu Ile Ser Asn Ile Asn Val Ile Val Leu Glu Leu 
                          85                  90                  95      
          Lys Gly Ser Glu Thr Thr Phe Met Cys Glu Tyr Ala Asp Glu Thr Ala 
                      100                 105                 110         
          Thr Ile Val Glu Phe Leu Asn Arg Trp Ile Thr Phe Ser Gln Ser Ile 
                  115                 120                 125             
          Ile Ser Thr Leu Thr 
              130             
          <![CDATA[<210>  143]]>
          <![CDATA[<211>  133]]>
          <![CDATA[<212>  PRT]]>
          <![CDATA[<213>  人工序列]]>
          <![CDATA[<220>]]>
          <![CDATA[<223>  合成：IL-2-T3A-H16N-L19N-E61R-P65R-D84S-C125S]]>
          <![CDATA[<400>  143]]>
          Ala Pro Ala Ser Ser Ser Thr Lys Lys Thr Gln Leu Gln Leu Glu Asn 
          1               5                   10                  15      
          Leu Leu Asn Asp Leu Gln Met Ile Leu Asn Gly Ile Asn Asn Tyr Lys 
                      20                  25                  30          
          Asn Pro Lys Leu Thr Arg Met Leu Thr Phe Lys Phe Tyr Met Pro Lys 
                  35                  40                  45              
          Lys Ala Thr Glu Leu Lys His Leu Gln Cys Leu Glu Arg Glu Leu Lys 
              50                  55                  60                  
          Arg Leu Glu Glu Val Leu Asn Leu Ala Gln Ser Lys Asn Phe His Leu 
          65                  70                  75                  80  
          Arg Pro Arg Ser Leu Ile Ser Asn Ile Asn Val Ile Val Leu Glu Leu 
                          85                  90                  95      
          Lys Gly Ser Glu Thr Thr Phe Met Cys Glu Tyr Ala Asp Glu Thr Ala 
                      100                 105                 110         
          Thr Ile Val Glu Phe Leu Asn Arg Trp Ile Thr Phe Ser Gln Ser Ile 
                  115                 120                 125             
          Ile Ser Thr Leu Thr 
              130             
          <![CDATA[<210>  144]]>
          <![CDATA[<211>  133]]>
          <![CDATA[<212>  PRT]]>
          <![CDATA[<213>  人工序列]]>
          <![CDATA[<220>]]>
          <![CDATA[<223>  合成：IL-2-T3A-H16A-L19N-E61R-P65R-D84T-C125S]]>
          <![CDATA[<400>  144]]>
          Ala Pro Ala Ser Ser Ser Thr Lys Lys Thr Gln Leu Gln Leu Glu Ala 
          1               5                   10                  15      
          Leu Leu Asn Asp Leu Gln Met Ile Leu Asn Gly Ile Asn Asn Tyr Lys 
                      20                  25                  30          
          Asn Pro Lys Leu Thr Arg Met Leu Thr Phe Lys Phe Tyr Met Pro Lys 
                  35                  40                  45              
          Lys Ala Thr Glu Leu Lys His Leu Gln Cys Leu Glu Arg Glu Leu Lys 
              50                  55                  60                  
          Arg Leu Glu Glu Val Leu Asn Leu Ala Gln Ser Lys Asn Phe His Leu 
          65                  70                  75                  80  
          Arg Pro Arg Thr Leu Ile Ser Asn Ile Asn Val Ile Val Leu Glu Leu 
                          85                  90                  95      
          Lys Gly Ser Glu Thr Thr Phe Met Cys Glu Tyr Ala Asp Glu Thr Ala 
                      100                 105                 110         
          Thr Ile Val Glu Phe Leu Asn Arg Trp Ile Thr Phe Ser Gln Ser Ile 
                  115                 120                 125             
          Ile Ser Thr Leu Thr 
              130             
          <![CDATA[<210>  145]]>
          <![CDATA[<211>  133]]>
          <![CDATA[<212>  PRT]]>
          <![CDATA[<213>  人工序列]]>
          <![CDATA[<220>]]>
          <![CDATA[<223>  合成：IL-2-T3A-H16A-L19N-E61R-P65R-D84V-C125S]]>
          <![CDATA[<400>  145]]>
          Ala Pro Ala Ser Ser Ser Thr Lys Lys Thr Gln Leu Gln Leu Glu Ala 
          1               5                   10                  15      
          Leu Leu Asn Asp Leu Gln Met Ile Leu Asn Gly Ile Asn Asn Tyr Lys 
                      20                  25                  30          
          Asn Pro Lys Leu Thr Arg Met Leu Thr Phe Lys Phe Tyr Met Pro Lys 
                  35                  40                  45              
          Lys Ala Thr Glu Leu Lys His Leu Gln Cys Leu Glu Arg Glu Leu Lys 
              50                  55                  60                  
          Arg Leu Glu Glu Val Leu Asn Leu Ala Gln Ser Lys Asn Phe His Leu 
          65                  70                  75                  80  
          Arg Pro Arg Val Leu Ile Ser Asn Ile Asn Val Ile Val Leu Glu Leu 
                          85                  90                  95      
          Lys Gly Ser Glu Thr Thr Phe Met Cys Glu Tyr Ala Asp Glu Thr Ala 
                      100                 105                 110         
          Thr Ile Val Glu Phe Leu Asn Arg Trp Ile Thr Phe Ser Gln Ser Ile 
                  115                 120                 125             
          Ile Ser Thr Leu Thr 
              130             
          <![CDATA[<210>  146]]>
          <![CDATA[<211>  133]]>
          <![CDATA[<212>  PRT]]>
          <![CDATA[<213>  人工序列]]>
          <![CDATA[<220>]]>
          <![CDATA[<223>  合成：IL-2-T3A-H16A-D20S-E61R-P65R-D84S-C125S]]>
          <![CDATA[<400>  146]]>
          Ala Pro Ala Ser Ser Ser Thr Lys Lys Thr Gln Leu Gln Leu Glu Ala 
          1               5                   10                  15      
          Leu Leu Leu Ser Leu Gln Met Ile Leu Asn Gly Ile Asn Asn Tyr Lys 
                      20                  25                  30          
          Asn Pro Lys Leu Thr Arg Met Leu Thr Phe Lys Phe Tyr Met Pro Lys 
                  35                  40                  45              
          Lys Ala Thr Glu Leu Lys His Leu Gln Cys Leu Glu Arg Glu Leu Lys 
              50                  55                  60                  
          Arg Leu Glu Glu Val Leu Asn Leu Ala Gln Ser Lys Asn Phe His Leu 
          65                  70                  75                  80  
          Arg Pro Arg Ser Leu Ile Ser Asn Ile Asn Val Ile Val Leu Glu Leu 
                          85                  90                  95      
          Lys Gly Ser Glu Thr Thr Phe Met Cys Glu Tyr Ala Asp Glu Thr Ala 
                      100                 105                 110         
          Thr Ile Val Glu Phe Leu Asn Arg Trp Ile Thr Phe Ser Gln Ser Ile 
                  115                 120                 125             
          Ile Ser Thr Leu Thr 
              130             
          <![CDATA[<210>  147]]>
          <![CDATA[<211>  133]]>
          <![CDATA[<212>  PRT]]>
          <![CDATA[<213>  人工序列]]>
          <![CDATA[<220>]]>
          <![CDATA[<223>  合成：IL-2-T3A-H16A-D20T-E61R-P65R-D84S-C125S]]>
          <![CDATA[<400>  147]]>
          Ala Pro Ala Ser Ser Ser Thr Lys Lys Thr Gln Leu Gln Leu Glu Ala 
          1               5                   10                  15      
          Leu Leu Leu Thr Leu Gln Met Ile Leu Asn Gly Ile Asn Asn Tyr Lys 
                      20                  25                  30          
          Asn Pro Lys Leu Thr Arg Met Leu Thr Phe Lys Phe Tyr Met Pro Lys 
                  35                  40                  45              
          Lys Ala Thr Glu Leu Lys His Leu Gln Cys Leu Glu Arg Glu Leu Lys 
              50                  55                  60                  
          Arg Leu Glu Glu Val Leu Asn Leu Ala Gln Ser Lys Asn Phe His Leu 
          65                  70                  75                  80  
          Arg Pro Arg Ser Leu Ile Ser Asn Ile Asn Val Ile Val Leu Glu Leu 
                          85                  90                  95      
          Lys Gly Ser Glu Thr Thr Phe Met Cys Glu Tyr Ala Asp Glu Thr Ala 
                      100                 105                 110         
          Thr Ile Val Glu Phe Leu Asn Arg Trp Ile Thr Phe Ser Gln Ser Ile 
                  115                 120                 125             
          Ile Ser Thr Leu Thr 
              130             
          <![CDATA[<210>  148]]>
          <![CDATA[<211>  133]]>
          <![CDATA[<212>  PRT]]>
          <![CDATA[<213>  人工序列]]>
          <![CDATA[<220>]]>
          <![CDATA[<223>  合成：IL-2-T3A-H16A-D20N-E61R-P65R-D84S-C125S]]>
          <![CDATA[<400>  148]]>
          Ala Pro Ala Ser Ser Ser Thr Lys Lys Thr Gln Leu Gln Leu Glu Ala 
          1               5                   10                  15      
          Leu Leu Leu Asn Leu Gln Met Ile Leu Asn Gly Ile Asn Asn Tyr Lys 
                      20                  25                  30          
          Asn Pro Lys Leu Thr Arg Met Leu Thr Phe Lys Phe Tyr Met Pro Lys 
                  35                  40                  45              
          Lys Ala Thr Glu Leu Lys His Leu Gln Cys Leu Glu Arg Glu Leu Lys 
              50                  55                  60                  
          Arg Leu Glu Glu Val Leu Asn Leu Ala Gln Ser Lys Asn Phe His Leu 
          65                  70                  75                  80  
          Arg Pro Arg Ser Leu Ile Ser Asn Ile Asn Val Ile Val Leu Glu Leu 
                          85                  90                  95      
          Lys Gly Ser Glu Thr Thr Phe Met Cys Glu Tyr Ala Asp Glu Thr Ala 
                      100                 105                 110         
          Thr Ile Val Glu Phe Leu Asn Arg Trp Ile Thr Phe Ser Gln Ser Ile 
                  115                 120                 125             
          Ile Ser Thr Leu Thr 
              130             
          <![CDATA[<210>  149]]>
          <![CDATA[<211>  133]]>
          <![CDATA[<212>  PRT]]>
          <![CDATA[<213>  人工序列]]>
          <![CDATA[<220>]]>
          <![CDATA[<223>  合成：IL-2-T3A-H16A-D20A-E61R-P65R-D84S-C125S]]>
          <![CDATA[<400>  149]]>
          Ala Pro Ala Ser Ser Ser Thr Lys Lys Thr Gln Leu Gln Leu Glu Ala 
          1               5                   10                  15      
          Leu Leu Leu Ala Leu Gln Met Ile Leu Asn Gly Ile Asn Asn Tyr Lys 
                      20                  25                  30          
          Asn Pro Lys Leu Thr Arg Met Leu Thr Phe Lys Phe Tyr Met Pro Lys 
                  35                  40                  45              
          Lys Ala Thr Glu Leu Lys His Leu Gln Cys Leu Glu Arg Glu Leu Lys 
              50                  55                  60                  
          Arg Leu Glu Glu Val Leu Asn Leu Ala Gln Ser Lys Asn Phe His Leu 
          65                  70                  75                  80  
          Arg Pro Arg Ser Leu Ile Ser Asn Ile Asn Val Ile Val Leu Glu Leu 
                          85                  90                  95      
          Lys Gly Ser Glu Thr Thr Phe Met Cys Glu Tyr Ala Asp Glu Thr Ala 
                      100                 105                 110         
          Thr Ile Val Glu Phe Leu Asn Arg Trp Ile Thr Phe Ser Gln Ser Ile 
                  115                 120                 125             
          Ile Ser Thr Leu Thr 
              130             
          <![CDATA[<210>  150]]>
          <![CDATA[<211>  133]]>
          <![CDATA[<212>  PRT]]>
          <![CDATA[<213>  人工序列]]>
          <![CDATA[<220>]]>
          <![CDATA[<223>  合成：IL-2-T3A-H16A-L19N-E61R-P65R-D84N-C125S]]>
          <![CDATA[<400>  150]]>
          Ala Pro Ala Ser Ser Ser Thr Lys Lys Thr Gln Leu Gln Leu Glu Ala 
          1               5                   10                  15      
          Leu Leu Asn Asp Leu Gln Met Ile Leu Asn Gly Ile Asn Asn Tyr Lys 
                      20                  25                  30          
          Asn Pro Lys Leu Thr Arg Met Leu Thr Phe Lys Phe Tyr Met Pro Lys 
                  35                  40                  45              
          Lys Ala Thr Glu Leu Lys His Leu Gln Cys Leu Glu Arg Glu Leu Lys 
              50                  55                  60                  
          Arg Leu Glu Glu Val Leu Asn Leu Ala Gln Ser Lys Asn Phe His Leu 
          65                  70                  75                  80  
          Arg Pro Arg Asn Leu Ile Ser Asn Ile Asn Val Ile Val Leu Glu Leu 
                          85                  90                  95      
          Lys Gly Ser Glu Thr Thr Phe Met Cys Glu Tyr Ala Asp Glu Thr Ala 
                      100                 105                 110         
          Thr Ile Val Glu Phe Leu Asn Arg Trp Ile Thr Phe Ser Gln Ser Ile 
                  115                 120                 125             
          Ile Ser Thr Leu Thr 
              130             
          <![CDATA[<210>  151]]>
          <![CDATA[<211>  133]]>
          <![CDATA[<212>  PRT]]>
          <![CDATA[<213>  人工序列]]>
          <![CDATA[<220>]]>
          <![CDATA[<223>  合成：IL-2-T3A-H16A-E61R-P65R-D84S-N88T-C125S]]>
          <![CDATA[<400>  151]]>
          Ala Pro Ala Ser Ser Ser Thr Lys Lys Thr Gln Leu Gln Leu Glu Ala 
          1               5                   10                  15      
          Leu Leu Leu Asp Leu Gln Met Ile Leu Asn Gly Ile Asn Asn Tyr Lys 
                      20                  25                  30          
          Asn Pro Lys Leu Thr Arg Met Leu Thr Phe Lys Phe Tyr Met Pro Lys 
                  35                  40                  45              
          Lys Ala Thr Glu Leu Lys His Leu Gln Cys Leu Glu Arg Glu Leu Lys 
              50                  55                  60                  
          Arg Leu Glu Glu Val Leu Asn Leu Ala Gln Ser Lys Asn Phe His Leu 
          65                  70                  75                  80  
          Arg Pro Arg Ser Leu Ile Ser Thr Ile Asn Val Ile Val Leu Glu Leu 
                          85                  90                  95      
          Lys Gly Ser Glu Thr Thr Phe Met Cys Glu Tyr Ala Asp Glu Thr Ala 
                      100                 105                 110         
          Thr Ile Val Glu Phe Leu Asn Arg Trp Ile Thr Phe Ser Gln Ser Ile 
                  115                 120                 125             
          Ile Ser Thr Leu Thr 
              130             
          <![CDATA[<210>  152]]>
          <![CDATA[<211>  133]]>
          <![CDATA[<212>  PRT]]>
          <![CDATA[<213>  人工序列]]>
          <![CDATA[<220>]]>
          <![CDATA[<223>  合成：IL-2-T3A-H16A-E61R-P65R-D84S-N88A-C125S]]>
          <![CDATA[<400>  152]]>
          Ala Pro Ala Ser Ser Ser Thr Lys Lys Thr Gln Leu Gln Leu Glu Ala 
          1               5                   10                  15      
          Leu Leu Leu Asp Leu Gln Met Ile Leu Asn Gly Ile Asn Asn Tyr Lys 
                      20                  25                  30          
          Asn Pro Lys Leu Thr Arg Met Leu Thr Phe Lys Phe Tyr Met Pro Lys 
                  35                  40                  45              
          Lys Ala Thr Glu Leu Lys His Leu Gln Cys Leu Glu Arg Glu Leu Lys 
              50                  55                  60                  
          Arg Leu Glu Glu Val Leu Asn Leu Ala Gln Ser Lys Asn Phe His Leu 
          65                  70                  75                  80  
          Arg Pro Arg Ser Leu Ile Ser Ala Ile Asn Val Ile Val Leu Glu Leu 
                          85                  90                  95      
          Lys Gly Ser Glu Thr Thr Phe Met Cys Glu Tyr Ala Asp Glu Thr Ala 
                      100                 105                 110         
          Thr Ile Val Glu Phe Leu Asn Arg Trp Ile Thr Phe Ser Gln Ser Ile 
                  115                 120                 125             
          Ile Ser Thr Leu Thr 
              130             
          <![CDATA[<210>  153]]>
          <![CDATA[<211>  133]]>
          <![CDATA[<212>  PRT]]>
          <![CDATA[<213>  人工序列]]>
          <![CDATA[<220>]]>
          <![CDATA[<223>  合成：IL-2-T3A-H16P-L19A-E61R-P65R-D84S-C125S]]>
          <![CDATA[<400>  153]]>
          Ala Pro Ala Ser Ser Ser Thr Lys Lys Thr Gln Leu Gln Leu Glu Pro 
          1               5                   10                  15      
          Leu Leu Ala Asp Leu Gln Met Ile Leu Asn Gly Ile Asn Asn Tyr Lys 
                      20                  25                  30          
          Asn Pro Lys Leu Thr Arg Met Leu Thr Phe Lys Phe Tyr Met Pro Lys 
                  35                  40                  45              
          Lys Ala Thr Glu Leu Lys His Leu Gln Cys Leu Glu Arg Glu Leu Lys 
              50                  55                  60                  
          Arg Leu Glu Glu Val Leu Asn Leu Ala Gln Ser Lys Asn Phe His Leu 
          65                  70                  75                  80  
          Arg Pro Arg Ser Leu Ile Ser Asn Ile Asn Val Ile Val Leu Glu Leu 
                          85                  90                  95      
          Lys Gly Ser Glu Thr Thr Phe Met Cys Glu Tyr Ala Asp Glu Thr Ala 
                      100                 105                 110         
          Thr Ile Val Glu Phe Leu Asn Arg Trp Ile Thr Phe Ser Gln Ser Ile 
                  115                 120                 125             
          Ile Ser Thr Leu Thr 
              130             
          <![CDATA[<210>  154]]>
          <![CDATA[<211>  133]]>
          <![CDATA[<212>  PRT]]>
          <![CDATA[<213>  人工序列]]>
          <![CDATA[<220>]]>
          <![CDATA[<223>  合成：IL-2-T3A-H16A-L19H-E61R-P65R-D84S-C125S]]>
          <![CDATA[<400>  154]]>
          Ala Pro Ala Ser Ser Ser Thr Lys Lys Thr Gln Leu Gln Leu Glu Ala 
          1               5                   10                  15      
          Leu Leu His Asp Leu Gln Met Ile Leu Asn Gly Ile Asn Asn Tyr Lys 
                      20                  25                  30          
          Asn Pro Lys Leu Thr Arg Met Leu Thr Phe Lys Phe Tyr Met Pro Lys 
                  35                  40                  45              
          Lys Ala Thr Glu Leu Lys His Leu Gln Cys Leu Glu Arg Glu Leu Lys 
              50                  55                  60                  
          Arg Leu Glu Glu Val Leu Asn Leu Ala Gln Ser Lys Asn Phe His Leu 
          65                  70                  75                  80  
          Arg Pro Arg Ser Leu Ile Ser Asn Ile Asn Val Ile Val Leu Glu Leu 
                          85                  90                  95      
          Lys Gly Ser Glu Thr Thr Phe Met Cys Glu Tyr Ala Asp Glu Thr Ala 
                      100                 105                 110         
          Thr Ile Val Glu Phe Leu Asn Arg Trp Ile Thr Phe Ser Gln Ser Ile 
                  115                 120                 125             
          Ile Ser Thr Leu Thr 
              130             
          <![CDATA[<210>  155]]>
          <![CDATA[<211>  133]]>
          <![CDATA[<212>  PRT]]>
          <![CDATA[<213>  人工序列]]>
          <![CDATA[<220>]]>
          <![CDATA[<223>  合成：IL-2-T3A-H16A-L19P-E61R-P65R-D84S-C125S]]>
          <![CDATA[<400>  155]]>
          Ala Pro Ala Ser Ser Ser Thr Lys Lys Thr Gln Leu Gln Leu Glu Ala 
          1               5                   10                  15      
          Leu Leu Pro Asp Leu Gln Met Ile Leu Asn Gly Ile Asn Asn Tyr Lys 
                      20                  25                  30          
          Asn Pro Lys Leu Thr Arg Met Leu Thr Phe Lys Phe Tyr Met Pro Lys 
                  35                  40                  45              
          Lys Ala Thr Glu Leu Lys His Leu Gln Cys Leu Glu Arg Glu Leu Lys 
              50                  55                  60                  
          Arg Leu Glu Glu Val Leu Asn Leu Ala Gln Ser Lys Asn Phe His Leu 
          65                  70                  75                  80  
          Arg Pro Arg Ser Leu Ile Ser Asn Ile Asn Val Ile Val Leu Glu Leu 
                          85                  90                  95      
          Lys Gly Ser Glu Thr Thr Phe Met Cys Glu Tyr Ala Asp Glu Thr Ala 
                      100                 105                 110         
          Thr Ile Val Glu Phe Leu Asn Arg Trp Ile Thr Phe Ser Gln Ser Ile 
                  115                 120                 125             
          Ile Ser Thr Leu Thr 
              130             
          <![CDATA[<210>  156]]>
          <![CDATA[<211>  133]]>
          <![CDATA[<212>  PRT]]>
          <![CDATA[<213>  人工序列]]>
          <![CDATA[<220>]]>
          <![CDATA[<223>  合成：IL-2-T3A-H16A-L19Q-E61R-P65R-D84S-C125S]]>
          <![CDATA[<400>  156]]>
          Ala Pro Ala Ser Ser Ser Thr Lys Lys Thr Gln Leu Gln Leu Glu Ala 
          1               5                   10                  15      
          Leu Leu Gln Asp Leu Gln Met Ile Leu Asn Gly Ile Asn Asn Tyr Lys 
                      20                  25                  30          
          Asn Pro Lys Leu Thr Arg Met Leu Thr Phe Lys Phe Tyr Met Pro Lys 
                  35                  40                  45              
          Lys Ala Thr Glu Leu Lys His Leu Gln Cys Leu Glu Arg Glu Leu Lys 
              50                  55                  60                  
          Arg Leu Glu Glu Val Leu Asn Leu Ala Gln Ser Lys Asn Phe His Leu 
          65                  70                  75                  80  
          Arg Pro Arg Ser Leu Ile Ser Asn Ile Asn Val Ile Val Leu Glu Leu 
                          85                  90                  95      
          Lys Gly Ser Glu Thr Thr Phe Met Cys Glu Tyr Ala Asp Glu Thr Ala 
                      100                 105                 110         
          Thr Ile Val Glu Phe Leu Asn Arg Trp Ile Thr Phe Ser Gln Ser Ile 
                  115                 120                 125             
          Ile Ser Thr Leu Thr 
              130             
          <![CDATA[<210>  157]]>
          <![CDATA[<211>  133]]>
          <![CDATA[<212>  PRT]]>
          <![CDATA[<213>  人工序列]]>
          <![CDATA[<220>]]>
          <![CDATA[<223>  合成：IL-2-T3A-H16A-L19Y-E61R-P65R-D84S-C125S]]>
          <![CDATA[<400>  157]]>
          Ala Pro Ala Ser Ser Ser Thr Lys Lys Thr Gln Leu Gln Leu Glu Ala 
          1               5                   10                  15      
          Leu Leu Tyr Asp Leu Gln Met Ile Leu Asn Gly Ile Asn Asn Tyr Lys 
                      20                  25                  30          
          Asn Pro Lys Leu Thr Arg Met Leu Thr Phe Lys Phe Tyr Met Pro Lys 
                  35                  40                  45              
          Lys Ala Thr Glu Leu Lys His Leu Gln Cys Leu Glu Arg Glu Leu Lys 
              50                  55                  60                  
          Arg Leu Glu Glu Val Leu Asn Leu Ala Gln Ser Lys Asn Phe His Leu 
          65                  70                  75                  80  
          Arg Pro Arg Ser Leu Ile Ser Asn Ile Asn Val Ile Val Leu Glu Leu 
                          85                  90                  95      
          Lys Gly Ser Glu Thr Thr Phe Met Cys Glu Tyr Ala Asp Glu Thr Ala 
                      100                 105                 110         
          Thr Ile Val Glu Phe Leu Asn Arg Trp Ile Thr Phe Ser Gln Ser Ile 
                  115                 120                 125             
          Ile Ser Thr Leu Thr 
              130             
          <![CDATA[<210>  158]]>
          <![CDATA[<211>  133]]>
          <![CDATA[<212>  PRT]]>
          <![CDATA[<213>  人工序列]]>
          <![CDATA[<220>]]>
          <![CDATA[<223>  合成：IL-2-T3A-H16A-L19A-E61R-P65R-D84P-C125S]]>
          <![CDATA[<400>  158]]>
          Ala Pro Ala Ser Ser Ser Thr Lys Lys Thr Gln Leu Gln Leu Glu Ala 
          1               5                   10                  15      
          Leu Leu Ala Asp Leu Gln Met Ile Leu Asn Gly Ile Asn Asn Tyr Lys 
                      20                  25                  30          
          Asn Pro Lys Leu Thr Arg Met Leu Thr Phe Lys Phe Tyr Met Pro Lys 
                  35                  40                  45              
          Lys Ala Thr Glu Leu Lys His Leu Gln Cys Leu Glu Arg Glu Leu Lys 
              50                  55                  60                  
          Arg Leu Glu Glu Val Leu Asn Leu Ala Gln Ser Lys Asn Phe His Leu 
          65                  70                  75                  80  
          Arg Pro Arg Pro Leu Ile Ser Asn Ile Asn Val Ile Val Leu Glu Leu 
                          85                  90                  95      
          Lys Gly Ser Glu Thr Thr Phe Met Cys Glu Tyr Ala Asp Glu Thr Ala 
                      100                 105                 110         
          Thr Ile Val Glu Phe Leu Asn Arg Trp Ile Thr Phe Ser Gln Ser Ile 
                  115                 120                 125             
          Ile Ser Thr Leu Thr 
              130             
          <![CDATA[<210>  159]]>
          <![CDATA[<211>  133]]>
          <![CDATA[<212>  PRT]]>
          <![CDATA[<213>  人工序列]]>
          <![CDATA[<220>]]>
          <![CDATA[<223>  合成：IL-2-T3A-H16A-L19A-E61R-P65R-D84V-C125S]]>
          <![CDATA[<400>  159]]>
          Ala Pro Ala Ser Ser Ser Thr Lys Lys Thr Gln Leu Gln Leu Glu Ala 
          1               5                   10                  15      
          Leu Leu Ala Asp Leu Gln Met Ile Leu Asn Gly Ile Asn Asn Tyr Lys 
                      20                  25                  30          
          Asn Pro Lys Leu Thr Arg Met Leu Thr Phe Lys Phe Tyr Met Pro Lys 
                  35                  40                  45              
          Lys Ala Thr Glu Leu Lys His Leu Gln Cys Leu Glu Arg Glu Leu Lys 
              50                  55                  60                  
          Arg Leu Glu Glu Val Leu Asn Leu Ala Gln Ser Lys Asn Phe His Leu 
          65                  70                  75                  80  
          Arg Pro Arg Val Leu Ile Ser Asn Ile Asn Val Ile Val Leu Glu Leu 
                          85                  90                  95      
          Lys Gly Ser Glu Thr Thr Phe Met Cys Glu Tyr Ala Asp Glu Thr Ala 
                      100                 105                 110         
          Thr Ile Val Glu Phe Leu Asn Arg Trp Ile Thr Phe Ser Gln Ser Ile 
                  115                 120                 125             
          Ile Ser Thr Leu Thr 
              130             
          <![CDATA[<210>  160]]>
          <![CDATA[<211>  133]]>
          <![CDATA[<212>  PRT]]>
          <![CDATA[<213>  人工序列]]>
          <![CDATA[<220>]]>
          <![CDATA[<223>  合成：IL-2-T3A-H16A-L19A-E61R-P65R-D84Y-C125S]]>
          <![CDATA[<400>  160]]>
          Ala Pro Ala Ser Ser Ser Thr Lys Lys Thr Gln Leu Gln Leu Glu Ala 
          1               5                   10                  15      
          Leu Leu Ala Asp Leu Gln Met Ile Leu Asn Gly Ile Asn Asn Tyr Lys 
                      20                  25                  30          
          Asn Pro Lys Leu Thr Arg Met Leu Thr Phe Lys Phe Tyr Met Pro Lys 
                  35                  40                  45              
          Lys Ala Thr Glu Leu Lys His Leu Gln Cys Leu Glu Arg Glu Leu Lys 
              50                  55                  60                  
          Arg Leu Glu Glu Val Leu Asn Leu Ala Gln Ser Lys Asn Phe His Leu 
          65                  70                  75                  80  
          Arg Pro Arg Tyr Leu Ile Ser Asn Ile Asn Val Ile Val Leu Glu Leu 
                          85                  90                  95      
          Lys Gly Ser Glu Thr Thr Phe Met Cys Glu Tyr Ala Asp Glu Thr Ala 
                      100                 105                 110         
          Thr Ile Val Glu Phe Leu Asn Arg Trp Ile Thr Phe Ser Gln Ser Ile 
                  115                 120                 125             
          Ile Ser Thr Leu Thr 
              130             
          <![CDATA[<210>  161]]>
          <![CDATA[<211>  133]]>
          <![CDATA[<212>  PRT]]>
          <![CDATA[<213>  人工序列]]>
          <![CDATA[<220>]]>
          <![CDATA[<223>  合成：IL-2-T3A-H16A-M23A-E61R-P65R-D84S-E95H-C125S]]>
          <![CDATA[<400>  161]]>
          Ala Pro Ala Ser Ser Ser Thr Lys Lys Thr Gln Leu Gln Leu Glu Ala 
          1               5                   10                  15      
          Leu Leu Leu Asp Leu Gln Ala Ile Leu Asn Gly Ile Asn Asn Tyr Lys 
                      20                  25                  30          
          Asn Pro Lys Leu Thr Arg Met Leu Thr Phe Lys Phe Tyr Met Pro Lys 
                  35                  40                  45              
          Lys Ala Thr Glu Leu Lys His Leu Gln Cys Leu Glu Arg Glu Leu Lys 
              50                  55                  60                  
          Arg Leu Glu Glu Val Leu Asn Leu Ala Gln Ser Lys Asn Phe His Leu 
          65                  70                  75                  80  
          Arg Pro Arg Ser Leu Ile Ser Asn Ile Asn Val Ile Val Leu His Leu 
                          85                  90                  95      
          Lys Gly Ser Glu Thr Thr Phe Met Cys Glu Tyr Ala Asp Glu Thr Ala 
                      100                 105                 110         
          Thr Ile Val Glu Phe Leu Asn Arg Trp Ile Thr Phe Ser Gln Ser Ile 
                  115                 120                 125             
          Ile Ser Thr Leu Thr 
              130             
          <![CDATA[<210>  162]]>
          <![CDATA[<211>  133]]>
          <![CDATA[<212>  PRT]]>
          <![CDATA[<213>  人工序列]]>
          <![CDATA[<220>]]>
          <![CDATA[<223>  合成：IL-2-T3A-H16A-M23A-E61R-P65R-D84S-E95N-C125S]]>
          <![CDATA[<400>  162]]>
          Ala Pro Ala Ser Ser Ser Thr Lys Lys Thr Gln Leu Gln Leu Glu Ala 
          1               5                   10                  15      
          Leu Leu Leu Asp Leu Gln Ala Ile Leu Asn Gly Ile Asn Asn Tyr Lys 
                      20                  25                  30          
          Asn Pro Lys Leu Thr Arg Met Leu Thr Phe Lys Phe Tyr Met Pro Lys 
                  35                  40                  45              
          Lys Ala Thr Glu Leu Lys His Leu Gln Cys Leu Glu Arg Glu Leu Lys 
              50                  55                  60                  
          Arg Leu Glu Glu Val Leu Asn Leu Ala Gln Ser Lys Asn Phe His Leu 
          65                  70                  75                  80  
          Arg Pro Arg Ser Leu Ile Ser Asn Ile Asn Val Ile Val Leu Asn Leu 
                          85                  90                  95      
          Lys Gly Ser Glu Thr Thr Phe Met Cys Glu Tyr Ala Asp Glu Thr Ala 
                      100                 105                 110         
          Thr Ile Val Glu Phe Leu Asn Arg Trp Ile Thr Phe Ser Gln Ser Ile 
                  115                 120                 125             
          Ile Ser Thr Leu Thr 
              130             
          <![CDATA[<210>  163]]>
          <![CDATA[<211>  133]]>
          <![CDATA[<212>  PRT]]>
          <![CDATA[<213>  人工序列]]>
          <![CDATA[<220>]]>
          <![CDATA[<223>  合成：IL-2-T3A-H16A-M23A-E61R-P65R-D84S-E95P-C125S]]>
          <![CDATA[<400>  163]]>
          Ala Pro Ala Ser Ser Ser Thr Lys Lys Thr Gln Leu Gln Leu Glu Ala 
          1               5                   10                  15      
          Leu Leu Leu Asp Leu Gln Ala Ile Leu Asn Gly Ile Asn Asn Tyr Lys 
                      20                  25                  30          
          Asn Pro Lys Leu Thr Arg Met Leu Thr Phe Lys Phe Tyr Met Pro Lys 
                  35                  40                  45              
          Lys Ala Thr Glu Leu Lys His Leu Gln Cys Leu Glu Arg Glu Leu Lys 
              50                  55                  60                  
          Arg Leu Glu Glu Val Leu Asn Leu Ala Gln Ser Lys Asn Phe His Leu 
          65                  70                  75                  80  
          Arg Pro Arg Ser Leu Ile Ser Asn Ile Asn Val Ile Val Leu Pro Leu 
                          85                  90                  95      
          Lys Gly Ser Glu Thr Thr Phe Met Cys Glu Tyr Ala Asp Glu Thr Ala 
                      100                 105                 110         
          Thr Ile Val Glu Phe Leu Asn Arg Trp Ile Thr Phe Ser Gln Ser Ile 
                  115                 120                 125             
          Ile Ser Thr Leu Thr 
              130             
          <![CDATA[<210>  164]]>
          <![CDATA[<211>  133]]>
          <![CDATA[<212>  PRT]]>
          <![CDATA[<213>  人工序列]]>
          <![CDATA[<220>]]>
          <![CDATA[<223>  合成：IL-2-T3A-H16A-M23A-E61R-P65R-D84S-E95S-C125S]]>
          <![CDATA[<400>  164]]>
          Ala Pro Ala Ser Ser Ser Thr Lys Lys Thr Gln Leu Gln Leu Glu Ala 
          1               5                   10                  15      
          Leu Leu Leu Asp Leu Gln Ala Ile Leu Asn Gly Ile Asn Asn Tyr Lys 
                      20                  25                  30          
          Asn Pro Lys Leu Thr Arg Met Leu Thr Phe Lys Phe Tyr Met Pro Lys 
                  35                  40                  45              
          Lys Ala Thr Glu Leu Lys His Leu Gln Cys Leu Glu Arg Glu Leu Lys 
              50                  55                  60                  
          Arg Leu Glu Glu Val Leu Asn Leu Ala Gln Ser Lys Asn Phe His Leu 
          65                  70                  75                  80  
          Arg Pro Arg Ser Leu Ile Ser Asn Ile Asn Val Ile Val Leu Ser Leu 
                          85                  90                  95      
          Lys Gly Ser Glu Thr Thr Phe Met Cys Glu Tyr Ala Asp Glu Thr Ala 
                      100                 105                 110         
          Thr Ile Val Glu Phe Leu Asn Arg Trp Ile Thr Phe Ser Gln Ser Ile 
                  115                 120                 125             
          Ile Ser Thr Leu Thr 
              130             
          <![CDATA[<210>  165]]>
          <![CDATA[<211>  133]]>
          <![CDATA[<212>  PRT]]>
          <![CDATA[<213>  人工序列]]>
          <![CDATA[<220>]]>
          <![CDATA[<223>  合成：IL-2-T3A-H16A-M23A-E61R-P65R-D84S-E95T-C125S]]>
          <![CDATA[<400>  165]]>
          Ala Pro Ala Ser Ser Ser Thr Lys Lys Thr Gln Leu Gln Leu Glu Ala 
          1               5                   10                  15      
          Leu Leu Leu Asp Leu Gln Ala Ile Leu Asn Gly Ile Asn Asn Tyr Lys 
                      20                  25                  30          
          Asn Pro Lys Leu Thr Arg Met Leu Thr Phe Lys Phe Tyr Met Pro Lys 
                  35                  40                  45              
          Lys Ala Thr Glu Leu Lys His Leu Gln Cys Leu Glu Arg Glu Leu Lys 
              50                  55                  60                  
          Arg Leu Glu Glu Val Leu Asn Leu Ala Gln Ser Lys Asn Phe His Leu 
          65                  70                  75                  80  
          Arg Pro Arg Ser Leu Ile Ser Asn Ile Asn Val Ile Val Leu Thr Leu 
                          85                  90                  95      
          Lys Gly Ser Glu Thr Thr Phe Met Cys Glu Tyr Ala Asp Glu Thr Ala 
                      100                 105                 110         
          Thr Ile Val Glu Phe Leu Asn Arg Trp Ile Thr Phe Ser Gln Ser Ile 
                  115                 120                 125             
          Ile Ser Thr Leu Thr 
              130             
          <![CDATA[<210>  166]]>
          <![CDATA[<211>  133]]>
          <![CDATA[<212>  PRT]]>
          <![CDATA[<213>  人工序列]]>
          <![CDATA[<220>]]>
          <![CDATA[<223>  合成：IL-2-T3A-H16A-M23A-E61R-P65R-D84S-E95V-C125S]]>
          <![CDATA[<400>  166]]>
          Ala Pro Ala Ser Ser Ser Thr Lys Lys Thr Gln Leu Gln Leu Glu Ala 
          1               5                   10                  15      
          Leu Leu Leu Asp Leu Gln Ala Ile Leu Asn Gly Ile Asn Asn Tyr Lys 
                      20                  25                  30          
          Asn Pro Lys Leu Thr Arg Met Leu Thr Phe Lys Phe Tyr Met Pro Lys 
                  35                  40                  45              
          Lys Ala Thr Glu Leu Lys His Leu Gln Cys Leu Glu Arg Glu Leu Lys 
              50                  55                  60                  
          Arg Leu Glu Glu Val Leu Asn Leu Ala Gln Ser Lys Asn Phe His Leu 
          65                  70                  75                  80  
          Arg Pro Arg Ser Leu Ile Ser Asn Ile Asn Val Ile Val Leu Val Leu 
                          85                  90                  95      
          Lys Gly Ser Glu Thr Thr Phe Met Cys Glu Tyr Ala Asp Glu Thr Ala 
                      100                 105                 110         
          Thr Ile Val Glu Phe Leu Asn Arg Trp Ile Thr Phe Ser Gln Ser Ile 
                  115                 120                 125             
          Ile Ser Thr Leu Thr 
              130             
          <![CDATA[<210>  167]]>
          <![CDATA[<211>  133]]>
          <![CDATA[<212>  PRT]]>
          <![CDATA[<213>  人工序列]]>
          <![CDATA[<220>]]>
          <![CDATA[<223>  合成：IL-2-T3A-H16A-M23A-E61R-P65R-D84S-E95Y-C125S]]>
          <![CDATA[<400>  167]]>
          Ala Pro Ala Ser Ser Ser Thr Lys Lys Thr Gln Leu Gln Leu Glu Ala 
          1               5                   10                  15      
          Leu Leu Leu Asp Leu Gln Ala Ile Leu Asn Gly Ile Asn Asn Tyr Lys 
                      20                  25                  30          
          Asn Pro Lys Leu Thr Arg Met Leu Thr Phe Lys Phe Tyr Met Pro Lys 
                  35                  40                  45              
          Lys Ala Thr Glu Leu Lys His Leu Gln Cys Leu Glu Arg Glu Leu Lys 
              50                  55                  60                  
          Arg Leu Glu Glu Val Leu Asn Leu Ala Gln Ser Lys Asn Phe His Leu 
          65                  70                  75                  80  
          Arg Pro Arg Ser Leu Ile Ser Asn Ile Asn Val Ile Val Leu Tyr Leu 
                          85                  90                  95      
          Lys Gly Ser Glu Thr Thr Phe Met Cys Glu Tyr Ala Asp Glu Thr Ala 
                      100                 105                 110         
          Thr Ile Val Glu Phe Leu Asn Arg Trp Ile Thr Phe Ser Gln Ser Ile 
                  115                 120                 125             
          Ile Ser Thr Leu Thr 
              130             
          <![CDATA[<210>  168]]>
          <![CDATA[<211>  133]]>
          <![CDATA[<212>  PRT]]>
          <![CDATA[<213>  人工序列]]>
          <![CDATA[<220>]]>
          <![CDATA[<223>  合成：IL-2-T3A-H16A-L19A-E61A-P65R-D84S-C125S]]>
          <![CDATA[<400>  168]]>
          Ala Pro Ala Ser Ser Ser Thr Lys Lys Thr Gln Leu Gln Leu Glu Ala 
          1               5                   10                  15      
          Leu Leu Ala Asp Leu Gln Met Ile Leu Asn Gly Ile Asn Asn Tyr Lys 
                      20                  25                  30          
          Asn Pro Lys Leu Thr Arg Met Leu Thr Phe Lys Phe Tyr Met Pro Lys 
                  35                  40                  45              
          Lys Ala Thr Glu Leu Lys His Leu Gln Cys Leu Glu Ala Glu Leu Lys 
              50                  55                  60                  
          Arg Leu Glu Glu Val Leu Asn Leu Ala Gln Ser Lys Asn Phe His Leu 
          65                  70                  75                  80  
          Arg Pro Arg Ser Leu Ile Ser Asn Ile Asn Val Ile Val Leu Glu Leu 
                          85                  90                  95      
          Lys Gly Ser Glu Thr Thr Phe Met Cys Glu Tyr Ala Asp Glu Thr Ala 
                      100                 105                 110         
          Thr Ile Val Glu Phe Leu Asn Arg Trp Ile Thr Phe Ser Gln Ser Ile 
                  115                 120                 125             
          Ile Ser Thr Leu Thr 
              130             
          <![CDATA[<210>  169]]>
          <![CDATA[<211>  133]]>
          <![CDATA[<212>  PRT]]>
          <![CDATA[<213>  人工序列]]>
          <![CDATA[<220>]]>
          <![CDATA[<223>  合成：IL-2-T3A-H16A-L19A-E61G-P65R-D84S-C125S]]>
          <![CDATA[<400>  169]]>
          Ala Pro Ala Ser Ser Ser Thr Lys Lys Thr Gln Leu Gln Leu Glu Ala 
          1               5                   10                  15      
          Leu Leu Ala Asp Leu Gln Met Ile Leu Asn Gly Ile Asn Asn Tyr Lys 
                      20                  25                  30          
          Asn Pro Lys Leu Thr Arg Met Leu Thr Phe Lys Phe Tyr Met Pro Lys 
                  35                  40                  45              
          Lys Ala Thr Glu Leu Lys His Leu Gln Cys Leu Glu Gly Glu Leu Lys 
              50                  55                  60                  
          Arg Leu Glu Glu Val Leu Asn Leu Ala Gln Ser Lys Asn Phe His Leu 
          65                  70                  75                  80  
          Arg Pro Arg Ser Leu Ile Ser Asn Ile Asn Val Ile Val Leu Glu Leu 
                          85                  90                  95      
          Lys Gly Ser Glu Thr Thr Phe Met Cys Glu Tyr Ala Asp Glu Thr Ala 
                      100                 105                 110         
          Thr Ile Val Glu Phe Leu Asn Arg Trp Ile Thr Phe Ser Gln Ser Ile 
                  115                 120                 125             
          Ile Ser Thr Leu Thr 
              130             
          <![CDATA[<210>  170]]>
          <![CDATA[<211>  133]]>
          <![CDATA[<212>  PRT]]>
          <![CDATA[<213>  人工序列]]>
          <![CDATA[<220>]]>
          <![CDATA[<223>  合成：IL-2-T3A-H16A-L19A-E61H-P65R-D84S-C125S]]>
          <![CDATA[<400>  170]]>
          Ala Pro Ala Ser Ser Ser Thr Lys Lys Thr Gln Leu Gln Leu Glu Ala 
          1               5                   10                  15      
          Leu Leu Ala Asp Leu Gln Met Ile Leu Asn Gly Ile Asn Asn Tyr Lys 
                      20                  25                  30          
          Asn Pro Lys Leu Thr Arg Met Leu Thr Phe Lys Phe Tyr Met Pro Lys 
                  35                  40                  45              
          Lys Ala Thr Glu Leu Lys His Leu Gln Cys Leu Glu His Glu Leu Lys 
              50                  55                  60                  
          Arg Leu Glu Glu Val Leu Asn Leu Ala Gln Ser Lys Asn Phe His Leu 
          65                  70                  75                  80  
          Arg Pro Arg Ser Leu Ile Ser Asn Ile Asn Val Ile Val Leu Glu Leu 
                          85                  90                  95      
          Lys Gly Ser Glu Thr Thr Phe Met Cys Glu Tyr Ala Asp Glu Thr Ala 
                      100                 105                 110         
          Thr Ile Val Glu Phe Leu Asn Arg Trp Ile Thr Phe Ser Gln Ser Ile 
                  115                 120                 125             
          Ile Ser Thr Leu Thr 
              130             
          <![CDATA[<210>  171]]>
          <![CDATA[<211>  133]]>
          <![CDATA[<212>  PRT]]>
          <![CDATA[<213>  人工序列]]>
          <![CDATA[<220>]]>
          <![CDATA[<223>  合成：IL-2-T3A-H16A-L19A-E61N-P65R-D84S-C125S]]>
          <![CDATA[<400>  171]]>
          Ala Pro Ala Ser Ser Ser Thr Lys Lys Thr Gln Leu Gln Leu Glu Ala 
          1               5                   10                  15      
          Leu Leu Ala Asp Leu Gln Met Ile Leu Asn Gly Ile Asn Asn Tyr Lys 
                      20                  25                  30          
          Asn Pro Lys Leu Thr Arg Met Leu Thr Phe Lys Phe Tyr Met Pro Lys 
                  35                  40                  45              
          Lys Ala Thr Glu Leu Lys His Leu Gln Cys Leu Glu Asn Glu Leu Lys 
              50                  55                  60                  
          Arg Leu Glu Glu Val Leu Asn Leu Ala Gln Ser Lys Asn Phe His Leu 
          65                  70                  75                  80  
          Arg Pro Arg Ser Leu Ile Ser Asn Ile Asn Val Ile Val Leu Glu Leu 
                          85                  90                  95      
          Lys Gly Ser Glu Thr Thr Phe Met Cys Glu Tyr Ala Asp Glu Thr Ala 
                      100                 105                 110         
          Thr Ile Val Glu Phe Leu Asn Arg Trp Ile Thr Phe Ser Gln Ser Ile 
                  115                 120                 125             
          Ile Ser Thr Leu Thr 
              130             
          <![CDATA[<210>  172]]>
          <![CDATA[<211>  133]]>
          <![CDATA[<212>  PRT]]>
          <![CDATA[<213>  人工序列]]>
          <![CDATA[<220>]]>
          <![CDATA[<223>  合成：IL-2-T3A-H16A-L19A-E61P-P65R-D84S-C125S]]>
          <![CDATA[<400>  172]]>
          Ala Pro Ala Ser Ser Ser Thr Lys Lys Thr Gln Leu Gln Leu Glu Ala 
          1               5                   10                  15      
          Leu Leu Ala Asp Leu Gln Met Ile Leu Asn Gly Ile Asn Asn Tyr Lys 
                      20                  25                  30          
          Asn Pro Lys Leu Thr Arg Met Leu Thr Phe Lys Phe Tyr Met Pro Lys 
                  35                  40                  45              
          Lys Ala Thr Glu Leu Lys His Leu Gln Cys Leu Glu Pro Glu Leu Lys 
              50                  55                  60                  
          Arg Leu Glu Glu Val Leu Asn Leu Ala Gln Ser Lys Asn Phe His Leu 
          65                  70                  75                  80  
          Arg Pro Arg Ser Leu Ile Ser Asn Ile Asn Val Ile Val Leu Glu Leu 
                          85                  90                  95      
          Lys Gly Ser Glu Thr Thr Phe Met Cys Glu Tyr Ala Asp Glu Thr Ala 
                      100                 105                 110         
          Thr Ile Val Glu Phe Leu Asn Arg Trp Ile Thr Phe Ser Gln Ser Ile 
                  115                 120                 125             
          Ile Ser Thr Leu Thr 
              130             
          <![CDATA[<210>  173]]>
          <![CDATA[<211>  133]]>
          <![CDATA[<212>  PRT]]>
          <![CDATA[<213>  人工序列]]>
          <![CDATA[<220>]]>
          <![CDATA[<223>  合成：IL-2-T3A-H16A-L19A-E61Q-P65R-D84S-C125S]]>
          <![CDATA[<400>  173]]>
          Ala Pro Ala Ser Ser Ser Thr Lys Lys Thr Gln Leu Gln Leu Glu Ala 
          1               5                   10                  15      
          Leu Leu Ala Asp Leu Gln Met Ile Leu Asn Gly Ile Asn Asn Tyr Lys 
                      20                  25                  30          
          Asn Pro Lys Leu Thr Arg Met Leu Thr Phe Lys Phe Tyr Met Pro Lys 
                  35                  40                  45              
          Lys Ala Thr Glu Leu Lys His Leu Gln Cys Leu Glu Gln Glu Leu Lys 
              50                  55                  60                  
          Arg Leu Glu Glu Val Leu Asn Leu Ala Gln Ser Lys Asn Phe His Leu 
          65                  70                  75                  80  
          Arg Pro Arg Ser Leu Ile Ser Asn Ile Asn Val Ile Val Leu Glu Leu 
                          85                  90                  95      
          Lys Gly Ser Glu Thr Thr Phe Met Cys Glu Tyr Ala Asp Glu Thr Ala 
                      100                 105                 110         
          Thr Ile Val Glu Phe Leu Asn Arg Trp Ile Thr Phe Ser Gln Ser Ile 
                  115                 120                 125             
          Ile Ser Thr Leu Thr 
              130             
          <![CDATA[<210>  174]]>
          <![CDATA[<211>  133]]>
          <![CDATA[<212>  PRT]]>
          <![CDATA[<213>  人工序列]]>
          <![CDATA[<220>]]>
          <![CDATA[<223>  合成：IL-2-T3A-H16A-L19A-E61S-P65R-D84S-C125S]]>
          <![CDATA[<400>  174]]>
          Ala Pro Ala Ser Ser Ser Thr Lys Lys Thr Gln Leu Gln Leu Glu Ala 
          1               5                   10                  15      
          Leu Leu Ala Asp Leu Gln Met Ile Leu Asn Gly Ile Asn Asn Tyr Lys 
                      20                  25                  30          
          Asn Pro Lys Leu Thr Arg Met Leu Thr Phe Lys Phe Tyr Met Pro Lys 
                  35                  40                  45              
          Lys Ala Thr Glu Leu Lys His Leu Gln Cys Leu Glu Ser Glu Leu Lys 
              50                  55                  60                  
          Arg Leu Glu Glu Val Leu Asn Leu Ala Gln Ser Lys Asn Phe His Leu 
          65                  70                  75                  80  
          Arg Pro Arg Ser Leu Ile Ser Asn Ile Asn Val Ile Val Leu Glu Leu 
                          85                  90                  95      
          Lys Gly Ser Glu Thr Thr Phe Met Cys Glu Tyr Ala Asp Glu Thr Ala 
                      100                 105                 110         
          Thr Ile Val Glu Phe Leu Asn Arg Trp Ile Thr Phe Ser Gln Ser Ile 
                  115                 120                 125             
          Ile Ser Thr Leu Thr 
              130             
          <![CDATA[<210>  175]]>
          <![CDATA[<211>  133]]>
          <![CDATA[<212>  PRT]]>
          <![CDATA[<213>  人工序列]]>
          <![CDATA[<220>]]>
          <![CDATA[<223>  合成：IL-2-T3A-H16A-L19A-E61T-P65R-D84S-C125S]]>
          <![CDATA[<400>  175]]>
          Ala Pro Ala Ser Ser Ser Thr Lys Lys Thr Gln Leu Gln Leu Glu Ala 
          1               5                   10                  15      
          Leu Leu Ala Asp Leu Gln Met Ile Leu Asn Gly Ile Asn Asn Tyr Lys 
                      20                  25                  30          
          Asn Pro Lys Leu Thr Arg Met Leu Thr Phe Lys Phe Tyr Met Pro Lys 
                  35                  40                  45              
          Lys Ala Thr Glu Leu Lys His Leu Gln Cys Leu Glu Thr Glu Leu Lys 
              50                  55                  60                  
          Arg Leu Glu Glu Val Leu Asn Leu Ala Gln Ser Lys Asn Phe His Leu 
          65                  70                  75                  80  
          Arg Pro Arg Ser Leu Ile Ser Asn Ile Asn Val Ile Val Leu Glu Leu 
                          85                  90                  95      
          Lys Gly Ser Glu Thr Thr Phe Met Cys Glu Tyr Ala Asp Glu Thr Ala 
                      100                 105                 110         
          Thr Ile Val Glu Phe Leu Asn Arg Trp Ile Thr Phe Ser Gln Ser Ile 
                  115                 120                 125             
          Ile Ser Thr Leu Thr 
              130             
          <![CDATA[<210>  176]]>
          <![CDATA[<211>  133]]>
          <![CDATA[<212>  PRT]]>
          <![CDATA[<213>  人工序列]]>
          <![CDATA[<220>]]>
          <![CDATA[<223>  合成：IL-2-T3A-H16A-L19A-E61V-P65R-D84S-C125S]]>
          <![CDATA[<400>  176]]>
          Ala Pro Ala Ser Ser Ser Thr Lys Lys Thr Gln Leu Gln Leu Glu Ala 
          1               5                   10                  15      
          Leu Leu Ala Asp Leu Gln Met Ile Leu Asn Gly Ile Asn Asn Tyr Lys 
                      20                  25                  30          
          Asn Pro Lys Leu Thr Arg Met Leu Thr Phe Lys Phe Tyr Met Pro Lys 
                  35                  40                  45              
          Lys Ala Thr Glu Leu Lys His Leu Gln Cys Leu Glu Val Glu Leu Lys 
              50                  55                  60                  
          Arg Leu Glu Glu Val Leu Asn Leu Ala Gln Ser Lys Asn Phe His Leu 
          65                  70                  75                  80  
          Arg Pro Arg Ser Leu Ile Ser Asn Ile Asn Val Ile Val Leu Glu Leu 
                          85                  90                  95      
          Lys Gly Ser Glu Thr Thr Phe Met Cys Glu Tyr Ala Asp Glu Thr Ala 
                      100                 105                 110         
          Thr Ile Val Glu Phe Leu Asn Arg Trp Ile Thr Phe Ser Gln Ser Ile 
                  115                 120                 125             
          Ile Ser Thr Leu Thr 
              130             
          <![CDATA[<210>  177]]>
          <![CDATA[<211>  133]]>
          <![CDATA[<212>  PRT]]>
          <![CDATA[<213>  人工序列]]>
          <![CDATA[<220>]]>
          <![CDATA[<223>  合成：IL-2-T3A-H16A-L19A-E61Y-P65R-D84S-C125S]]>
          <![CDATA[<400>  177]]>
          Ala Pro Ala Ser Ser Ser Thr Lys Lys Thr Gln Leu Gln Leu Glu Ala 
          1               5                   10                  15      
          Leu Leu Ala Asp Leu Gln Met Ile Leu Asn Gly Ile Asn Asn Tyr Lys 
                      20                  25                  30          
          Asn Pro Lys Leu Thr Arg Met Leu Thr Phe Lys Phe Tyr Met Pro Lys 
                  35                  40                  45              
          Lys Ala Thr Glu Leu Lys His Leu Gln Cys Leu Glu Tyr Glu Leu Lys 
              50                  55                  60                  
          Arg Leu Glu Glu Val Leu Asn Leu Ala Gln Ser Lys Asn Phe His Leu 
          65                  70                  75                  80  
          Arg Pro Arg Ser Leu Ile Ser Asn Ile Asn Val Ile Val Leu Glu Leu 
                          85                  90                  95      
          Lys Gly Ser Glu Thr Thr Phe Met Cys Glu Tyr Ala Asp Glu Thr Ala 
                      100                 105                 110         
          Thr Ile Val Glu Phe Leu Asn Arg Trp Ile Thr Phe Ser Gln Ser Ile 
                  115                 120                 125             
          Ile Ser Thr Leu Thr 
              130             
          <![CDATA[<210>  178]]>
          <![CDATA[<211>  133]]>
          <![CDATA[<212>  PRT]]>
          <![CDATA[<213>  人工序列]]>
          <![CDATA[<220>]]>
          <![CDATA[<223>  合成：IL-2-T3A-H16A-M23D-E61R-P65R-D84S-E95Q-C125S]]>
          <![CDATA[<400>  178]]>
          Ala Pro Ala Ser Ser Ser Thr Lys Lys Thr Gln Leu Gln Leu Glu Ala 
          1               5                   10                  15      
          Leu Leu Leu Asp Leu Gln Asp Ile Leu Asn Gly Ile Asn Asn Tyr Lys 
                      20                  25                  30          
          Asn Pro Lys Leu Thr Arg Met Leu Thr Phe Lys Phe Tyr Met Pro Lys 
                  35                  40                  45              
          Lys Ala Thr Glu Leu Lys His Leu Gln Cys Leu Glu Arg Glu Leu Lys 
              50                  55                  60                  
          Arg Leu Glu Glu Val Leu Asn Leu Ala Gln Ser Lys Asn Phe His Leu 
          65                  70                  75                  80  
          Arg Pro Arg Ser Leu Ile Ser Asn Ile Asn Val Ile Val Leu Gln Leu 
                          85                  90                  95      
          Lys Gly Ser Glu Thr Thr Phe Met Cys Glu Tyr Ala Asp Glu Thr Ala 
                      100                 105                 110         
          Thr Ile Val Glu Phe Leu Asn Arg Trp Ile Thr Phe Ser Gln Ser Ile 
                  115                 120                 125             
          Ile Ser Thr Leu Thr 
              130             
          <![CDATA[<210>  179]]>
          <![CDATA[<211>  133]]>
          <![CDATA[<212>  PRT]]>
          <![CDATA[<213>  人工序列]]>
          <![CDATA[<220>]]>
          <![CDATA[<223>  合成：IL-2-T3A-H16A-M23E-E61R-P65R-D84S-E95Q-C125S]]>
          <![CDATA[<400>  179]]>
          Ala Pro Ala Ser Ser Ser Thr Lys Lys Thr Gln Leu Gln Leu Glu Ala 
          1               5                   10                  15      
          Leu Leu Leu Asp Leu Gln Glu Ile Leu Asn Gly Ile Asn Asn Tyr Lys 
                      20                  25                  30          
          Asn Pro Lys Leu Thr Arg Met Leu Thr Phe Lys Phe Tyr Met Pro Lys 
                  35                  40                  45              
          Lys Ala Thr Glu Leu Lys His Leu Gln Cys Leu Glu Arg Glu Leu Lys 
              50                  55                  60                  
          Arg Leu Glu Glu Val Leu Asn Leu Ala Gln Ser Lys Asn Phe His Leu 
          65                  70                  75                  80  
          Arg Pro Arg Ser Leu Ile Ser Asn Ile Asn Val Ile Val Leu Gln Leu 
                          85                  90                  95      
          Lys Gly Ser Glu Thr Thr Phe Met Cys Glu Tyr Ala Asp Glu Thr Ala 
                      100                 105                 110         
          Thr Ile Val Glu Phe Leu Asn Arg Trp Ile Thr Phe Ser Gln Ser Ile 
                  115                 120                 125             
          Ile Ser Thr Leu Thr 
              130             
          <![CDATA[<210>  180]]>
          <![CDATA[<211>  133]]>
          <![CDATA[<212>  PRT]]>
          <![CDATA[<213>  人工序列]]>
          <![CDATA[<220>]]>
          <![CDATA[<223>  合成：IL-2-T3A-H16A-M23G-E61R-P65R-D84S-E95Q-C125S]]>
          <![CDATA[<400>  180]]>
          Ala Pro Ala Ser Ser Ser Thr Lys Lys Thr Gln Leu Gln Leu Glu Ala 
          1               5                   10                  15      
          Leu Leu Leu Asp Leu Gln Gly Ile Leu Asn Gly Ile Asn Asn Tyr Lys 
                      20                  25                  30          
          Asn Pro Lys Leu Thr Arg Met Leu Thr Phe Lys Phe Tyr Met Pro Lys 
                  35                  40                  45              
          Lys Ala Thr Glu Leu Lys His Leu Gln Cys Leu Glu Arg Glu Leu Lys 
              50                  55                  60                  
          Arg Leu Glu Glu Val Leu Asn Leu Ala Gln Ser Lys Asn Phe His Leu 
          65                  70                  75                  80  
          Arg Pro Arg Ser Leu Ile Ser Asn Ile Asn Val Ile Val Leu Gln Leu 
                          85                  90                  95      
          Lys Gly Ser Glu Thr Thr Phe Met Cys Glu Tyr Ala Asp Glu Thr Ala 
                      100                 105                 110         
          Thr Ile Val Glu Phe Leu Asn Arg Trp Ile Thr Phe Ser Gln Ser Ile 
                  115                 120                 125             
          Ile Ser Thr Leu Thr 
              130             
          <![CDATA[<210>  181]]>
          <![CDATA[<211>  133]]>
          <![CDATA[<212>  PRT]]>
          <![CDATA[<213>  人工序列]]>
          <![CDATA[<220>]]>
          <![CDATA[<223>  合成：IL-2-T3A-H16A-M23I-E61R-P65R-D84S-E95Q-C125S]]>
          <![CDATA[<400>  181]]>
          Ala Pro Ala Ser Ser Ser Thr Lys Lys Thr Gln Leu Gln Leu Glu Ala 
          1               5                   10                  15      
          Leu Leu Leu Asp Leu Gln Ile Ile Leu Asn Gly Ile Asn Asn Tyr Lys 
                      20                  25                  30          
          Asn Pro Lys Leu Thr Arg Met Leu Thr Phe Lys Phe Tyr Met Pro Lys 
                  35                  40                  45              
          Lys Ala Thr Glu Leu Lys His Leu Gln Cys Leu Glu Arg Glu Leu Lys 
              50                  55                  60                  
          Arg Leu Glu Glu Val Leu Asn Leu Ala Gln Ser Lys Asn Phe His Leu 
          65                  70                  75                  80  
          Arg Pro Arg Ser Leu Ile Ser Asn Ile Asn Val Ile Val Leu Gln Leu 
                          85                  90                  95      
          Lys Gly Ser Glu Thr Thr Phe Met Cys Glu Tyr Ala Asp Glu Thr Ala 
                      100                 105                 110         
          Thr Ile Val Glu Phe Leu Asn Arg Trp Ile Thr Phe Ser Gln Ser Ile 
                  115                 120                 125             
          Ile Ser Thr Leu Thr 
              130             
          <![CDATA[<210>  182]]>
          <![CDATA[<211>  133]]>
          <![CDATA[<212>  PRT]]>
          <![CDATA[<213>  人工序列]]>
          <![CDATA[<220>]]>
          <![CDATA[<223>  合成：IL-2-T3A-H16A-M23K-E61R-P65R-D84S-E95Q-C125S]]>
          <![CDATA[<400>  182]]>
          Ala Pro Ala Ser Ser Ser Thr Lys Lys Thr Gln Leu Gln Leu Glu Ala 
          1               5                   10                  15      
          Leu Leu Leu Asp Leu Gln Lys Ile Leu Asn Gly Ile Asn Asn Tyr Lys 
                      20                  25                  30          
          Asn Pro Lys Leu Thr Arg Met Leu Thr Phe Lys Phe Tyr Met Pro Lys 
                  35                  40                  45              
          Lys Ala Thr Glu Leu Lys His Leu Gln Cys Leu Glu Arg Glu Leu Lys 
              50                  55                  60                  
          Arg Leu Glu Glu Val Leu Asn Leu Ala Gln Ser Lys Asn Phe His Leu 
          65                  70                  75                  80  
          Arg Pro Arg Ser Leu Ile Ser Asn Ile Asn Val Ile Val Leu Gln Leu 
                          85                  90                  95      
          Lys Gly Ser Glu Thr Thr Phe Met Cys Glu Tyr Ala Asp Glu Thr Ala 
                      100                 105                 110         
          Thr Ile Val Glu Phe Leu Asn Arg Trp Ile Thr Phe Ser Gln Ser Ile 
                  115                 120                 125             
          Ile Ser Thr Leu Thr 
              130             
          <![CDATA[<210>  183]]>
          <![CDATA[<211>  133]]>
          <![CDATA[<212>  PRT]]>
          <![CDATA[<213>  人工序列]]>
          <![CDATA[<220>]]>
          <![CDATA[<223>  合成：IL-2-T3A-H16A-M23L-E61R-P65R-D84S-E95Q-C125S]]>
          <![CDATA[<400>  183]]>
          Ala Pro Ala Ser Ser Ser Thr Lys Lys Thr Gln Leu Gln Leu Glu Ala 
          1               5                   10                  15      
          Leu Leu Leu Asp Leu Gln Leu Ile Leu Asn Gly Ile Asn Asn Tyr Lys 
                      20                  25                  30          
          Asn Pro Lys Leu Thr Arg Met Leu Thr Phe Lys Phe Tyr Met Pro Lys 
                  35                  40                  45              
          Lys Ala Thr Glu Leu Lys His Leu Gln Cys Leu Glu Arg Glu Leu Lys 
              50                  55                  60                  
          Arg Leu Glu Glu Val Leu Asn Leu Ala Gln Ser Lys Asn Phe His Leu 
          65                  70                  75                  80  
          Arg Pro Arg Ser Leu Ile Ser Asn Ile Asn Val Ile Val Leu Gln Leu 
                          85                  90                  95      
          Lys Gly Ser Glu Thr Thr Phe Met Cys Glu Tyr Ala Asp Glu Thr Ala 
                      100                 105                 110         
          Thr Ile Val Glu Phe Leu Asn Arg Trp Ile Thr Phe Ser Gln Ser Ile 
                  115                 120                 125             
          Ile Ser Thr Leu Thr 
              130             
          <![CDATA[<210>  184]]>
          <![CDATA[<211>  133]]>
          <![CDATA[<212>  PRT]]>
          <![CDATA[<213>  人工序列]]>
          <![CDATA[<220>]]>
          <![CDATA[<223>  合成：IL-2-T3A-H16A-M23N-E61R-P65R-D84S-E95Q-C125S]]>
          <![CDATA[<400>  184]]>
          Ala Pro Ala Ser Ser Ser Thr Lys Lys Thr Gln Leu Gln Leu Glu Ala 
          1               5                   10                  15      
          Leu Leu Leu Asp Leu Gln Asn Ile Leu Asn Gly Ile Asn Asn Tyr Lys 
                      20                  25                  30          
          Asn Pro Lys Leu Thr Arg Met Leu Thr Phe Lys Phe Tyr Met Pro Lys 
                  35                  40                  45              
          Lys Ala Thr Glu Leu Lys His Leu Gln Cys Leu Glu Arg Glu Leu Lys 
              50                  55                  60                  
          Arg Leu Glu Glu Val Leu Asn Leu Ala Gln Ser Lys Asn Phe His Leu 
          65                  70                  75                  80  
          Arg Pro Arg Ser Leu Ile Ser Asn Ile Asn Val Ile Val Leu Gln Leu 
                          85                  90                  95      
          Lys Gly Ser Glu Thr Thr Phe Met Cys Glu Tyr Ala Asp Glu Thr Ala 
                      100                 105                 110         
          Thr Ile Val Glu Phe Leu Asn Arg Trp Ile Thr Phe Ser Gln Ser Ile 
                  115                 120                 125             
          Ile Ser Thr Leu Thr 
              130             
          <![CDATA[<210>  185]]>
          <![CDATA[<211>  133]]>
          <![CDATA[<212>  PRT]]>
          <![CDATA[<213>  人工序列]]>
          <![CDATA[<220>]]>
          <![CDATA[<223>  合成：IL-2-T3A-H16A-M23P-E61R-P65R-D84S-E95Q-C125S]]>
          <![CDATA[<400>  185]]>
          Ala Pro Ala Ser Ser Ser Thr Lys Lys Thr Gln Leu Gln Leu Glu Ala 
          1               5                   10                  15      
          Leu Leu Leu Asp Leu Gln Pro Ile Leu Asn Gly Ile Asn Asn Tyr Lys 
                      20                  25                  30          
          Asn Pro Lys Leu Thr Arg Met Leu Thr Phe Lys Phe Tyr Met Pro Lys 
                  35                  40                  45              
          Lys Ala Thr Glu Leu Lys His Leu Gln Cys Leu Glu Arg Glu Leu Lys 
              50                  55                  60                  
          Arg Leu Glu Glu Val Leu Asn Leu Ala Gln Ser Lys Asn Phe His Leu 
          65                  70                  75                  80  
          Arg Pro Arg Ser Leu Ile Ser Asn Ile Asn Val Ile Val Leu Gln Leu 
                          85                  90                  95      
          Lys Gly Ser Glu Thr Thr Phe Met Cys Glu Tyr Ala Asp Glu Thr Ala 
                      100                 105                 110         
          Thr Ile Val Glu Phe Leu Asn Arg Trp Ile Thr Phe Ser Gln Ser Ile 
                  115                 120                 125             
          Ile Ser Thr Leu Thr 
              130             
          <![CDATA[<210>  186]]>
          <![CDATA[<211>  133]]>
          <![CDATA[<212>  PRT]]>
          <![CDATA[<213>  人工序列]]>
          <![CDATA[<220>]]>
          <![CDATA[<223>  合成：IL-2-T3A-H16A-M23Q-E61R-P65R-D84S-E95Q-C125S]]>
          <![CDATA[<400>  186]]>
          Ala Pro Ala Ser Ser Ser Thr Lys Lys Thr Gln Leu Gln Leu Glu Ala 
          1               5                   10                  15      
          Leu Leu Leu Asp Leu Gln Gln Ile Leu Asn Gly Ile Asn Asn Tyr Lys 
                      20                  25                  30          
          Asn Pro Lys Leu Thr Arg Met Leu Thr Phe Lys Phe Tyr Met Pro Lys 
                  35                  40                  45              
          Lys Ala Thr Glu Leu Lys His Leu Gln Cys Leu Glu Arg Glu Leu Lys 
              50                  55                  60                  
          Arg Leu Glu Glu Val Leu Asn Leu Ala Gln Ser Lys Asn Phe His Leu 
          65                  70                  75                  80  
          Arg Pro Arg Ser Leu Ile Ser Asn Ile Asn Val Ile Val Leu Gln Leu 
                          85                  90                  95      
          Lys Gly Ser Glu Thr Thr Phe Met Cys Glu Tyr Ala Asp Glu Thr Ala 
                      100                 105                 110         
          Thr Ile Val Glu Phe Leu Asn Arg Trp Ile Thr Phe Ser Gln Ser Ile 
                  115                 120                 125             
          Ile Ser Thr Leu Thr 
              130             
          <![CDATA[<210>  187]]>
          <![CDATA[<211>  133]]>
          <![CDATA[<212>  PRT]]>
          <![CDATA[<213>  人工序列]]>
          <![CDATA[<220>]]>
          <![CDATA[<223>  合成：IL-2-T3A-H16A-M23R-E61R-P65R-D84S-E95Q-C125S]]>
          <![CDATA[<400>  187]]>
          Ala Pro Ala Ser Ser Ser Thr Lys Lys Thr Gln Leu Gln Leu Glu Ala 
          1               5                   10                  15      
          Leu Leu Leu Asp Leu Gln Arg Ile Leu Asn Gly Ile Asn Asn Tyr Lys 
                      20                  25                  30          
          Asn Pro Lys Leu Thr Arg Met Leu Thr Phe Lys Phe Tyr Met Pro Lys 
                  35                  40                  45              
          Lys Ala Thr Glu Leu Lys His Leu Gln Cys Leu Glu Arg Glu Leu Lys 
              50                  55                  60                  
          Arg Leu Glu Glu Val Leu Asn Leu Ala Gln Ser Lys Asn Phe His Leu 
          65                  70                  75                  80  
          Arg Pro Arg Ser Leu Ile Ser Asn Ile Asn Val Ile Val Leu Gln Leu 
                          85                  90                  95      
          Lys Gly Ser Glu Thr Thr Phe Met Cys Glu Tyr Ala Asp Glu Thr Ala 
                      100                 105                 110         
          Thr Ile Val Glu Phe Leu Asn Arg Trp Ile Thr Phe Ser Gln Ser Ile 
                  115                 120                 125             
          Ile Ser Thr Leu Thr 
              130             
          <![CDATA[<210>  188]]>
          <![CDATA[<211>  133]]>
          <![CDATA[<212>  PRT]]>
          <![CDATA[<213>  人工序列]]>
          <![CDATA[<220>]]>
          <![CDATA[<223>  合成：IL-2-T3A-H16A-M23T-E61R-P65R-D84S-E95Q-C125S]]>
          <![CDATA[<400>  188]]>
          Ala Pro Ala Ser Ser Ser Thr Lys Lys Thr Gln Leu Gln Leu Glu Ala 
          1               5                   10                  15      
          Leu Leu Leu Asp Leu Gln Thr Ile Leu Asn Gly Ile Asn Asn Tyr Lys 
                      20                  25                  30          
          Asn Pro Lys Leu Thr Arg Met Leu Thr Phe Lys Phe Tyr Met Pro Lys 
                  35                  40                  45              
          Lys Ala Thr Glu Leu Lys His Leu Gln Cys Leu Glu Arg Glu Leu Lys 
              50                  55                  60                  
          Arg Leu Glu Glu Val Leu Asn Leu Ala Gln Ser Lys Asn Phe His Leu 
          65                  70                  75                  80  
          Arg Pro Arg Ser Leu Ile Ser Asn Ile Asn Val Ile Val Leu Gln Leu 
                          85                  90                  95      
          Lys Gly Ser Glu Thr Thr Phe Met Cys Glu Tyr Ala Asp Glu Thr Ala 
                      100                 105                 110         
          Thr Ile Val Glu Phe Leu Asn Arg Trp Ile Thr Phe Ser Gln Ser Ile 
                  115                 120                 125             
          Ile Ser Thr Leu Thr 
              130             
          <![CDATA[<210>  189]]>
          <![CDATA[<211>  133]]>
          <![CDATA[<212>  PRT]]>
          <![CDATA[<213>  人工序列]]>
          <![CDATA[<220>]]>
          <![CDATA[<223>  合成：IL-2-T3A-H16A-M23V-E61R-P65R-D84S-E95Q-C125S]]>
          <![CDATA[<400>  189]]>
          Ala Pro Ala Ser Ser Ser Thr Lys Lys Thr Gln Leu Gln Leu Glu Ala 
          1               5                   10                  15      
          Leu Leu Leu Asp Leu Gln Val Ile Leu Asn Gly Ile Asn Asn Tyr Lys 
                      20                  25                  30          
          Asn Pro Lys Leu Thr Arg Met Leu Thr Phe Lys Phe Tyr Met Pro Lys 
                  35                  40                  45              
          Lys Ala Thr Glu Leu Lys His Leu Gln Cys Leu Glu Arg Glu Leu Lys 
              50                  55                  60                  
          Arg Leu Glu Glu Val Leu Asn Leu Ala Gln Ser Lys Asn Phe His Leu 
          65                  70                  75                  80  
          Arg Pro Arg Ser Leu Ile Ser Asn Ile Asn Val Ile Val Leu Gln Leu 
                          85                  90                  95      
          Lys Gly Ser Glu Thr Thr Phe Met Cys Glu Tyr Ala Asp Glu Thr Ala 
                      100                 105                 110         
          Thr Ile Val Glu Phe Leu Asn Arg Trp Ile Thr Phe Ser Gln Ser Ile 
                  115                 120                 125             
          Ile Ser Thr Leu Thr 
              130             
          <![CDATA[<210>  190]]>
          <![CDATA[<211>  133]]>
          <![CDATA[<212>  PRT]]>
          <![CDATA[<213>  人工序列]]>
          <![CDATA[<220>]]>
          <![CDATA[<223>  合成：IL-2-T3A-H16A-Q22A-E61R-P65R-D84S-C125S]]>
          <![CDATA[<400>  190]]>
          Ala Pro Ala Ser Ser Ser Thr Lys Lys Thr Gln Leu Gln Leu Glu Ala 
          1               5                   10                  15      
          Leu Leu Leu Asp Leu Ala Met Ile Leu Asn Gly Ile Asn Asn Tyr Lys 
                      20                  25                  30          
          Asn Pro Lys Leu Thr Arg Met Leu Thr Phe Lys Phe Tyr Met Pro Lys 
                  35                  40                  45              
          Lys Ala Thr Glu Leu Lys His Leu Gln Cys Leu Glu Arg Glu Leu Lys 
              50                  55                  60                  
          Arg Leu Glu Glu Val Leu Asn Leu Ala Gln Ser Lys Asn Phe His Leu 
          65                  70                  75                  80  
          Arg Pro Arg Ser Leu Ile Ser Asn Ile Asn Val Ile Val Leu Glu Leu 
                          85                  90                  95      
          Lys Gly Ser Glu Thr Thr Phe Met Cys Glu Tyr Ala Asp Glu Thr Ala 
                      100                 105                 110         
          Thr Ile Val Glu Phe Leu Asn Arg Trp Ile Thr Phe Ser Gln Ser Ile 
                  115                 120                 125             
          Ile Ser Thr Leu Thr 
              130             
          <![CDATA[<210>  191]]>
          <![CDATA[<211>  133]]>
          <![CDATA[<212>  PRT]]>
          <![CDATA[<213>  人工序列]]>
          <![CDATA[<220>]]>
          <![CDATA[<223>  合成：IL-2-T3A-H16A-Q22D-E61R-P65R-D84S-C125S]]>
          <![CDATA[<400>  191]]>
          Ala Pro Ala Ser Ser Ser Thr Lys Lys Thr Gln Leu Gln Leu Glu Ala 
          1               5                   10                  15      
          Leu Leu Leu Asp Leu Asp Met Ile Leu Asn Gly Ile Asn Asn Tyr Lys 
                      20                  25                  30          
          Asn Pro Lys Leu Thr Arg Met Leu Thr Phe Lys Phe Tyr Met Pro Lys 
                  35                  40                  45              
          Lys Ala Thr Glu Leu Lys His Leu Gln Cys Leu Glu Arg Glu Leu Lys 
              50                  55                  60                  
          Arg Leu Glu Glu Val Leu Asn Leu Ala Gln Ser Lys Asn Phe His Leu 
          65                  70                  75                  80  
          Arg Pro Arg Ser Leu Ile Ser Asn Ile Asn Val Ile Val Leu Glu Leu 
                          85                  90                  95      
          Lys Gly Ser Glu Thr Thr Phe Met Cys Glu Tyr Ala Asp Glu Thr Ala 
                      100                 105                 110         
          Thr Ile Val Glu Phe Leu Asn Arg Trp Ile Thr Phe Ser Gln Ser Ile 
                  115                 120                 125             
          Ile Ser Thr Leu Thr 
              130             
          <![CDATA[<210>  192]]>
          <![CDATA[<211>  133]]>
          <![CDATA[<212>  PRT]]>
          <![CDATA[<213>  人工序列]]>
          <![CDATA[<220>]]>
          <![CDATA[<223>  合成：IL-2-T3A-H16A-Q22E-E61R-P65R-D84S-C125S]]>
          <![CDATA[<400>  192]]>
          Ala Pro Ala Ser Ser Ser Thr Lys Lys Thr Gln Leu Gln Leu Glu Ala 
          1               5                   10                  15      
          Leu Leu Leu Asp Leu Glu Met Ile Leu Asn Gly Ile Asn Asn Tyr Lys 
                      20                  25                  30          
          Asn Pro Lys Leu Thr Arg Met Leu Thr Phe Lys Phe Tyr Met Pro Lys 
                  35                  40                  45              
          Lys Ala Thr Glu Leu Lys His Leu Gln Cys Leu Glu Arg Glu Leu Lys 
              50                  55                  60                  
          Arg Leu Glu Glu Val Leu Asn Leu Ala Gln Ser Lys Asn Phe His Leu 
          65                  70                  75                  80  
          Arg Pro Arg Ser Leu Ile Ser Asn Ile Asn Val Ile Val Leu Glu Leu 
                          85                  90                  95      
          Lys Gly Ser Glu Thr Thr Phe Met Cys Glu Tyr Ala Asp Glu Thr Ala 
                      100                 105                 110         
          Thr Ile Val Glu Phe Leu Asn Arg Trp Ile Thr Phe Ser Gln Ser Ile 
                  115                 120                 125             
          Ile Ser Thr Leu Thr 
              130             
          <![CDATA[<210>  193]]>
          <![CDATA[<211>  133]]>
          <![CDATA[<212>  PRT]]>
          <![CDATA[<213>  人工序列]]>
          <![CDATA[<220>]]>
          <![CDATA[<223>  合成：IL-2-T3A-H16A-Q22G-E61R-P65R-D84S-C125S]]>
          <![CDATA[<400>  193]]>
          Ala Pro Ala Ser Ser Ser Thr Lys Lys Thr Gln Leu Gln Leu Glu Ala 
          1               5                   10                  15      
          Leu Leu Leu Asp Leu Gly Met Ile Leu Asn Gly Ile Asn Asn Tyr Lys 
                      20                  25                  30          
          Asn Pro Lys Leu Thr Arg Met Leu Thr Phe Lys Phe Tyr Met Pro Lys 
                  35                  40                  45              
          Lys Ala Thr Glu Leu Lys His Leu Gln Cys Leu Glu Arg Glu Leu Lys 
              50                  55                  60                  
          Arg Leu Glu Glu Val Leu Asn Leu Ala Gln Ser Lys Asn Phe His Leu 
          65                  70                  75                  80  
          Arg Pro Arg Ser Leu Ile Ser Asn Ile Asn Val Ile Val Leu Glu Leu 
                          85                  90                  95      
          Lys Gly Ser Glu Thr Thr Phe Met Cys Glu Tyr Ala Asp Glu Thr Ala 
                      100                 105                 110         
          Thr Ile Val Glu Phe Leu Asn Arg Trp Ile Thr Phe Ser Gln Ser Ile 
                  115                 120                 125             
          Ile Ser Thr Leu Thr 
              130             
          <![CDATA[<210>  194]]>
          <![CDATA[<211>  133]]>
          <![CDATA[<212>  PRT]]>
          <![CDATA[<213>  人工序列]]>
          <![CDATA[<220>]]>
          <![CDATA[<223>  合成：IL-2-T3A-H16A-Q22H-E61R-P65R-D84S-C125S]]>
          <![CDATA[<400>  194]]>
          Ala Pro Ala Ser Ser Ser Thr Lys Lys Thr Gln Leu Gln Leu Glu Ala 
          1               5                   10                  15      
          Leu Leu Leu Asp Leu His Met Ile Leu Asn Gly Ile Asn Asn Tyr Lys 
                      20                  25                  30          
          Asn Pro Lys Leu Thr Arg Met Leu Thr Phe Lys Phe Tyr Met Pro Lys 
                  35                  40                  45              
          Lys Ala Thr Glu Leu Lys His Leu Gln Cys Leu Glu Arg Glu Leu Lys 
              50                  55                  60                  
          Arg Leu Glu Glu Val Leu Asn Leu Ala Gln Ser Lys Asn Phe His Leu 
          65                  70                  75                  80  
          Arg Pro Arg Ser Leu Ile Ser Asn Ile Asn Val Ile Val Leu Glu Leu 
                          85                  90                  95      
          Lys Gly Ser Glu Thr Thr Phe Met Cys Glu Tyr Ala Asp Glu Thr Ala 
                      100                 105                 110         
          Thr Ile Val Glu Phe Leu Asn Arg Trp Ile Thr Phe Ser Gln Ser Ile 
                  115                 120                 125             
          Ile Ser Thr Leu Thr 
              130             
          <![CDATA[<210>  195]]>
          <![CDATA[<211>  133]]>
          <![CDATA[<212>  PRT]]>
          <![CDATA[<213>  人工序列]]>
          <![CDATA[<220>]]>
          <![CDATA[<223>  合成：IL-2-T3A-H16A-Q22K-E61R-P65R-D84S-C125S]]>
          <![CDATA[<400>  195]]>
          Ala Pro Ala Ser Ser Ser Thr Lys Lys Thr Gln Leu Gln Leu Glu Ala 
          1               5                   10                  15      
          Leu Leu Leu Asp Leu Lys Met Ile Leu Asn Gly Ile Asn Asn Tyr Lys 
                      20                  25                  30          
          Asn Pro Lys Leu Thr Arg Met Leu Thr Phe Lys Phe Tyr Met Pro Lys 
                  35                  40                  45              
          Lys Ala Thr Glu Leu Lys His Leu Gln Cys Leu Glu Arg Glu Leu Lys 
              50                  55                  60                  
          Arg Leu Glu Glu Val Leu Asn Leu Ala Gln Ser Lys Asn Phe His Leu 
          65                  70                  75                  80  
          Arg Pro Arg Ser Leu Ile Ser Asn Ile Asn Val Ile Val Leu Glu Leu 
                          85                  90                  95      
          Lys Gly Ser Glu Thr Thr Phe Met Cys Glu Tyr Ala Asp Glu Thr Ala 
                      100                 105                 110         
          Thr Ile Val Glu Phe Leu Asn Arg Trp Ile Thr Phe Ser Gln Ser Ile 
                  115                 120                 125             
          Ile Ser Thr Leu Thr 
              130             
          <![CDATA[<210>  196]]>
          <![CDATA[<211>  133]]>
          <![CDATA[<212>  PRT]]>
          <![CDATA[<213>  人工序列]]>
          <![CDATA[<220>]]>
          <![CDATA[<223>  合成：IL-2-T3A-H16A-Q22N-E61R-P65R-D84S-C125S]]>
          <![CDATA[<400>  196]]>
          Ala Pro Ala Ser Ser Ser Thr Lys Lys Thr Gln Leu Gln Leu Glu Ala 
          1               5                   10                  15      
          Leu Leu Leu Asp Leu Asn Met Ile Leu Asn Gly Ile Asn Asn Tyr Lys 
                      20                  25                  30          
          Asn Pro Lys Leu Thr Arg Met Leu Thr Phe Lys Phe Tyr Met Pro Lys 
                  35                  40                  45              
          Lys Ala Thr Glu Leu Lys His Leu Gln Cys Leu Glu Arg Glu Leu Lys 
              50                  55                  60                  
          Arg Leu Glu Glu Val Leu Asn Leu Ala Gln Ser Lys Asn Phe His Leu 
          65                  70                  75                  80  
          Arg Pro Arg Ser Leu Ile Ser Asn Ile Asn Val Ile Val Leu Glu Leu 
                          85                  90                  95      
          Lys Gly Ser Glu Thr Thr Phe Met Cys Glu Tyr Ala Asp Glu Thr Ala 
                      100                 105                 110         
          Thr Ile Val Glu Phe Leu Asn Arg Trp Ile Thr Phe Ser Gln Ser Ile 
                  115                 120                 125             
          Ile Ser Thr Leu Thr 
              130             
          <![CDATA[<210>  197]]>
          <![CDATA[<211>  133]]>
          <![CDATA[<212>  PRT]]>
          <![CDATA[<213>  人工序列]]>
          <![CDATA[<220>]]>
          <![CDATA[<223>  合成：IL-2-T3A-H16A-Q22P-E61R-P65R-D84S-C125S]]>
          <![CDATA[<400>  197]]>
          Ala Pro Ala Ser Ser Ser Thr Lys Lys Thr Gln Leu Gln Leu Glu Ala 
          1               5                   10                  15      
          Leu Leu Leu Asp Leu Pro Met Ile Leu Asn Gly Ile Asn Asn Tyr Lys 
                      20                  25                  30          
          Asn Pro Lys Leu Thr Arg Met Leu Thr Phe Lys Phe Tyr Met Pro Lys 
                  35                  40                  45              
          Lys Ala Thr Glu Leu Lys His Leu Gln Cys Leu Glu Arg Glu Leu Lys 
              50                  55                  60                  
          Arg Leu Glu Glu Val Leu Asn Leu Ala Gln Ser Lys Asn Phe His Leu 
          65                  70                  75                  80  
          Arg Pro Arg Ser Leu Ile Ser Asn Ile Asn Val Ile Val Leu Glu Leu 
                          85                  90                  95      
          Lys Gly Ser Glu Thr Thr Phe Met Cys Glu Tyr Ala Asp Glu Thr Ala 
                      100                 105                 110         
          Thr Ile Val Glu Phe Leu Asn Arg Trp Ile Thr Phe Ser Gln Ser Ile 
                  115                 120                 125             
          Ile Ser Thr Leu Thr 
              130             
          <![CDATA[<210>  198]]>
          <![CDATA[<211>  133]]>
          <![CDATA[<212>  PRT]]>
          <![CDATA[<213>  人工序列]]>
          <![CDATA[<220>]]>
          <![CDATA[<223>  合成：IL-2-T3A-H16A-Q22R-E61R-P65R-D84S-C125S]]>
          <![CDATA[<400>  198]]>
          Ala Pro Ala Ser Ser Ser Thr Lys Lys Thr Gln Leu Gln Leu Glu Ala 
          1               5                   10                  15      
          Leu Leu Leu Asp Leu Arg Met Ile Leu Asn Gly Ile Asn Asn Tyr Lys 
                      20                  25                  30          
          Asn Pro Lys Leu Thr Arg Met Leu Thr Phe Lys Phe Tyr Met Pro Lys 
                  35                  40                  45              
          Lys Ala Thr Glu Leu Lys His Leu Gln Cys Leu Glu Arg Glu Leu Lys 
              50                  55                  60                  
          Arg Leu Glu Glu Val Leu Asn Leu Ala Gln Ser Lys Asn Phe His Leu 
          65                  70                  75                  80  
          Arg Pro Arg Ser Leu Ile Ser Asn Ile Asn Val Ile Val Leu Glu Leu 
                          85                  90                  95      
          Lys Gly Ser Glu Thr Thr Phe Met Cys Glu Tyr Ala Asp Glu Thr Ala 
                      100                 105                 110         
          Thr Ile Val Glu Phe Leu Asn Arg Trp Ile Thr Phe Ser Gln Ser Ile 
                  115                 120                 125             
          Ile Ser Thr Leu Thr 
              130             
          <![CDATA[<210>  199]]>
          <![CDATA[<211>  133]]>
          <![CDATA[<212>  PRT]]>
          <![CDATA[<213>  人工序列]]>
          <![CDATA[<220>]]>
          <![CDATA[<223>  合成：IL-2-T3A-H16A-Q22S-E61R-P65R-D84S-C125S]]>
          <![CDATA[<400>  199]]>
          Ala Pro Ala Ser Ser Ser Thr Lys Lys Thr Gln Leu Gln Leu Glu Ala 
          1               5                   10                  15      
          Leu Leu Leu Asp Leu Ser Met Ile Leu Asn Gly Ile Asn Asn Tyr Lys 
                      20                  25                  30          
          Asn Pro Lys Leu Thr Arg Met Leu Thr Phe Lys Phe Tyr Met Pro Lys 
                  35                  40                  45              
          Lys Ala Thr Glu Leu Lys His Leu Gln Cys Leu Glu Arg Glu Leu Lys 
              50                  55                  60                  
          Arg Leu Glu Glu Val Leu Asn Leu Ala Gln Ser Lys Asn Phe His Leu 
          65                  70                  75                  80  
          Arg Pro Arg Ser Leu Ile Ser Asn Ile Asn Val Ile Val Leu Glu Leu 
                          85                  90                  95      
          Lys Gly Ser Glu Thr Thr Phe Met Cys Glu Tyr Ala Asp Glu Thr Ala 
                      100                 105                 110         
          Thr Ile Val Glu Phe Leu Asn Arg Trp Ile Thr Phe Ser Gln Ser Ile 
                  115                 120                 125             
          Ile Ser Thr Leu Thr 
              130             
          <![CDATA[<210>  200]]>
          <![CDATA[<211>  133]]>
          <![CDATA[<212>  PRT]]>
          <![CDATA[<213>  人工序列]]>
          <![CDATA[<220>]]>
          <![CDATA[<223>  合成：IL-2-T3A-H16A-Q22T-E61R-P65R-D84S-C125S]]>
          <![CDATA[<400>  200]]>
          Ala Pro Ala Ser Ser Ser Thr Lys Lys Thr Gln Leu Gln Leu Glu Ala 
          1               5                   10                  15      
          Leu Leu Leu Asp Leu Thr Met Ile Leu Asn Gly Ile Asn Asn Tyr Lys 
                      20                  25                  30          
          Asn Pro Lys Leu Thr Arg Met Leu Thr Phe Lys Phe Tyr Met Pro Lys 
                  35                  40                  45              
          Lys Ala Thr Glu Leu Lys His Leu Gln Cys Leu Glu Arg Glu Leu Lys 
              50                  55                  60                  
          Arg Leu Glu Glu Val Leu Asn Leu Ala Gln Ser Lys Asn Phe His Leu 
          65                  70                  75                  80  
          Arg Pro Arg Ser Leu Ile Ser Asn Ile Asn Val Ile Val Leu Glu Leu 
                          85                  90                  95      
          Lys Gly Ser Glu Thr Thr Phe Met Cys Glu Tyr Ala Asp Glu Thr Ala 
                      100                 105                 110         
          Thr Ile Val Glu Phe Leu Asn Arg Trp Ile Thr Phe Ser Gln Ser Ile 
                  115                 120                 125             
          Ile Ser Thr Leu Thr 
              130             
          <![CDATA[<210>  201]]>
          <![CDATA[<211>  133]]>
          <![CDATA[<212>  PRT]]>
          <![CDATA[<213>  人工序列]]>
          <![CDATA[<220>]]>
          <![CDATA[<223>  合成：IL-2-T3A-H16A-Q22V-E61R-P65R-D84S-C125S]]>
          <![CDATA[<400>  201]]>
          Ala Pro Ala Ser Ser Ser Thr Lys Lys Thr Gln Leu Gln Leu Glu Ala 
          1               5                   10                  15      
          Leu Leu Leu Asp Leu Val Met Ile Leu Asn Gly Ile Asn Asn Tyr Lys 
                      20                  25                  30          
          Asn Pro Lys Leu Thr Arg Met Leu Thr Phe Lys Phe Tyr Met Pro Lys 
                  35                  40                  45              
          Lys Ala Thr Glu Leu Lys His Leu Gln Cys Leu Glu Arg Glu Leu Lys 
              50                  55                  60                  
          Arg Leu Glu Glu Val Leu Asn Leu Ala Gln Ser Lys Asn Phe His Leu 
          65                  70                  75                  80  
          Arg Pro Arg Ser Leu Ile Ser Asn Ile Asn Val Ile Val Leu Glu Leu 
                          85                  90                  95      
          Lys Gly Ser Glu Thr Thr Phe Met Cys Glu Tyr Ala Asp Glu Thr Ala 
                      100                 105                 110         
          Thr Ile Val Glu Phe Leu Asn Arg Trp Ile Thr Phe Ser Gln Ser Ile 
                  115                 120                 125             
          Ile Ser Thr Leu Thr 
              130             
          <![CDATA[<210>  202]]>
          <![CDATA[<211>  133]]>
          <![CDATA[<212>  PRT]]>
          <![CDATA[<213>  人工序列]]>
          <![CDATA[<220>]]>
          <![CDATA[<223>  合成：IL-2-T3A-H16A-Q22Y-E61R-P65R-D84S-C125S]]>
          <![CDATA[<400>  202]]>
          Ala Pro Ala Ser Ser Ser Thr Lys Lys Thr Gln Leu Gln Leu Glu Ala 
          1               5                   10                  15      
          Leu Leu Leu Asp Leu Tyr Met Ile Leu Asn Gly Ile Asn Asn Tyr Lys 
                      20                  25                  30          
          Asn Pro Lys Leu Thr Arg Met Leu Thr Phe Lys Phe Tyr Met Pro Lys 
                  35                  40                  45              
          Lys Ala Thr Glu Leu Lys His Leu Gln Cys Leu Glu Arg Glu Leu Lys 
              50                  55                  60                  
          Arg Leu Glu Glu Val Leu Asn Leu Ala Gln Ser Lys Asn Phe His Leu 
          65                  70                  75                  80  
          Arg Pro Arg Ser Leu Ile Ser Asn Ile Asn Val Ile Val Leu Glu Leu 
                          85                  90                  95      
          Lys Gly Ser Glu Thr Thr Phe Met Cys Glu Tyr Ala Asp Glu Thr Ala 
                      100                 105                 110         
          Thr Ile Val Glu Phe Leu Asn Arg Trp Ile Thr Phe Ser Gln Ser Ile 
                  115                 120                 125             
          Ile Ser Thr Leu Thr 
              130             
          <![CDATA[<210>  203]]>
          <![CDATA[<211>  133]]>
          <![CDATA[<212>  PRT]]>
          <![CDATA[<213>  人工序列]]>
          <![CDATA[<220>]]>
          <![CDATA[<223>  合成：IL-2-T3A-H16A-E61R-P65R-D84S-R120A-C125S]]>
          <![CDATA[<400>  203]]>
          Ala Pro Ala Ser Ser Ser Thr Lys Lys Thr Gln Leu Gln Leu Glu Ala 
          1               5                   10                  15      
          Leu Leu Leu Asp Leu Gln Met Ile Leu Asn Gly Ile Asn Asn Tyr Lys 
                      20                  25                  30          
          Asn Pro Lys Leu Thr Arg Met Leu Thr Phe Lys Phe Tyr Met Pro Lys 
                  35                  40                  45              
          Lys Ala Thr Glu Leu Lys His Leu Gln Cys Leu Glu Arg Glu Leu Lys 
              50                  55                  60                  
          Arg Leu Glu Glu Val Leu Asn Leu Ala Gln Ser Lys Asn Phe His Leu 
          65                  70                  75                  80  
          Arg Pro Arg Ser Leu Ile Ser Asn Ile Asn Val Ile Val Leu Glu Leu 
                          85                  90                  95      
          Lys Gly Ser Glu Thr Thr Phe Met Cys Glu Tyr Ala Asp Glu Thr Ala 
                      100                 105                 110         
          Thr Ile Val Glu Phe Leu Asn Ala Trp Ile Thr Phe Ser Gln Ser Ile 
                  115                 120                 125             
          Ile Ser Thr Leu Thr 
              130             
          <![CDATA[<210>  204]]>
          <![CDATA[<211>  133]]>
          <![CDATA[<212>  PRT]]>
          <![CDATA[<213>  人工序列]]>
          <![CDATA[<220>]]>
          <![CDATA[<223>  合成：IL-2-T3A-H16A-E61R-P65R-D84S-R120D-C125S]]>
          <![CDATA[<400>  204]]>
          Ala Pro Ala Ser Ser Ser Thr Lys Lys Thr Gln Leu Gln Leu Glu Ala 
          1               5                   10                  15      
          Leu Leu Leu Asp Leu Gln Met Ile Leu Asn Gly Ile Asn Asn Tyr Lys 
                      20                  25                  30          
          Asn Pro Lys Leu Thr Arg Met Leu Thr Phe Lys Phe Tyr Met Pro Lys 
                  35                  40                  45              
          Lys Ala Thr Glu Leu Lys His Leu Gln Cys Leu Glu Arg Glu Leu Lys 
              50                  55                  60                  
          Arg Leu Glu Glu Val Leu Asn Leu Ala Gln Ser Lys Asn Phe His Leu 
          65                  70                  75                  80  
          Arg Pro Arg Ser Leu Ile Ser Asn Ile Asn Val Ile Val Leu Glu Leu 
                          85                  90                  95      
          Lys Gly Ser Glu Thr Thr Phe Met Cys Glu Tyr Ala Asp Glu Thr Ala 
                      100                 105                 110         
          Thr Ile Val Glu Phe Leu Asn Asp Trp Ile Thr Phe Ser Gln Ser Ile 
                  115                 120                 125             
          Ile Ser Thr Leu Thr 
              130             
          <![CDATA[<210>  205]]>
          <![CDATA[<211>  133]]>
          <![CDATA[<212>  PRT]]>
          <![CDATA[<213>  人工序列]]>
          <![CDATA[<220>]]>
          <![CDATA[<223>  合成：IL-2-T3A-H16A-E61R-P65R-D84S-R120E-C125S]]>
          <![CDATA[<400>  205]]>
          Ala Pro Ala Ser Ser Ser Thr Lys Lys Thr Gln Leu Gln Leu Glu Ala 
          1               5                   10                  15      
          Leu Leu Leu Asp Leu Gln Met Ile Leu Asn Gly Ile Asn Asn Tyr Lys 
                      20                  25                  30          
          Asn Pro Lys Leu Thr Arg Met Leu Thr Phe Lys Phe Tyr Met Pro Lys 
                  35                  40                  45              
          Lys Ala Thr Glu Leu Lys His Leu Gln Cys Leu Glu Arg Glu Leu Lys 
              50                  55                  60                  
          Arg Leu Glu Glu Val Leu Asn Leu Ala Gln Ser Lys Asn Phe His Leu 
          65                  70                  75                  80  
          Arg Pro Arg Ser Leu Ile Ser Asn Ile Asn Val Ile Val Leu Glu Leu 
                          85                  90                  95      
          Lys Gly Ser Glu Thr Thr Phe Met Cys Glu Tyr Ala Asp Glu Thr Ala 
                      100                 105                 110         
          Thr Ile Val Glu Phe Leu Asn Glu Trp Ile Thr Phe Ser Gln Ser Ile 
                  115                 120                 125             
          Ile Ser Thr Leu Thr 
              130             
          <![CDATA[<210>  206]]>
          <![CDATA[<211>  133]]>
          <![CDATA[<212>  PRT]]>
          <![CDATA[<213>  人工序列]]>
          <![CDATA[<220>]]>
          <![CDATA[<223>  合成：IL-2-T3A-H16A-E61R-P65R-D84S-R120F-C125S]]>
          <![CDATA[<400>  206]]>
          Ala Pro Ala Ser Ser Ser Thr Lys Lys Thr Gln Leu Gln Leu Glu Ala 
          1               5                   10                  15      
          Leu Leu Leu Asp Leu Gln Met Ile Leu Asn Gly Ile Asn Asn Tyr Lys 
                      20                  25                  30          
          Asn Pro Lys Leu Thr Arg Met Leu Thr Phe Lys Phe Tyr Met Pro Lys 
                  35                  40                  45              
          Lys Ala Thr Glu Leu Lys His Leu Gln Cys Leu Glu Arg Glu Leu Lys 
              50                  55                  60                  
          Arg Leu Glu Glu Val Leu Asn Leu Ala Gln Ser Lys Asn Phe His Leu 
          65                  70                  75                  80  
          Arg Pro Arg Ser Leu Ile Ser Asn Ile Asn Val Ile Val Leu Glu Leu 
                          85                  90                  95      
          Lys Gly Ser Glu Thr Thr Phe Met Cys Glu Tyr Ala Asp Glu Thr Ala 
                      100                 105                 110         
          Thr Ile Val Glu Phe Leu Asn Phe Trp Ile Thr Phe Ser Gln Ser Ile 
                  115                 120                 125             
          Ile Ser Thr Leu Thr 
              130             
          <![CDATA[<210>  207]]>
          <![CDATA[<211>  133]]>
          <![CDATA[<212>  PRT]]>
          <![CDATA[<213>  人工序列]]>
          <![CDATA[<220>]]>
          <![CDATA[<223>  合成：IL-2-T3A-H16A-E61R-P65R-D84S-R120G-C125S]]>
          <![CDATA[<400>  207]]>
          Ala Pro Ala Ser Ser Ser Thr Lys Lys Thr Gln Leu Gln Leu Glu Ala 
          1               5                   10                  15      
          Leu Leu Leu Asp Leu Gln Met Ile Leu Asn Gly Ile Asn Asn Tyr Lys 
                      20                  25                  30          
          Asn Pro Lys Leu Thr Arg Met Leu Thr Phe Lys Phe Tyr Met Pro Lys 
                  35                  40                  45              
          Lys Ala Thr Glu Leu Lys His Leu Gln Cys Leu Glu Arg Glu Leu Lys 
              50                  55                  60                  
          Arg Leu Glu Glu Val Leu Asn Leu Ala Gln Ser Lys Asn Phe His Leu 
          65                  70                  75                  80  
          Arg Pro Arg Ser Leu Ile Ser Asn Ile Asn Val Ile Val Leu Glu Leu 
                          85                  90                  95      
          Lys Gly Ser Glu Thr Thr Phe Met Cys Glu Tyr Ala Asp Glu Thr Ala 
                      100                 105                 110         
          Thr Ile Val Glu Phe Leu Asn Gly Trp Ile Thr Phe Ser Gln Ser Ile 
                  115                 120                 125             
          Ile Ser Thr Leu Thr 
              130             
          <![CDATA[<210>  208]]>
          <![CDATA[<211>  133]]>
          <![CDATA[<212>  PRT]]>
          <![CDATA[<213>  人工序列]]>
          <![CDATA[<220>]]>
          <![CDATA[<223>  合成：IL-2-T3A-H16A-E61R-P65R-D84S-R120H-C125S]]>
          <![CDATA[<400>  208]]>
          Ala Pro Ala Ser Ser Ser Thr Lys Lys Thr Gln Leu Gln Leu Glu Ala 
          1               5                   10                  15      
          Leu Leu Leu Asp Leu Gln Met Ile Leu Asn Gly Ile Asn Asn Tyr Lys 
                      20                  25                  30          
          Asn Pro Lys Leu Thr Arg Met Leu Thr Phe Lys Phe Tyr Met Pro Lys 
                  35                  40                  45              
          Lys Ala Thr Glu Leu Lys His Leu Gln Cys Leu Glu Arg Glu Leu Lys 
              50                  55                  60                  
          Arg Leu Glu Glu Val Leu Asn Leu Ala Gln Ser Lys Asn Phe His Leu 
          65                  70                  75                  80  
          Arg Pro Arg Ser Leu Ile Ser Asn Ile Asn Val Ile Val Leu Glu Leu 
                          85                  90                  95      
          Lys Gly Ser Glu Thr Thr Phe Met Cys Glu Tyr Ala Asp Glu Thr Ala 
                      100                 105                 110         
          Thr Ile Val Glu Phe Leu Asn His Trp Ile Thr Phe Ser Gln Ser Ile 
                  115                 120                 125             
          Ile Ser Thr Leu Thr 
              130             
          <![CDATA[<210>  209]]>
          <![CDATA[<211>  133]]>
          <![CDATA[<212>  PRT]]>
          <![CDATA[<213>  人工序列]]>
          <![CDATA[<220>]]>
          <![CDATA[<223>  合成：IL-2-T3A-H16A-E61R-P65R-D84S-R120K-C125S]]>
          <![CDATA[<400>  209]]>
          Ala Pro Ala Ser Ser Ser Thr Lys Lys Thr Gln Leu Gln Leu Glu Ala 
          1               5                   10                  15      
          Leu Leu Leu Asp Leu Gln Met Ile Leu Asn Gly Ile Asn Asn Tyr Lys 
                      20                  25                  30          
          Asn Pro Lys Leu Thr Arg Met Leu Thr Phe Lys Phe Tyr Met Pro Lys 
                  35                  40                  45              
          Lys Ala Thr Glu Leu Lys His Leu Gln Cys Leu Glu Arg Glu Leu Lys 
              50                  55                  60                  
          Arg Leu Glu Glu Val Leu Asn Leu Ala Gln Ser Lys Asn Phe His Leu 
          65                  70                  75                  80  
          Arg Pro Arg Ser Leu Ile Ser Asn Ile Asn Val Ile Val Leu Glu Leu 
                          85                  90                  95      
          Lys Gly Ser Glu Thr Thr Phe Met Cys Glu Tyr Ala Asp Glu Thr Ala 
                      100                 105                 110         
          Thr Ile Val Glu Phe Leu Asn Lys Trp Ile Thr Phe Ser Gln Ser Ile 
                  115                 120                 125             
          Ile Ser Thr Leu Thr 
              130             
          <![CDATA[<210>  210]]>
          <![CDATA[<211>  133]]>
          <![CDATA[<212>  PRT]]>
          <![CDATA[<213>  人工序列]]>
          <![CDATA[<220>]]>
          <![CDATA[<223>  合成：IL-2-T3A-H16A-E61R-P65R-D84S-R120N-C125S]]>
          <![CDATA[<400>  210]]>
          Ala Pro Ala Ser Ser Ser Thr Lys Lys Thr Gln Leu Gln Leu Glu Ala 
          1               5                   10                  15      
          Leu Leu Leu Asp Leu Gln Met Ile Leu Asn Gly Ile Asn Asn Tyr Lys 
                      20                  25                  30          
          Asn Pro Lys Leu Thr Arg Met Leu Thr Phe Lys Phe Tyr Met Pro Lys 
                  35                  40                  45              
          Lys Ala Thr Glu Leu Lys His Leu Gln Cys Leu Glu Arg Glu Leu Lys 
              50                  55                  60                  
          Arg Leu Glu Glu Val Leu Asn Leu Ala Gln Ser Lys Asn Phe His Leu 
          65                  70                  75                  80  
          Arg Pro Arg Ser Leu Ile Ser Asn Ile Asn Val Ile Val Leu Glu Leu 
                          85                  90                  95      
          Lys Gly Ser Glu Thr Thr Phe Met Cys Glu Tyr Ala Asp Glu Thr Ala 
                      100                 105                 110         
          Thr Ile Val Glu Phe Leu Asn Asn Trp Ile Thr Phe Ser Gln Ser Ile 
                  115                 120                 125             
          Ile Ser Thr Leu Thr 
              130             
          <![CDATA[<210>  211]]>
          <![CDATA[<211>  133]]>
          <![CDATA[<212>  PRT]]>
          <![CDATA[<213>  人工序列]]>
          <![CDATA[<220>]]>
          <![CDATA[<223>  合成：IL-2-T3A-H16A-E61R-P65R-D84S-R120P-C125S]]>
          <![CDATA[<400>  211]]>
          Ala Pro Ala Ser Ser Ser Thr Lys Lys Thr Gln Leu Gln Leu Glu Ala 
          1               5                   10                  15      
          Leu Leu Leu Asp Leu Gln Met Ile Leu Asn Gly Ile Asn Asn Tyr Lys 
                      20                  25                  30          
          Asn Pro Lys Leu Thr Arg Met Leu Thr Phe Lys Phe Tyr Met Pro Lys 
                  35                  40                  45              
          Lys Ala Thr Glu Leu Lys His Leu Gln Cys Leu Glu Arg Glu Leu Lys 
              50                  55                  60                  
          Arg Leu Glu Glu Val Leu Asn Leu Ala Gln Ser Lys Asn Phe His Leu 
          65                  70                  75                  80  
          Arg Pro Arg Ser Leu Ile Ser Asn Ile Asn Val Ile Val Leu Glu Leu 
                          85                  90                  95      
          Lys Gly Ser Glu Thr Thr Phe Met Cys Glu Tyr Ala Asp Glu Thr Ala 
                      100                 105                 110         
          Thr Ile Val Glu Phe Leu Asn Pro Trp Ile Thr Phe Ser Gln Ser Ile 
                  115                 120                 125             
          Ile Ser Thr Leu Thr 
              130             
          <![CDATA[<210>  212]]>
          <![CDATA[<211>  133]]>
          <![CDATA[<212>  PRT]]>
          <![CDATA[<213>  人工序列]]>
          <![CDATA[<220>]]>
          <![CDATA[<223>  合成：IL-2-T3A-H16A-E61R-P65R-D84S-R120Q-C125S]]>
          <![CDATA[<400>  212]]>
          Ala Pro Ala Ser Ser Ser Thr Lys Lys Thr Gln Leu Gln Leu Glu Ala 
          1               5                   10                  15      
          Leu Leu Leu Asp Leu Gln Met Ile Leu Asn Gly Ile Asn Asn Tyr Lys 
                      20                  25                  30          
          Asn Pro Lys Leu Thr Arg Met Leu Thr Phe Lys Phe Tyr Met Pro Lys 
                  35                  40                  45              
          Lys Ala Thr Glu Leu Lys His Leu Gln Cys Leu Glu Arg Glu Leu Lys 
              50                  55                  60                  
          Arg Leu Glu Glu Val Leu Asn Leu Ala Gln Ser Lys Asn Phe His Leu 
          65                  70                  75                  80  
          Arg Pro Arg Ser Leu Ile Ser Asn Ile Asn Val Ile Val Leu Glu Leu 
                          85                  90                  95      
          Lys Gly Ser Glu Thr Thr Phe Met Cys Glu Tyr Ala Asp Glu Thr Ala 
                      100                 105                 110         
          Thr Ile Val Glu Phe Leu Asn Gln Trp Ile Thr Phe Ser Gln Ser Ile 
                  115                 120                 125             
          Ile Ser Thr Leu Thr 
              130             
          <![CDATA[<210>  213]]>
          <![CDATA[<211>  133]]>
          <![CDATA[<212>  PRT]]>
          <![CDATA[<213>  人工序列]]>
          <![CDATA[<220>]]>
          <![CDATA[<223>  合成：IL-2-T3A-H16A-E61R-P65R-D84S-R120S-C125S]]>
          <![CDATA[<400>  213]]>
          Ala Pro Ala Ser Ser Ser Thr Lys Lys Thr Gln Leu Gln Leu Glu Ala 
          1               5                   10                  15      
          Leu Leu Leu Asp Leu Gln Met Ile Leu Asn Gly Ile Asn Asn Tyr Lys 
                      20                  25                  30          
          Asn Pro Lys Leu Thr Arg Met Leu Thr Phe Lys Phe Tyr Met Pro Lys 
                  35                  40                  45              
          Lys Ala Thr Glu Leu Lys His Leu Gln Cys Leu Glu Arg Glu Leu Lys 
              50                  55                  60                  
          Arg Leu Glu Glu Val Leu Asn Leu Ala Gln Ser Lys Asn Phe His Leu 
          65                  70                  75                  80  
          Arg Pro Arg Ser Leu Ile Ser Asn Ile Asn Val Ile Val Leu Glu Leu 
                          85                  90                  95      
          Lys Gly Ser Glu Thr Thr Phe Met Cys Glu Tyr Ala Asp Glu Thr Ala 
                      100                 105                 110         
          Thr Ile Val Glu Phe Leu Asn Ser Trp Ile Thr Phe Ser Gln Ser Ile 
                  115                 120                 125             
          Ile Ser Thr Leu Thr 
              130             
          <![CDATA[<210>  214]]>
          <![CDATA[<211>  133]]>
          <![CDATA[<212>  PRT]]>
          <![CDATA[<213>  人工序列]]>
          <![CDATA[<220>]]>
          <![CDATA[<223>  合成：IL-2-T3A-H16A-E61R-P65R-D84S-R120T-C125S]]>
          <![CDATA[<400>  214]]>
          Ala Pro Ala Ser Ser Ser Thr Lys Lys Thr Gln Leu Gln Leu Glu Ala 
          1               5                   10                  15      
          Leu Leu Leu Asp Leu Gln Met Ile Leu Asn Gly Ile Asn Asn Tyr Lys 
                      20                  25                  30          
          Asn Pro Lys Leu Thr Arg Met Leu Thr Phe Lys Phe Tyr Met Pro Lys 
                  35                  40                  45              
          Lys Ala Thr Glu Leu Lys His Leu Gln Cys Leu Glu Arg Glu Leu Lys 
              50                  55                  60                  
          Arg Leu Glu Glu Val Leu Asn Leu Ala Gln Ser Lys Asn Phe His Leu 
          65                  70                  75                  80  
          Arg Pro Arg Ser Leu Ile Ser Asn Ile Asn Val Ile Val Leu Glu Leu 
                          85                  90                  95      
          Lys Gly Ser Glu Thr Thr Phe Met Cys Glu Tyr Ala Asp Glu Thr Ala 
                      100                 105                 110         
          Thr Ile Val Glu Phe Leu Asn Thr Trp Ile Thr Phe Ser Gln Ser Ile 
                  115                 120                 125             
          Ile Ser Thr Leu Thr 
              130             
          <![CDATA[<210>  215]]>
          <![CDATA[<211>  133]]>
          <![CDATA[<212>  PRT]]>
          <![CDATA[<213>  人工序列]]>
          <![CDATA[<220>]]>
          <![CDATA[<223>  合成：IL-2-T3A-H16A-E61R-P65R-D84S-R120V-C125S]]>
          <![CDATA[<400>  215]]>
          Ala Pro Ala Ser Ser Ser Thr Lys Lys Thr Gln Leu Gln Leu Glu Ala 
          1               5                   10                  15      
          Leu Leu Leu Asp Leu Gln Met Ile Leu Asn Gly Ile Asn Asn Tyr Lys 
                      20                  25                  30          
          Asn Pro Lys Leu Thr Arg Met Leu Thr Phe Lys Phe Tyr Met Pro Lys 
                  35                  40                  45              
          Lys Ala Thr Glu Leu Lys His Leu Gln Cys Leu Glu Arg Glu Leu Lys 
              50                  55                  60                  
          Arg Leu Glu Glu Val Leu Asn Leu Ala Gln Ser Lys Asn Phe His Leu 
          65                  70                  75                  80  
          Arg Pro Arg Ser Leu Ile Ser Asn Ile Asn Val Ile Val Leu Glu Leu 
                          85                  90                  95      
          Lys Gly Ser Glu Thr Thr Phe Met Cys Glu Tyr Ala Asp Glu Thr Ala 
                      100                 105                 110         
          Thr Ile Val Glu Phe Leu Asn Val Trp Ile Thr Phe Ser Gln Ser Ile 
                  115                 120                 125             
          Ile Ser Thr Leu Thr 
              130             
          <![CDATA[<210>  216]]>
          <![CDATA[<211>  133]]>
          <![CDATA[<212>  PRT]]>
          <![CDATA[<213>  人工序列]]>
          <![CDATA[<220>]]>
          <![CDATA[<223>  合成：IL-2-T3A-H16A-E61R-P65R-D84S-R120Y-C125S]]>
          <![CDATA[<400>  216]]>
          Ala Pro Ala Ser Ser Ser Thr Lys Lys Thr Gln Leu Gln Leu Glu Ala 
          1               5                   10                  15      
          Leu Leu Leu Asp Leu Gln Met Ile Leu Asn Gly Ile Asn Asn Tyr Lys 
                      20                  25                  30          
          Asn Pro Lys Leu Thr Arg Met Leu Thr Phe Lys Phe Tyr Met Pro Lys 
                  35                  40                  45              
          Lys Ala Thr Glu Leu Lys His Leu Gln Cys Leu Glu Arg Glu Leu Lys 
              50                  55                  60                  
          Arg Leu Glu Glu Val Leu Asn Leu Ala Gln Ser Lys Asn Phe His Leu 
          65                  70                  75                  80  
          Arg Pro Arg Ser Leu Ile Ser Asn Ile Asn Val Ile Val Leu Glu Leu 
                          85                  90                  95      
          Lys Gly Ser Glu Thr Thr Phe Met Cys Glu Tyr Ala Asp Glu Thr Ala 
                      100                 105                 110         
          Thr Ile Val Glu Phe Leu Asn Tyr Trp Ile Thr Phe Ser Gln Ser Ile 
                  115                 120                 125             
          Ile Ser Thr Leu Thr 
              130             
          <![CDATA[<210>  217]]>
          <![CDATA[<211>  133]]>
          <![CDATA[<212>  PRT]]>
          <![CDATA[<213>  人工序列]]>
          <![CDATA[<220>]]>
          <![CDATA[<223>  合成：IL-2-T3A-H16A-E61R-P65R-D84S-T123D-C125S]]>
          <![CDATA[<400>  217]]>
          Ala Pro Ala Ser Ser Ser Thr Lys Lys Thr Gln Leu Gln Leu Glu Ala 
          1               5                   10                  15      
          Leu Leu Leu Asp Leu Gln Met Ile Leu Asn Gly Ile Asn Asn Tyr Lys 
                      20                  25                  30          
          Asn Pro Lys Leu Thr Arg Met Leu Thr Phe Lys Phe Tyr Met Pro Lys 
                  35                  40                  45              
          Lys Ala Thr Glu Leu Lys His Leu Gln Cys Leu Glu Arg Glu Leu Lys 
              50                  55                  60                  
          Arg Leu Glu Glu Val Leu Asn Leu Ala Gln Ser Lys Asn Phe His Leu 
          65                  70                  75                  80  
          Arg Pro Arg Ser Leu Ile Ser Asn Ile Asn Val Ile Val Leu Glu Leu 
                          85                  90                  95      
          Lys Gly Ser Glu Thr Thr Phe Met Cys Glu Tyr Ala Asp Glu Thr Ala 
                      100                 105                 110         
          Thr Ile Val Glu Phe Leu Asn Arg Trp Ile Asp Phe Ser Gln Ser Ile 
                  115                 120                 125             
          Ile Ser Thr Leu Thr 
              130             
          <![CDATA[<210>  218]]>
          <![CDATA[<211>  133]]>
          <![CDATA[<212>  PRT]]>
          <![CDATA[<213>  人工序列]]>
          <![CDATA[<220>]]>
          <![CDATA[<223>  合成：IL-2-T3A-H16A-E61R-P65R-D84S-T123E-C125S]]>
          <![CDATA[<400>  218]]>
          Ala Pro Ala Ser Ser Ser Thr Lys Lys Thr Gln Leu Gln Leu Glu Ala 
          1               5                   10                  15      
          Leu Leu Leu Asp Leu Gln Met Ile Leu Asn Gly Ile Asn Asn Tyr Lys 
                      20                  25                  30          
          Asn Pro Lys Leu Thr Arg Met Leu Thr Phe Lys Phe Tyr Met Pro Lys 
                  35                  40                  45              
          Lys Ala Thr Glu Leu Lys His Leu Gln Cys Leu Glu Arg Glu Leu Lys 
              50                  55                  60                  
          Arg Leu Glu Glu Val Leu Asn Leu Ala Gln Ser Lys Asn Phe His Leu 
          65                  70                  75                  80  
          Arg Pro Arg Ser Leu Ile Ser Asn Ile Asn Val Ile Val Leu Glu Leu 
                          85                  90                  95      
          Lys Gly Ser Glu Thr Thr Phe Met Cys Glu Tyr Ala Asp Glu Thr Ala 
                      100                 105                 110         
          Thr Ile Val Glu Phe Leu Asn Arg Trp Ile Glu Phe Ser Gln Ser Ile 
                  115                 120                 125             
          Ile Ser Thr Leu Thr 
              130             
          <![CDATA[<210>  219]]>
          <![CDATA[<211>  133]]>
          <![CDATA[<212>  PRT]]>
          <![CDATA[<213>  人工序列]]>
          <![CDATA[<220>]]>
          <![CDATA[<223>  合成：IL-2-T3A-H16A-E61R-P65R-D84S-T123H-C125S]]>
          <![CDATA[<400>  219]]>
          Ala Pro Ala Ser Ser Ser Thr Lys Lys Thr Gln Leu Gln Leu Glu Ala 
          1               5                   10                  15      
          Leu Leu Leu Asp Leu Gln Met Ile Leu Asn Gly Ile Asn Asn Tyr Lys 
                      20                  25                  30          
          Asn Pro Lys Leu Thr Arg Met Leu Thr Phe Lys Phe Tyr Met Pro Lys 
                  35                  40                  45              
          Lys Ala Thr Glu Leu Lys His Leu Gln Cys Leu Glu Arg Glu Leu Lys 
              50                  55                  60                  
          Arg Leu Glu Glu Val Leu Asn Leu Ala Gln Ser Lys Asn Phe His Leu 
          65                  70                  75                  80  
          Arg Pro Arg Ser Leu Ile Ser Asn Ile Asn Val Ile Val Leu Glu Leu 
                          85                  90                  95      
          Lys Gly Ser Glu Thr Thr Phe Met Cys Glu Tyr Ala Asp Glu Thr Ala 
                      100                 105                 110         
          Thr Ile Val Glu Phe Leu Asn Arg Trp Ile His Phe Ser Gln Ser Ile 
                  115                 120                 125             
          Ile Ser Thr Leu Thr 
              130             
          <![CDATA[<210>  220]]>
          <![CDATA[<211>  133]]>
          <![CDATA[<212>  PRT]]>
          <![CDATA[<213>  人工序列]]>
          <![CDATA[<220>]]>
          <![CDATA[<223>  合成：IL-2-T3A-H16A-E61R-P65R-D84S-T123K-C125S]]>
          <![CDATA[<400>  220]]>
          Ala Pro Ala Ser Ser Ser Thr Lys Lys Thr Gln Leu Gln Leu Glu Ala 
          1               5                   10                  15      
          Leu Leu Leu Asp Leu Gln Met Ile Leu Asn Gly Ile Asn Asn Tyr Lys 
                      20                  25                  30          
          Asn Pro Lys Leu Thr Arg Met Leu Thr Phe Lys Phe Tyr Met Pro Lys 
                  35                  40                  45              
          Lys Ala Thr Glu Leu Lys His Leu Gln Cys Leu Glu Arg Glu Leu Lys 
              50                  55                  60                  
          Arg Leu Glu Glu Val Leu Asn Leu Ala Gln Ser Lys Asn Phe His Leu 
          65                  70                  75                  80  
          Arg Pro Arg Ser Leu Ile Ser Asn Ile Asn Val Ile Val Leu Glu Leu 
                          85                  90                  95      
          Lys Gly Ser Glu Thr Thr Phe Met Cys Glu Tyr Ala Asp Glu Thr Ala 
                      100                 105                 110         
          Thr Ile Val Glu Phe Leu Asn Arg Trp Ile Lys Phe Ser Gln Ser Ile 
                  115                 120                 125             
          Ile Ser Thr Leu Thr 
              130             
          <![CDATA[<210>  221]]>
          <![CDATA[<211>  133]]>
          <![CDATA[<212>  PRT]]>
          <![CDATA[<213>  人工序列]]>
          <![CDATA[<220>]]>
          <![CDATA[<223>  合成：IL-2-T3A-H16A-E61R-P65R-D84S-T123N-C125S]]>
          <![CDATA[<400>  221]]>
          Ala Pro Ala Ser Ser Ser Thr Lys Lys Thr Gln Leu Gln Leu Glu Ala 
          1               5                   10                  15      
          Leu Leu Leu Asp Leu Gln Met Ile Leu Asn Gly Ile Asn Asn Tyr Lys 
                      20                  25                  30          
          Asn Pro Lys Leu Thr Arg Met Leu Thr Phe Lys Phe Tyr Met Pro Lys 
                  35                  40                  45              
          Lys Ala Thr Glu Leu Lys His Leu Gln Cys Leu Glu Arg Glu Leu Lys 
              50                  55                  60                  
          Arg Leu Glu Glu Val Leu Asn Leu Ala Gln Ser Lys Asn Phe His Leu 
          65                  70                  75                  80  
          Arg Pro Arg Ser Leu Ile Ser Asn Ile Asn Val Ile Val Leu Glu Leu 
                          85                  90                  95      
          Lys Gly Ser Glu Thr Thr Phe Met Cys Glu Tyr Ala Asp Glu Thr Ala 
                      100                 105                 110         
          Thr Ile Val Glu Phe Leu Asn Arg Trp Ile Asn Phe Ser Gln Ser Ile 
                  115                 120                 125             
          Ile Ser Thr Leu Thr 
              130             
          <![CDATA[<210>  222]]>
          <![CDATA[<211>  133]]>
          <![CDATA[<212>  PRT]]>
          <![CDATA[<213>  人工序列]]>
          <![CDATA[<220>]]>
          <![CDATA[<223>  合成：IL-2-T3A-H16A-E61R-P65R-D84S-T123Q-C125S]]>
          <![CDATA[<400>  222]]>
          Ala Pro Ala Ser Ser Ser Thr Lys Lys Thr Gln Leu Gln Leu Glu Ala 
          1               5                   10                  15      
          Leu Leu Leu Asp Leu Gln Met Ile Leu Asn Gly Ile Asn Asn Tyr Lys 
                      20                  25                  30          
          Asn Pro Lys Leu Thr Arg Met Leu Thr Phe Lys Phe Tyr Met Pro Lys 
                  35                  40                  45              
          Lys Ala Thr Glu Leu Lys His Leu Gln Cys Leu Glu Arg Glu Leu Lys 
              50                  55                  60                  
          Arg Leu Glu Glu Val Leu Asn Leu Ala Gln Ser Lys Asn Phe His Leu 
          65                  70                  75                  80  
          Arg Pro Arg Ser Leu Ile Ser Asn Ile Asn Val Ile Val Leu Glu Leu 
                          85                  90                  95      
          Lys Gly Ser Glu Thr Thr Phe Met Cys Glu Tyr Ala Asp Glu Thr Ala 
                      100                 105                 110         
          Thr Ile Val Glu Phe Leu Asn Arg Trp Ile Gln Phe Ser Gln Ser Ile 
                  115                 120                 125             
          Ile Ser Thr Leu Thr 
              130             
          <![CDATA[<210>  223]]>
          <![CDATA[<211>  133]]>
          <![CDATA[<212>  PRT]]>
          <![CDATA[<213>  人工序列]]>
          <![CDATA[<220>]]>
          <![CDATA[<223>  合成：IL-2-T3A-H16A-E61R-P65R-D84S-T123R-C125S]]>
          <![CDATA[<400>  223]]>
          Ala Pro Ala Ser Ser Ser Thr Lys Lys Thr Gln Leu Gln Leu Glu Ala 
          1               5                   10                  15      
          Leu Leu Leu Asp Leu Gln Met Ile Leu Asn Gly Ile Asn Asn Tyr Lys 
                      20                  25                  30          
          Asn Pro Lys Leu Thr Arg Met Leu Thr Phe Lys Phe Tyr Met Pro Lys 
                  35                  40                  45              
          Lys Ala Thr Glu Leu Lys His Leu Gln Cys Leu Glu Arg Glu Leu Lys 
              50                  55                  60                  
          Arg Leu Glu Glu Val Leu Asn Leu Ala Gln Ser Lys Asn Phe His Leu 
          65                  70                  75                  80  
          Arg Pro Arg Ser Leu Ile Ser Asn Ile Asn Val Ile Val Leu Glu Leu 
                          85                  90                  95      
          Lys Gly Ser Glu Thr Thr Phe Met Cys Glu Tyr Ala Asp Glu Thr Ala 
                      100                 105                 110         
          Thr Ile Val Glu Phe Leu Asn Arg Trp Ile Arg Phe Ser Gln Ser Ile 
                  115                 120                 125             
          Ile Ser Thr Leu Thr 
              130             
          <![CDATA[<210>  224]]>
          <![CDATA[<211>  133]]>
          <![CDATA[<212>  PRT]]>
          <![CDATA[<213>  人工序列]]>
          <![CDATA[<220>]]>
          <![CDATA[<223>  合成：IL-2-T3A-H16A-E61R-P65R-D84S-C125S-S130D]]>
          <![CDATA[<400>  224]]>
          Ala Pro Ala Ser Ser Ser Thr Lys Lys Thr Gln Leu Gln Leu Glu Ala 
          1               5                   10                  15      
          Leu Leu Leu Asp Leu Gln Met Ile Leu Asn Gly Ile Asn Asn Tyr Lys 
                      20                  25                  30          
          Asn Pro Lys Leu Thr Arg Met Leu Thr Phe Lys Phe Tyr Met Pro Lys 
                  35                  40                  45              
          Lys Ala Thr Glu Leu Lys His Leu Gln Cys Leu Glu Arg Glu Leu Lys 
              50                  55                  60                  
          Arg Leu Glu Glu Val Leu Asn Leu Ala Gln Ser Lys Asn Phe His Leu 
          65                  70                  75                  80  
          Arg Pro Arg Ser Leu Ile Ser Asn Ile Asn Val Ile Val Leu Glu Leu 
                          85                  90                  95      
          Lys Gly Ser Glu Thr Thr Phe Met Cys Glu Tyr Ala Asp Glu Thr Ala 
                      100                 105                 110         
          Thr Ile Val Glu Phe Leu Asn Arg Trp Ile Thr Phe Ser Gln Ser Ile 
                  115                 120                 125             
          Ile Asp Thr Leu Thr 
              130             
          <![CDATA[<210>  225]]>
          <![CDATA[<211>  133]]>
          <![CDATA[<212>  PRT]]>
          <![CDATA[<213>  人工序列]]>
          <![CDATA[<220>]]>
          <![CDATA[<223>  合成：IL-2-T3A-H16A-E61R-P65R-D84S-C125S-S130E]]>
          <![CDATA[<400>  225]]>
          Ala Pro Ala Ser Ser Ser Thr Lys Lys Thr Gln Leu Gln Leu Glu Ala 
          1               5                   10                  15      
          Leu Leu Leu Asp Leu Gln Met Ile Leu Asn Gly Ile Asn Asn Tyr Lys 
                      20                  25                  30          
          Asn Pro Lys Leu Thr Arg Met Leu Thr Phe Lys Phe Tyr Met Pro Lys 
                  35                  40                  45              
          Lys Ala Thr Glu Leu Lys His Leu Gln Cys Leu Glu Arg Glu Leu Lys 
              50                  55                  60                  
          Arg Leu Glu Glu Val Leu Asn Leu Ala Gln Ser Lys Asn Phe His Leu 
          65                  70                  75                  80  
          Arg Pro Arg Ser Leu Ile Ser Asn Ile Asn Val Ile Val Leu Glu Leu 
                          85                  90                  95      
          Lys Gly Ser Glu Thr Thr Phe Met Cys Glu Tyr Ala Asp Glu Thr Ala 
                      100                 105                 110         
          Thr Ile Val Glu Phe Leu Asn Arg Trp Ile Thr Phe Ser Gln Ser Ile 
                  115                 120                 125             
          Ile Glu Thr Leu Thr 
              130             
          <![CDATA[<210>  226]]>
          <![CDATA[<211>  133]]>
          <![CDATA[<212>  PRT]]>
          <![CDATA[<213>  人工序列]]>
          <![CDATA[<220>]]>
          <![CDATA[<223>  合成：IL-2-T3A-H16A-E61R-P65R-D84S-C125S-S130K]]>
          <![CDATA[<400>  226]]>
          Ala Pro Ala Ser Ser Ser Thr Lys Lys Thr Gln Leu Gln Leu Glu Ala 
          1               5                   10                  15      
          Leu Leu Leu Asp Leu Gln Met Ile Leu Asn Gly Ile Asn Asn Tyr Lys 
                      20                  25                  30          
          Asn Pro Lys Leu Thr Arg Met Leu Thr Phe Lys Phe Tyr Met Pro Lys 
                  35                  40                  45              
          Lys Ala Thr Glu Leu Lys His Leu Gln Cys Leu Glu Arg Glu Leu Lys 
              50                  55                  60                  
          Arg Leu Glu Glu Val Leu Asn Leu Ala Gln Ser Lys Asn Phe His Leu 
          65                  70                  75                  80  
          Arg Pro Arg Ser Leu Ile Ser Asn Ile Asn Val Ile Val Leu Glu Leu 
                          85                  90                  95      
          Lys Gly Ser Glu Thr Thr Phe Met Cys Glu Tyr Ala Asp Glu Thr Ala 
                      100                 105                 110         
          Thr Ile Val Glu Phe Leu Asn Arg Trp Ile Thr Phe Ser Gln Ser Ile 
                  115                 120                 125             
          Ile Lys Thr Leu Thr 
              130             
          <![CDATA[<210>  227]]>
          <![CDATA[<211>  133]]>
          <![CDATA[<212>  PRT]]>
          <![CDATA[<213>  人工序列]]>
          <![CDATA[<220>]]>
          <![CDATA[<223>  合成：IL-2-T3A-H16A-E61R-P65R-D84S-C125S-S130N]]>
          <![CDATA[<400>  227]]>
          Ala Pro Ala Ser Ser Ser Thr Lys Lys Thr Gln Leu Gln Leu Glu Ala 
          1               5                   10                  15      
          Leu Leu Leu Asp Leu Gln Met Ile Leu Asn Gly Ile Asn Asn Tyr Lys 
                      20                  25                  30          
          Asn Pro Lys Leu Thr Arg Met Leu Thr Phe Lys Phe Tyr Met Pro Lys 
                  35                  40                  45              
          Lys Ala Thr Glu Leu Lys His Leu Gln Cys Leu Glu Arg Glu Leu Lys 
              50                  55                  60                  
          Arg Leu Glu Glu Val Leu Asn Leu Ala Gln Ser Lys Asn Phe His Leu 
          65                  70                  75                  80  
          Arg Pro Arg Ser Leu Ile Ser Asn Ile Asn Val Ile Val Leu Glu Leu 
                          85                  90                  95      
          Lys Gly Ser Glu Thr Thr Phe Met Cys Glu Tyr Ala Asp Glu Thr Ala 
                      100                 105                 110         
          Thr Ile Val Glu Phe Leu Asn Arg Trp Ile Thr Phe Ser Gln Ser Ile 
                  115                 120                 125             
          Ile Asn Thr Leu Thr 
              130             
          <![CDATA[<210>  228]]>
          <![CDATA[<211>  133]]>
          <![CDATA[<212>  PRT]]>
          <![CDATA[<213>  人工序列]]>
          <![CDATA[<220>]]>
          <![CDATA[<223>  合成：IL-2-T3A-H16A-E61R-P65R-D84S-C125S-S130Q]]>
          <![CDATA[<400>  228]]>
          Ala Pro Ala Ser Ser Ser Thr Lys Lys Thr Gln Leu Gln Leu Glu Ala 
          1               5                   10                  15      
          Leu Leu Leu Asp Leu Gln Met Ile Leu Asn Gly Ile Asn Asn Tyr Lys 
                      20                  25                  30          
          Asn Pro Lys Leu Thr Arg Met Leu Thr Phe Lys Phe Tyr Met Pro Lys 
                  35                  40                  45              
          Lys Ala Thr Glu Leu Lys His Leu Gln Cys Leu Glu Arg Glu Leu Lys 
              50                  55                  60                  
          Arg Leu Glu Glu Val Leu Asn Leu Ala Gln Ser Lys Asn Phe His Leu 
          65                  70                  75                  80  
          Arg Pro Arg Ser Leu Ile Ser Asn Ile Asn Val Ile Val Leu Glu Leu 
                          85                  90                  95      
          Lys Gly Ser Glu Thr Thr Phe Met Cys Glu Tyr Ala Asp Glu Thr Ala 
                      100                 105                 110         
          Thr Ile Val Glu Phe Leu Asn Arg Trp Ile Thr Phe Ser Gln Ser Ile 
                  115                 120                 125             
          Ile Gln Thr Leu Thr 
              130             
          <![CDATA[<210>  229]]>
          <![CDATA[<211>  133]]>
          <![CDATA[<212>  PRT]]>
          <![CDATA[<213>  人工序列]]>
          <![CDATA[<220>]]>
          <![CDATA[<223>  合成：IL-2-T3A-H16A-E61R-P65R-D84S-C125S-S130R]]>
          <![CDATA[<400>  229]]>
          Ala Pro Ala Ser Ser Ser Thr Lys Lys Thr Gln Leu Gln Leu Glu Ala 
          1               5                   10                  15      
          Leu Leu Leu Asp Leu Gln Met Ile Leu Asn Gly Ile Asn Asn Tyr Lys 
                      20                  25                  30          
          Asn Pro Lys Leu Thr Arg Met Leu Thr Phe Lys Phe Tyr Met Pro Lys 
                  35                  40                  45              
          Lys Ala Thr Glu Leu Lys His Leu Gln Cys Leu Glu Arg Glu Leu Lys 
              50                  55                  60                  
          Arg Leu Glu Glu Val Leu Asn Leu Ala Gln Ser Lys Asn Phe His Leu 
          65                  70                  75                  80  
          Arg Pro Arg Ser Leu Ile Ser Asn Ile Asn Val Ile Val Leu Glu Leu 
                          85                  90                  95      
          Lys Gly Ser Glu Thr Thr Phe Met Cys Glu Tyr Ala Asp Glu Thr Ala 
                      100                 105                 110         
          Thr Ile Val Glu Phe Leu Asn Arg Trp Ile Thr Phe Ser Gln Ser Ile 
                  115                 120                 125             
          Ile Arg Thr Leu Thr 
              130             
          <![CDATA[<210>  230]]>
          <![CDATA[<211>  133]]>
          <![CDATA[<212>  PRT]]>
          <![CDATA[<213>  人工序列]]>
          <![CDATA[<220>]]>
          <![CDATA[<223>  合成：IL-2-T3A-H16A-E61R-P65R-D84S-C125S-S127D]]>
          <![CDATA[<400>  230]]>
          Ala Pro Ala Ser Ser Ser Thr Lys Lys Thr Gln Leu Gln Leu Glu Ala 
          1               5                   10                  15      
          Leu Leu Leu Asp Leu Gln Met Ile Leu Asn Gly Ile Asn Asn Tyr Lys 
                      20                  25                  30          
          Asn Pro Lys Leu Thr Arg Met Leu Thr Phe Lys Phe Tyr Met Pro Lys 
                  35                  40                  45              
          Lys Ala Thr Glu Leu Lys His Leu Gln Cys Leu Glu Arg Glu Leu Lys 
              50                  55                  60                  
          Arg Leu Glu Glu Val Leu Asn Leu Ala Gln Ser Lys Asn Phe His Leu 
          65                  70                  75                  80  
          Arg Pro Arg Ser Leu Ile Ser Asn Ile Asn Val Ile Val Leu Glu Leu 
                          85                  90                  95      
          Lys Gly Ser Glu Thr Thr Phe Met Cys Glu Tyr Ala Asp Glu Thr Ala 
                      100                 105                 110         
          Thr Ile Val Glu Phe Leu Asn Arg Trp Ile Thr Phe Ser Gln Asp Ile 
                  115                 120                 125             
          Ile Ser Thr Leu Thr 
              130             
          <![CDATA[<210>  231]]>
          <![CDATA[<211>  133]]>
          <![CDATA[<212>  PRT]]>
          <![CDATA[<213>  人工序列]]>
          <![CDATA[<220>]]>
          <![CDATA[<223>  合成：IL-2-T3A-H16A-E61R-P65R-D84S-C125S-S127E]]>
          <![CDATA[<400>  231]]>
          Ala Pro Ala Ser Ser Ser Thr Lys Lys Thr Gln Leu Gln Leu Glu Ala 
          1               5                   10                  15      
          Leu Leu Leu Asp Leu Gln Met Ile Leu Asn Gly Ile Asn Asn Tyr Lys 
                      20                  25                  30          
          Asn Pro Lys Leu Thr Arg Met Leu Thr Phe Lys Phe Tyr Met Pro Lys 
                  35                  40                  45              
          Lys Ala Thr Glu Leu Lys His Leu Gln Cys Leu Glu Arg Glu Leu Lys 
              50                  55                  60                  
          Arg Leu Glu Glu Val Leu Asn Leu Ala Gln Ser Lys Asn Phe His Leu 
          65                  70                  75                  80  
          Arg Pro Arg Ser Leu Ile Ser Asn Ile Asn Val Ile Val Leu Glu Leu 
                          85                  90                  95      
          Lys Gly Ser Glu Thr Thr Phe Met Cys Glu Tyr Ala Asp Glu Thr Ala 
                      100                 105                 110         
          Thr Ile Val Glu Phe Leu Asn Arg Trp Ile Thr Phe Ser Gln Glu Ile 
                  115                 120                 125             
          Ile Ser Thr Leu Thr 
              130             
          <![CDATA[<210>  232]]>
          <![CDATA[<211>  133]]>
          <![CDATA[<212>  PRT]]>
          <![CDATA[<213>  人工序列]]>
          <![CDATA[<220>]]>
          <![CDATA[<223>  合成：IL-2-T3A-H16A-E61R-P65R-D84S-C125S-S127H]]>
          <![CDATA[<400>  232]]>
          Ala Pro Ala Ser Ser Ser Thr Lys Lys Thr Gln Leu Gln Leu Glu Ala 
          1               5                   10                  15      
          Leu Leu Leu Asp Leu Gln Met Ile Leu Asn Gly Ile Asn Asn Tyr Lys 
                      20                  25                  30          
          Asn Pro Lys Leu Thr Arg Met Leu Thr Phe Lys Phe Tyr Met Pro Lys 
                  35                  40                  45              
          Lys Ala Thr Glu Leu Lys His Leu Gln Cys Leu Glu Arg Glu Leu Lys 
              50                  55                  60                  
          Arg Leu Glu Glu Val Leu Asn Leu Ala Gln Ser Lys Asn Phe His Leu 
          65                  70                  75                  80  
          Arg Pro Arg Ser Leu Ile Ser Asn Ile Asn Val Ile Val Leu Glu Leu 
                          85                  90                  95      
          Lys Gly Ser Glu Thr Thr Phe Met Cys Glu Tyr Ala Asp Glu Thr Ala 
                      100                 105                 110         
          Thr Ile Val Glu Phe Leu Asn Arg Trp Ile Thr Phe Ser Gln His Ile 
                  115                 120                 125             
          Ile Ser Thr Leu Thr 
              130             
          <![CDATA[<210>  233]]>
          <![CDATA[<211>  133]]>
          <![CDATA[<212>  PRT]]>
          <![CDATA[<213>  人工序列]]>
          <![CDATA[<220>]]>
          <![CDATA[<223>  合成：IL-2-T3A-H16A-E61R-P65R-D84S-C125S-S127P]]>
          <![CDATA[<400>  233]]>
          Ala Pro Ala Ser Ser Ser Thr Lys Lys Thr Gln Leu Gln Leu Glu Ala 
          1               5                   10                  15      
          Leu Leu Leu Asp Leu Gln Met Ile Leu Asn Gly Ile Asn Asn Tyr Lys 
                      20                  25                  30          
          Asn Pro Lys Leu Thr Arg Met Leu Thr Phe Lys Phe Tyr Met Pro Lys 
                  35                  40                  45              
          Lys Ala Thr Glu Leu Lys His Leu Gln Cys Leu Glu Arg Glu Leu Lys 
              50                  55                  60                  
          Arg Leu Glu Glu Val Leu Asn Leu Ala Gln Ser Lys Asn Phe His Leu 
          65                  70                  75                  80  
          Arg Pro Arg Ser Leu Ile Ser Asn Ile Asn Val Ile Val Leu Glu Leu 
                          85                  90                  95      
          Lys Gly Ser Glu Thr Thr Phe Met Cys Glu Tyr Ala Asp Glu Thr Ala 
                      100                 105                 110         
          Thr Ile Val Glu Phe Leu Asn Arg Trp Ile Thr Phe Ser Gln Pro Ile 
                  115                 120                 125             
          Ile Ser Thr Leu Thr 
              130             
          <![CDATA[<210>  234]]>
          <![CDATA[<211>  133]]>
          <![CDATA[<212>  PRT]]>
          <![CDATA[<213>  人工序列]]>
          <![CDATA[<220>]]>
          <![CDATA[<223>  合成：IL-2-T3A-H16A-E61R-P65R-D84S-C125S-S127Q]]>
          <![CDATA[<400>  234]]>
          Ala Pro Ala Ser Ser Ser Thr Lys Lys Thr Gln Leu Gln Leu Glu Ala 
          1               5                   10                  15      
          Leu Leu Leu Asp Leu Gln Met Ile Leu Asn Gly Ile Asn Asn Tyr Lys 
                      20                  25                  30          
          Asn Pro Lys Leu Thr Arg Met Leu Thr Phe Lys Phe Tyr Met Pro Lys 
                  35                  40                  45              
          Lys Ala Thr Glu Leu Lys His Leu Gln Cys Leu Glu Arg Glu Leu Lys 
              50                  55                  60                  
          Arg Leu Glu Glu Val Leu Asn Leu Ala Gln Ser Lys Asn Phe His Leu 
          65                  70                  75                  80  
          Arg Pro Arg Ser Leu Ile Ser Asn Ile Asn Val Ile Val Leu Glu Leu 
                          85                  90                  95      
          Lys Gly Ser Glu Thr Thr Phe Met Cys Glu Tyr Ala Asp Glu Thr Ala 
                      100                 105                 110         
          Thr Ile Val Glu Phe Leu Asn Arg Trp Ile Thr Phe Ser Gln Gln Ile 
                  115                 120                 125             
          Ile Ser Thr Leu Thr 
              130             
          <![CDATA[<210>  235]]>
          <![CDATA[<211>  133]]>
          <![CDATA[<212>  PRT]]>
          <![CDATA[<213>  人工序列]]>
          <![CDATA[<220>]]>
          <![CDATA[<223>  合成：IL-2-T3A-H16A-E61R-P65R-D84S-C125S-S127R]]>
          <![CDATA[<400>  235]]>
          Ala Pro Ala Ser Ser Ser Thr Lys Lys Thr Gln Leu Gln Leu Glu Ala 
          1               5                   10                  15      
          Leu Leu Leu Asp Leu Gln Met Ile Leu Asn Gly Ile Asn Asn Tyr Lys 
                      20                  25                  30          
          Asn Pro Lys Leu Thr Arg Met Leu Thr Phe Lys Phe Tyr Met Pro Lys 
                  35                  40                  45              
          Lys Ala Thr Glu Leu Lys His Leu Gln Cys Leu Glu Arg Glu Leu Lys 
              50                  55                  60                  
          Arg Leu Glu Glu Val Leu Asn Leu Ala Gln Ser Lys Asn Phe His Leu 
          65                  70                  75                  80  
          Arg Pro Arg Ser Leu Ile Ser Asn Ile Asn Val Ile Val Leu Glu Leu 
                          85                  90                  95      
          Lys Gly Ser Glu Thr Thr Phe Met Cys Glu Tyr Ala Asp Glu Thr Ala 
                      100                 105                 110         
          Thr Ile Val Glu Phe Leu Asn Arg Trp Ile Thr Phe Ser Gln Arg Ile 
                  115                 120                 125             
          Ile Ser Thr Leu Thr 
              130             
          <![CDATA[<210>  236]]>
          <![CDATA[<211>  133]]>
          <![CDATA[<212>  PRT]]>
          <![CDATA[<213>  人工序列]]>
          <![CDATA[<220>]]>
          <![CDATA[<223>  合成：IL-2-T3A-H16A-L19A-Q22A-R38A-P65R-D84S-C125S]]>
          <![CDATA[<400>  236]]>
          Ala Pro Ala Ser Ser Ser Thr Lys Lys Thr Gln Leu Gln Leu Glu Ala 
          1               5                   10                  15      
          Leu Leu Ala Asp Leu Ala Met Ile Leu Asn Gly Ile Asn Asn Tyr Lys 
                      20                  25                  30          
          Asn Pro Lys Leu Thr Ala Met Leu Thr Phe Lys Phe Tyr Met Pro Lys 
                  35                  40                  45              
          Lys Ala Thr Glu Leu Lys His Leu Gln Cys Leu Glu Glu Glu Leu Lys 
              50                  55                  60                  
          Arg Leu Glu Glu Val Leu Asn Leu Ala Gln Ser Lys Asn Phe His Leu 
          65                  70                  75                  80  
          Arg Pro Arg Ser Leu Ile Ser Asn Ile Asn Val Ile Val Leu Glu Leu 
                          85                  90                  95      
          Lys Gly Ser Glu Thr Thr Phe Met Cys Glu Tyr Ala Asp Glu Thr Ala 
                      100                 105                 110         
          Thr Ile Val Glu Phe Leu Asn Arg Trp Ile Thr Phe Ser Gln Ser Ile 
                  115                 120                 125             
          Ile Ser Thr Leu Thr 
              130             
          <![CDATA[<210>  237]]>
          <![CDATA[<211>  133]]>
          <![CDATA[<212>  PRT]]>
          <![CDATA[<213>  人工序列]]>
          <![CDATA[<220>]]>
          <![CDATA[<223>  合成：IL-2-T3A-H16A-L19A-R38A-P65R-D84S-R120A-C125S]]>
          <![CDATA[<400>  237]]>
          Ala Pro Ala Ser Ser Ser Thr Lys Lys Thr Gln Leu Gln Leu Glu Ala 
          1               5                   10                  15      
          Leu Leu Ala Asp Leu Gln Met Ile Leu Asn Gly Ile Asn Asn Tyr Lys 
                      20                  25                  30          
          Asn Pro Lys Leu Thr Ala Met Leu Thr Phe Lys Phe Tyr Met Pro Lys 
                  35                  40                  45              
          Lys Ala Thr Glu Leu Lys His Leu Gln Cys Leu Glu Glu Glu Leu Lys 
              50                  55                  60                  
          Arg Leu Glu Glu Val Leu Asn Leu Ala Gln Ser Lys Asn Phe His Leu 
          65                  70                  75                  80  
          Arg Pro Arg Ser Leu Ile Ser Asn Ile Asn Val Ile Val Leu Glu Leu 
                          85                  90                  95      
          Lys Gly Ser Glu Thr Thr Phe Met Cys Glu Tyr Ala Asp Glu Thr Ala 
                      100                 105                 110         
          Thr Ile Val Glu Phe Leu Asn Ala Trp Ile Thr Phe Ser Gln Ser Ile 
                  115                 120                 125             
          Ile Ser Thr Leu Thr 
              130             
          <![CDATA[<210>  238]]>
          <![CDATA[<211>  133]]>
          <![CDATA[<212>  PRT]]>
          <![CDATA[<213>  人工序列]]>
          <![CDATA[<220>]]>
          <![CDATA[<223>  合成：IL-2-T3A-H16A-L19A-Q22A-R38A-P65R-D84S-R120A-C125S]]>
          <![CDATA[<400>  238]]>
          Ala Pro Ala Ser Ser Ser Thr Lys Lys Thr Gln Leu Gln Leu Glu Ala 
          1               5                   10                  15      
          Leu Leu Ala Asp Leu Ala Met Ile Leu Asn Gly Ile Asn Asn Tyr Lys 
                      20                  25                  30          
          Asn Pro Lys Leu Thr Ala Met Leu Thr Phe Lys Phe Tyr Met Pro Lys 
                  35                  40                  45              
          Lys Ala Thr Glu Leu Lys His Leu Gln Cys Leu Glu Glu Glu Leu Lys 
              50                  55                  60                  
          Arg Leu Glu Glu Val Leu Asn Leu Ala Gln Ser Lys Asn Phe His Leu 
          65                  70                  75                  80  
          Arg Pro Arg Ser Leu Ile Ser Asn Ile Asn Val Ile Val Leu Glu Leu 
                          85                  90                  95      
          Lys Gly Ser Glu Thr Thr Phe Met Cys Glu Tyr Ala Asp Glu Thr Ala 
                      100                 105                 110         
          Thr Ile Val Glu Phe Leu Asn Ala Trp Ile Thr Phe Ser Gln Ser Ile 
                  115                 120                 125             
          Ile Ser Thr Leu Thr 
              130             
          <![CDATA[<210>  239]]>
          <![CDATA[<211>  133]]>
          <![CDATA[<212>  PRT]]>
          <![CDATA[<213>  人工序列]]>
          <![CDATA[<220>]]>
          <![CDATA[<223>  合成：IL-2-T3A-H16A-Q22A-M23A-R38A-P65R-D84S-E95Q-C125S]]>
          <![CDATA[<400>  239]]>
          Ala Pro Ala Ser Ser Ser Thr Lys Lys Thr Gln Leu Gln Leu Glu Ala 
          1               5                   10                  15      
          Leu Leu Leu Asp Leu Ala Ala Ile Leu Asn Gly Ile Asn Asn Tyr Lys 
                      20                  25                  30          
          Asn Pro Lys Leu Thr Ala Met Leu Thr Phe Lys Phe Tyr Met Pro Lys 
                  35                  40                  45              
          Lys Ala Thr Glu Leu Lys His Leu Gln Cys Leu Glu Glu Glu Leu Lys 
              50                  55                  60                  
          Arg Leu Glu Glu Val Leu Asn Leu Ala Gln Ser Lys Asn Phe His Leu 
          65                  70                  75                  80  
          Arg Pro Arg Ser Leu Ile Ser Asn Ile Asn Val Ile Val Leu Gln Leu 
                          85                  90                  95      
          Lys Gly Ser Glu Thr Thr Phe Met Cys Glu Tyr Ala Asp Glu Thr Ala 
                      100                 105                 110         
          Thr Ile Val Glu Phe Leu Asn Arg Trp Ile Thr Phe Ser Gln Ser Ile 
                  115                 120                 125             
          Ile Ser Thr Leu Thr 
              130             
          <![CDATA[<210>  240]]>
          <![CDATA[<211>  133]]>
          <![CDATA[<212>  PRT]]>
          <![CDATA[<213>  人工序列]]>
          <![CDATA[<220>]]>
          <![CDATA[<223>  合成：IL-2-T3A-H16A-M23A-R38A-P65R-D84S-E95Q-R120A-C125S]]>
          <![CDATA[<400>  240]]>
          Ala Pro Ala Ser Ser Ser Thr Lys Lys Thr Gln Leu Gln Leu Glu Ala 
          1               5                   10                  15      
          Leu Leu Leu Asp Leu Gln Ala Ile Leu Asn Gly Ile Asn Asn Tyr Lys 
                      20                  25                  30          
          Asn Pro Lys Leu Thr Ala Met Leu Thr Phe Lys Phe Tyr Met Pro Lys 
                  35                  40                  45              
          Lys Ala Thr Glu Leu Lys His Leu Gln Cys Leu Glu Glu Glu Leu Lys 
              50                  55                  60                  
          Arg Leu Glu Glu Val Leu Asn Leu Ala Gln Ser Lys Asn Phe His Leu 
          65                  70                  75                  80  
          Arg Pro Arg Ser Leu Ile Ser Asn Ile Asn Val Ile Val Leu Gln Leu 
                          85                  90                  95      
          Lys Gly Ser Glu Thr Thr Phe Met Cys Glu Tyr Ala Asp Glu Thr Ala 
                      100                 105                 110         
          Thr Ile Val Glu Phe Leu Asn Ala Trp Ile Thr Phe Ser Gln Ser Ile 
                  115                 120                 125             
          Ile Ser Thr Leu Thr 
              130             
          <![CDATA[<210>  241]]>
          <![CDATA[<211>  133]]>
          <![CDATA[<212>  PRT]]>
          <![CDATA[<213>  人工序列]]>
          <![CDATA[<220>]]>
          <![CDATA[<223>  合成：IL-2-T3A-H16A-Q22A-M23A-R38A-P65R-D84S-E95Q-R120A-C125S]]>
          <![CDATA[<400>  241]]>
          Ala Pro Ala Ser Ser Ser Thr Lys Lys Thr Gln Leu Gln Leu Glu Ala 
          1               5                   10                  15      
          Leu Leu Leu Asp Leu Ala Ala Ile Leu Asn Gly Ile Asn Asn Tyr Lys 
                      20                  25                  30          
          Asn Pro Lys Leu Thr Ala Met Leu Thr Phe Lys Phe Tyr Met Pro Lys 
                  35                  40                  45              
          Lys Ala Thr Glu Leu Lys His Leu Gln Cys Leu Glu Glu Glu Leu Lys 
              50                  55                  60                  
          Arg Leu Glu Glu Val Leu Asn Leu Ala Gln Ser Lys Asn Phe His Leu 
          65                  70                  75                  80  
          Arg Pro Arg Ser Leu Ile Ser Asn Ile Asn Val Ile Val Leu Gln Leu 
                          85                  90                  95      
          Lys Gly Ser Glu Thr Thr Phe Met Cys Glu Tyr Ala Asp Glu Thr Ala 
                      100                 105                 110         
          Thr Ile Val Glu Phe Leu Asn Ala Trp Ile Thr Phe Ser Gln Ser Ile 
                  115                 120                 125             
          Ile Ser Thr Leu Thr 
              130             
          <![CDATA[<210>  242]]>
          <![CDATA[<211>  133]]>
          <![CDATA[<212>  PRT]]>
          <![CDATA[<213>  人工序列]]>
          <![CDATA[<220>]]>
          <![CDATA[<223>  合成：IL-2-T3A-H16A-L19N-Q22A-R38A-P65R-D84S-C125S]]>
          <![CDATA[<400>  242]]>
          Ala Pro Ala Ser Ser Ser Thr Lys Lys Thr Gln Leu Gln Leu Glu Ala 
          1               5                   10                  15      
          Leu Leu Asn Asp Leu Ala Met Ile Leu Asn Gly Ile Asn Asn Tyr Lys 
                      20                  25                  30          
          Asn Pro Lys Leu Thr Ala Met Leu Thr Phe Lys Phe Tyr Met Pro Lys 
                  35                  40                  45              
          Lys Ala Thr Glu Leu Lys His Leu Gln Cys Leu Glu Glu Glu Leu Lys 
              50                  55                  60                  
          Arg Leu Glu Glu Val Leu Asn Leu Ala Gln Ser Lys Asn Phe His Leu 
          65                  70                  75                  80  
          Arg Pro Arg Ser Leu Ile Ser Asn Ile Asn Val Ile Val Leu Glu Leu 
                          85                  90                  95      
          Lys Gly Ser Glu Thr Thr Phe Met Cys Glu Tyr Ala Asp Glu Thr Ala 
                      100                 105                 110         
          Thr Ile Val Glu Phe Leu Asn Arg Trp Ile Thr Phe Ser Gln Ser Ile 
                  115                 120                 125             
          Ile Ser Thr Leu Thr 
              130             
          <![CDATA[<210>  243]]>
          <![CDATA[<211>  133]]>
          <![CDATA[<212>  PRT]]>
          <![CDATA[<213>  人工序列]]>
          <![CDATA[<220>]]>
          <![CDATA[<223>  合成：IL-2-T3A-H16A-L19N-R38A-P65R-D84S-R120A-C125S]]>
          <![CDATA[<400>  243]]>
          Ala Pro Ala Ser Ser Ser Thr Lys Lys Thr Gln Leu Gln Leu Glu Ala 
          1               5                   10                  15      
          Leu Leu Asn Asp Leu Gln Met Ile Leu Asn Gly Ile Asn Asn Tyr Lys 
                      20                  25                  30          
          Asn Pro Lys Leu Thr Ala Met Leu Thr Phe Lys Phe Tyr Met Pro Lys 
                  35                  40                  45              
          Lys Ala Thr Glu Leu Lys His Leu Gln Cys Leu Glu Glu Glu Leu Lys 
              50                  55                  60                  
          Arg Leu Glu Glu Val Leu Asn Leu Ala Gln Ser Lys Asn Phe His Leu 
          65                  70                  75                  80  
          Arg Pro Arg Ser Leu Ile Ser Asn Ile Asn Val Ile Val Leu Glu Leu 
                          85                  90                  95      
          Lys Gly Ser Glu Thr Thr Phe Met Cys Glu Tyr Ala Asp Glu Thr Ala 
                      100                 105                 110         
          Thr Ile Val Glu Phe Leu Asn Ala Trp Ile Thr Phe Ser Gln Ser Ile 
                  115                 120                 125             
          Ile Ser Thr Leu Thr 
              130             
          <![CDATA[<210>  244]]>
          <![CDATA[<211>  133]]>
          <![CDATA[<212>  PRT]]>
          <![CDATA[<213>  人工序列]]>
          <![CDATA[<220>]]>
          <![CDATA[<223>  合成：IL-2-T3A-H16A-L19N-Q22A-R38A-P65R-D84S-R120A-C125S]]>
          <![CDATA[<400>  244]]>
          Ala Pro Ala Ser Ser Ser Thr Lys Lys Thr Gln Leu Gln Leu Glu Ala 
          1               5                   10                  15      
          Leu Leu Asn Asp Leu Ala Met Ile Leu Asn Gly Ile Asn Asn Tyr Lys 
                      20                  25                  30          
          Asn Pro Lys Leu Thr Ala Met Leu Thr Phe Lys Phe Tyr Met Pro Lys 
                  35                  40                  45              
          Lys Ala Thr Glu Leu Lys His Leu Gln Cys Leu Glu Glu Glu Leu Lys 
              50                  55                  60                  
          Arg Leu Glu Glu Val Leu Asn Leu Ala Gln Ser Lys Asn Phe His Leu 
          65                  70                  75                  80  
          Arg Pro Arg Ser Leu Ile Ser Asn Ile Asn Val Ile Val Leu Glu Leu 
                          85                  90                  95      
          Lys Gly Ser Glu Thr Thr Phe Met Cys Glu Tyr Ala Asp Glu Thr Ala 
                      100                 105                 110         
          Thr Ile Val Glu Phe Leu Asn Ala Trp Ile Thr Phe Ser Gln Ser Ile 
                  115                 120                 125             
          Ile Ser Thr Leu Thr 
              130             
          <![CDATA[<210>  245]]>
          <![CDATA[<211>  133]]>
          <![CDATA[<212>  PRT]]>
          <![CDATA[<213>  人工序列]]>
          <![CDATA[<220>]]>
          <![CDATA[<223>  合成：IL-2-A1G-P2G-T3S-S4G-S5G-H16A-L19A-R38A-P65R-D84S-C125S]]>
          <![CDATA[<400>  245]]>
          Gly Gly Ser Gly Gly Ser Thr Lys Lys Thr Gln Leu Gln Leu Glu Ala 
          1               5                   10                  15      
          Leu Leu Ala Asp Leu Gln Met Ile Leu Asn Gly Ile Asn Asn Tyr Lys 
                      20                  25                  30          
          Asn Pro Lys Leu Thr Ala Met Leu Thr Phe Lys Phe Tyr Met Pro Lys 
                  35                  40                  45              
          Lys Ala Thr Glu Leu Lys His Leu Gln Cys Leu Glu Glu Glu Leu Lys 
              50                  55                  60                  
          Arg Leu Glu Glu Val Leu Asn Leu Ala Gln Ser Lys Asn Phe His Leu 
          65                  70                  75                  80  
          Arg Pro Arg Ser Leu Ile Ser Asn Ile Asn Val Ile Val Leu Glu Leu 
                          85                  90                  95      
          Lys Gly Ser Glu Thr Thr Phe Met Cys Glu Tyr Ala Asp Glu Thr Ala 
                      100                 105                 110         
          Thr Ile Val Glu Phe Leu Asn Arg Trp Ile Thr Phe Ser Gln Ser Ile 
                  115                 120                 125             
          Ile Ser Thr Leu Thr 
              130             
          <![CDATA[<210>  246]]>
          <![CDATA[<211>  128]]>
          <![CDATA[<212>  PRT]]>
          <![CDATA[<213>  人工序列]]>
          <![CDATA[<220>]]>
          <![CDATA[<223>  合成：IL-2-del1-5-H16A-L19A-R38A-P65R-D84S-C125S]]>
          <![CDATA[<400>  246]]>
          Ser Thr Lys Lys Thr Gln Leu Gln Leu Glu Ala Leu Leu Ala Asp Leu 
          1               5                   10                  15      
          Gln Met Ile Leu Asn Gly Ile Asn Asn Tyr Lys Asn Pro Lys Leu Thr 
                      20                  25                  30          
          Ala Met Leu Thr Phe Lys Phe Tyr Met Pro Lys Lys Ala Thr Glu Leu 
                  35                  40                  45              
          Lys His Leu Gln Cys Leu Glu Glu Glu Leu Lys Arg Leu Glu Glu Val 
              50                  55                  60                  
          Leu Asn Leu Ala Gln Ser Lys Asn Phe His Leu Arg Pro Arg Ser Leu 
          65                  70                  75                  80  
          Ile Ser Asn Ile Asn Val Ile Val Leu Glu Leu Lys Gly Ser Glu Thr 
                          85                  90                  95      
          Thr Phe Met Cys Glu Tyr Ala Asp Glu Thr Ala Thr Ile Val Glu Phe 
                      100                 105                 110         
          Leu Asn Arg Trp Ile Thr Phe Ser Gln Ser Ile Ile Ser Thr Leu Thr 
                  115                 120                 125             
          <![CDATA[<210>  247]]>
          <![CDATA[<211>  128]]>
          <![CDATA[<212>  PRT]]>
          <![CDATA[<213>  人工序列]]>
          <![CDATA[<220>]]>
          <![CDATA[<223>  合成：IL-2-del1-5-H16A-L19A-R38A-P65R-D84S-C125V]]>
          <![CDATA[<400>  247]]>
          Ser Thr Lys Lys Thr Gln Leu Gln Leu Glu Ala Leu Leu Ala Asp Leu 
          1               5                   10                  15      
          Gln Met Ile Leu Asn Gly Ile Asn Asn Tyr Lys Asn Pro Lys Leu Thr 
                      20                  25                  30          
          Ala Met Leu Thr Phe Lys Phe Tyr Met Pro Lys Lys Ala Thr Glu Leu 
                  35                  40                  45              
          Lys His Leu Gln Cys Leu Glu Glu Glu Leu Lys Arg Leu Glu Glu Val 
              50                  55                  60                  
          Leu Asn Leu Ala Gln Ser Lys Asn Phe His Leu Arg Pro Arg Ser Leu 
          65                  70                  75                  80  
          Ile Ser Asn Ile Asn Val Ile Val Leu Glu Leu Lys Gly Ser Glu Thr 
                          85                  90                  95      
          Thr Phe Met Cys Glu Tyr Ala Asp Glu Thr Ala Thr Ile Val Glu Phe 
                      100                 105                 110         
          Leu Asn Arg Trp Ile Thr Phe Val Gln Ser Ile Ile Ser Thr Leu Thr 
                  115                 120                 125             
          <![CDATA[<210>  248]]>
          <![CDATA[<211>  133]]>
          <![CDATA[<212>  PRT]]>
          <![CDATA[<213>  人工序列]]>
          <![CDATA[<220>]]>
          <![CDATA[<223>  合成：IL-2-T3A-L19N-R38A-P65R-D84S-C125S]]>
          <![CDATA[<400>  248]]>
          Ala Pro Ala Ser Ser Ser Thr Lys Lys Thr Gln Leu Gln Leu Glu His 
          1               5                   10                  15      
          Leu Leu Asn Asp Leu Gln Met Ile Leu Asn Gly Ile Asn Asn Tyr Lys 
                      20                  25                  30          
          Asn Pro Lys Leu Thr Ala Met Leu Thr Phe Lys Phe Tyr Met Pro Lys 
                  35                  40                  45              
          Lys Ala Thr Glu Leu Lys His Leu Gln Cys Leu Glu Glu Glu Leu Lys 
              50                  55                  60                  
          Arg Leu Glu Glu Val Leu Asn Leu Ala Gln Ser Lys Asn Phe His Leu 
          65                  70                  75                  80  
          Arg Pro Arg Ser Leu Ile Ser Asn Ile Asn Val Ile Val Leu Glu Leu 
                          85                  90                  95      
          Lys Gly Ser Glu Thr Thr Phe Met Cys Glu Tyr Ala Asp Glu Thr Ala 
                      100                 105                 110         
          Thr Ile Val Glu Phe Leu Asn Arg Trp Ile Thr Phe Ser Gln Ser Ile 
                  115                 120                 125             
          Ile Ser Thr Leu Thr 
              130             
          <![CDATA[<210>  249]]>
          <![CDATA[<211>  133]]>
          <![CDATA[<212>  PRT]]>
          <![CDATA[<213>  人工序列]]>
          <![CDATA[<220>]]>
          <![CDATA[<223>  合成：IL-2-T3A-H16A-L19N-R38A-P65R-C125S]]>
          <![CDATA[<400>  249]]>
          Ala Pro Ala Ser Ser Ser Thr Lys Lys Thr Gln Leu Gln Leu Glu Ala 
          1               5                   10                  15      
          Leu Leu Asn Asp Leu Gln Met Ile Leu Asn Gly Ile Asn Asn Tyr Lys 
                      20                  25                  30          
          Asn Pro Lys Leu Thr Ala Met Leu Thr Phe Lys Phe Tyr Met Pro Lys 
                  35                  40                  45              
          Lys Ala Thr Glu Leu Lys His Leu Gln Cys Leu Glu Glu Glu Leu Lys 
              50                  55                  60                  
          Arg Leu Glu Glu Val Leu Asn Leu Ala Gln Ser Lys Asn Phe His Leu 
          65                  70                  75                  80  
          Arg Pro Arg Asp Leu Ile Ser Asn Ile Asn Val Ile Val Leu Glu Leu 
                          85                  90                  95      
          Lys Gly Ser Glu Thr Thr Phe Met Cys Glu Tyr Ala Asp Glu Thr Ala 
                      100                 105                 110         
          Thr Ile Val Glu Phe Leu Asn Arg Trp Ile Thr Phe Ser Gln Ser Ile 
                  115                 120                 125             
          Ile Ser Thr Leu Thr 
              130             
          <![CDATA[<210>  250]]>
          <![CDATA[<211>  133]]>
          <![CDATA[<212>  PRT]]>
          <![CDATA[<213>  人工序列]]>
          <![CDATA[<220>]]>
          <![CDATA[<223>  合成：IL-2-T3A-L19N-Q22A-R38A-P65R-D84S-C125S]]>
          <![CDATA[<400>  250]]>
          Ala Pro Ala Ser Ser Ser Thr Lys Lys Thr Gln Leu Gln Leu Glu His 
          1               5                   10                  15      
          Leu Leu Asn Asp Leu Ala Met Ile Leu Asn Gly Ile Asn Asn Tyr Lys 
                      20                  25                  30          
          Asn Pro Lys Leu Thr Ala Met Leu Thr Phe Lys Phe Tyr Met Pro Lys 
                  35                  40                  45              
          Lys Ala Thr Glu Leu Lys His Leu Gln Cys Leu Glu Glu Glu Leu Lys 
              50                  55                  60                  
          Arg Leu Glu Glu Val Leu Asn Leu Ala Gln Ser Lys Asn Phe His Leu 
          65                  70                  75                  80  
          Arg Pro Arg Ser Leu Ile Ser Asn Ile Asn Val Ile Val Leu Glu Leu 
                          85                  90                  95      
          Lys Gly Ser Glu Thr Thr Phe Met Cys Glu Tyr Ala Asp Glu Thr Ala 
                      100                 105                 110         
          Thr Ile Val Glu Phe Leu Asn Arg Trp Ile Thr Phe Ser Gln Ser Ile 
                  115                 120                 125             
          Ile Ser Thr Leu Thr 
              130             
          <![CDATA[<210>  251]]>
          <![CDATA[<211>  133]]>
          <![CDATA[<212>  PRT]]>
          <![CDATA[<213>  人工序列]]>
          <![CDATA[<220>]]>
          <![CDATA[<223>  合成：IL-2-T3A-H16A-L19N-Q22A-R38A-P65R-C125S]]>
          <![CDATA[<400>  251]]>
          Ala Pro Ala Ser Ser Ser Thr Lys Lys Thr Gln Leu Gln Leu Glu Ala 
          1               5                   10                  15      
          Leu Leu Asn Asp Leu Ala Met Ile Leu Asn Gly Ile Asn Asn Tyr Lys 
                      20                  25                  30          
          Asn Pro Lys Leu Thr Ala Met Leu Thr Phe Lys Phe Tyr Met Pro Lys 
                  35                  40                  45              
          Lys Ala Thr Glu Leu Lys His Leu Gln Cys Leu Glu Glu Glu Leu Lys 
              50                  55                  60                  
          Arg Leu Glu Glu Val Leu Asn Leu Ala Gln Ser Lys Asn Phe His Leu 
          65                  70                  75                  80  
          Arg Pro Arg Asp Leu Ile Ser Asn Ile Asn Val Ile Val Leu Glu Leu 
                          85                  90                  95      
          Lys Gly Ser Glu Thr Thr Phe Met Cys Glu Tyr Ala Asp Glu Thr Ala 
                      100                 105                 110         
          Thr Ile Val Glu Phe Leu Asn Arg Trp Ile Thr Phe Ser Gln Ser Ile 
                  115                 120                 125             
          Ile Ser Thr Leu Thr 
              130             
          <![CDATA[<210>  252]]>
          <![CDATA[<211>  133]]>
          <![CDATA[<212>  PRT]]>
          <![CDATA[<213>  人工序列]]>
          <![CDATA[<220>]]>
          <![CDATA[<223>  合成：IL-2-T3A-L19N-Q22A-R38A-P65R-D84S-R120A-C125S]]>
          <![CDATA[<400>  252]]>
          Ala Pro Ala Ser Ser Ser Thr Lys Lys Thr Gln Leu Gln Leu Glu His 
          1               5                   10                  15      
          Leu Leu Asn Asp Leu Ala Met Ile Leu Asn Gly Ile Asn Asn Tyr Lys 
                      20                  25                  30          
          Asn Pro Lys Leu Thr Ala Met Leu Thr Phe Lys Phe Tyr Met Pro Lys 
                  35                  40                  45              
          Lys Ala Thr Glu Leu Lys His Leu Gln Cys Leu Glu Glu Glu Leu Lys 
              50                  55                  60                  
          Arg Leu Glu Glu Val Leu Asn Leu Ala Gln Ser Lys Asn Phe His Leu 
          65                  70                  75                  80  
          Arg Pro Arg Ser Leu Ile Ser Asn Ile Asn Val Ile Val Leu Glu Leu 
                          85                  90                  95      
          Lys Gly Ser Glu Thr Thr Phe Met Cys Glu Tyr Ala Asp Glu Thr Ala 
                      100                 105                 110         
          Thr Ile Val Glu Phe Leu Asn Ala Trp Ile Thr Phe Ser Gln Ser Ile 
                  115                 120                 125             
          Ile Ser Thr Leu Thr 
              130             
          <![CDATA[<210>  253]]>
          <![CDATA[<211>  133]]>
          <![CDATA[<212>  PRT]]>
          <![CDATA[<213>  人工序列]]>
          <![CDATA[<220>]]>
          <![CDATA[<223>  合成：IL-2-T3A-H16A-L19N-Q22A-R38A-P65R-R120A-C125S]]>
          <![CDATA[<400>  253]]>
          Ala Pro Ala Ser Ser Ser Thr Lys Lys Thr Gln Leu Gln Leu Glu Ala 
          1               5                   10                  15      
          Leu Leu Asn Asp Leu Ala Met Ile Leu Asn Gly Ile Asn Asn Tyr Lys 
                      20                  25                  30          
          Asn Pro Lys Leu Thr Ala Met Leu Thr Phe Lys Phe Tyr Met Pro Lys 
                  35                  40                  45              
          Lys Ala Thr Glu Leu Lys His Leu Gln Cys Leu Glu Glu Glu Leu Lys 
              50                  55                  60                  
          Arg Leu Glu Glu Val Leu Asn Leu Ala Gln Ser Lys Asn Phe His Leu 
          65                  70                  75                  80  
          Arg Pro Arg Asp Leu Ile Ser Asn Ile Asn Val Ile Val Leu Glu Leu 
                          85                  90                  95      
          Lys Gly Ser Glu Thr Thr Phe Met Cys Glu Tyr Ala Asp Glu Thr Ala 
                      100                 105                 110         
          Thr Ile Val Glu Phe Leu Asn Ala Trp Ile Thr Phe Ser Gln Ser Ile 
                  115                 120                 125             
          Ile Ser Thr Leu Thr 
              130             
          <![CDATA[<210>  254]]>
          <![CDATA[<211>  133]]>
          <![CDATA[<212>  PRT]]>
          <![CDATA[<213>  人工序列]]>
          <![CDATA[<220>]]>
          <![CDATA[<223>  合成：IL-2-T3A-Q22A-M23A-R38A-P65R-D84S-E95Q-C125S]]>
          <![CDATA[<400>  254]]>
          Ala Pro Ala Ser Ser Ser Thr Lys Lys Thr Gln Leu Gln Leu Glu His 
          1               5                   10                  15      
          Leu Leu Leu Asp Leu Ala Ala Ile Leu Asn Gly Ile Asn Asn Tyr Lys 
                      20                  25                  30          
          Asn Pro Lys Leu Thr Ala Met Leu Thr Phe Lys Phe Tyr Met Pro Lys 
                  35                  40                  45              
          Lys Ala Thr Glu Leu Lys His Leu Gln Cys Leu Glu Glu Glu Leu Lys 
              50                  55                  60                  
          Arg Leu Glu Glu Val Leu Asn Leu Ala Gln Ser Lys Asn Phe His Leu 
          65                  70                  75                  80  
          Arg Pro Arg Ser Leu Ile Ser Asn Ile Asn Val Ile Val Leu Gln Leu 
                          85                  90                  95      
          Lys Gly Ser Glu Thr Thr Phe Met Cys Glu Tyr Ala Asp Glu Thr Ala 
                      100                 105                 110         
          Thr Ile Val Glu Phe Leu Asn Arg Trp Ile Thr Phe Ser Gln Ser Ile 
                  115                 120                 125             
          Ile Ser Thr Leu Thr 
              130             
          <![CDATA[<210>  255]]>
          <![CDATA[<211>  133]]>
          <![CDATA[<212>  PRT]]>
          <![CDATA[<213>  人工序列]]>
          <![CDATA[<220>]]>
          <![CDATA[<223>  合成：IL-2-T3A-Q22A-M23A-R38A-P65R-E95Q-C125S]]>
          <![CDATA[<400>  255]]>
          Ala Pro Ala Ser Ser Ser Thr Lys Lys Thr Gln Leu Gln Leu Glu Ala 
          1               5                   10                  15      
          Leu Leu Leu Asp Leu Ala Ala Ile Leu Asn Gly Ile Asn Asn Tyr Lys 
                      20                  25                  30          
          Asn Pro Lys Leu Thr Ala Met Leu Thr Phe Lys Phe Tyr Met Pro Lys 
                  35                  40                  45              
          Lys Ala Thr Glu Leu Lys His Leu Gln Cys Leu Glu Glu Glu Leu Lys 
              50                  55                  60                  
          Arg Leu Glu Glu Val Leu Asn Leu Ala Gln Ser Lys Asn Phe His Leu 
          65                  70                  75                  80  
          Arg Pro Arg Asp Leu Ile Ser Asn Ile Asn Val Ile Val Leu Gln Leu 
                          85                  90                  95      
          Lys Gly Ser Glu Thr Thr Phe Met Cys Glu Tyr Ala Asp Glu Thr Ala 
                      100                 105                 110         
          Thr Ile Val Glu Phe Leu Asn Arg Trp Ile Thr Phe Ser Gln Ser Ile 
                  115                 120                 125             
          Ile Ser Thr Leu Thr 
              130             
          <![CDATA[<210>  256]]>
          <![CDATA[<211>  133]]>
          <![CDATA[<212>  PRT]]>
          <![CDATA[<213>  人工序列]]>
          <![CDATA[<220>]]>
          <![CDATA[<223>  合成：IL-2-T3A-Q22A-M23A-R38A-P65R-D84S-E95Q-R120A-C125S]]>
          <![CDATA[<400>  256]]>
          Ala Pro Ala Ser Ser Ser Thr Lys Lys Thr Gln Leu Gln Leu Glu His 
          1               5                   10                  15      
          Leu Leu Leu Asp Leu Ala Ala Ile Leu Asn Gly Ile Asn Asn Tyr Lys 
                      20                  25                  30          
          Asn Pro Lys Leu Thr Ala Met Leu Thr Phe Lys Phe Tyr Met Pro Lys 
                  35                  40                  45              
          Lys Ala Thr Glu Leu Lys His Leu Gln Cys Leu Glu Glu Glu Leu Lys 
              50                  55                  60                  
          Arg Leu Glu Glu Val Leu Asn Leu Ala Gln Ser Lys Asn Phe His Leu 
          65                  70                  75                  80  
          Arg Pro Arg Ser Leu Ile Ser Asn Ile Asn Val Ile Val Leu Gln Leu 
                          85                  90                  95      
          Lys Gly Ser Glu Thr Thr Phe Met Cys Glu Tyr Ala Asp Glu Thr Ala 
                      100                 105                 110         
          Thr Ile Val Glu Phe Leu Asn Ala Trp Ile Thr Phe Ser Gln Ser Ile 
                  115                 120                 125             
          Ile Ser Thr Leu Thr 
              130             
          <![CDATA[<210>  257]]>
          <![CDATA[<211>  133]]>
          <![CDATA[<212>  PRT]]>
          <![CDATA[<213>  人工序列]]>
          <![CDATA[<220>]]>
          <![CDATA[<223>  合成：IL-2-T3A-H16A-Q22A-M23A-R38A-P65R-E95Q-R120A-C125S]]>
          <![CDATA[<400>  257]]>
          Ala Pro Ala Ser Ser Ser Thr Lys Lys Thr Gln Leu Gln Leu Glu Ala 
          1               5                   10                  15      
          Leu Leu Leu Asp Leu Ala Ala Ile Leu Asn Gly Ile Asn Asn Tyr Lys 
                      20                  25                  30          
          Asn Pro Lys Leu Thr Ala Met Leu Thr Phe Lys Phe Tyr Met Pro Lys 
                  35                  40                  45              
          Lys Ala Thr Glu Leu Lys His Leu Gln Cys Leu Glu Glu Glu Leu Lys 
              50                  55                  60                  
          Arg Leu Glu Glu Val Leu Asn Leu Ala Gln Ser Lys Asn Phe His Leu 
          65                  70                  75                  80  
          Arg Pro Arg Asp Leu Ile Ser Asn Ile Asn Val Ile Val Leu Gln Leu 
                          85                  90                  95      
          Lys Gly Ser Glu Thr Thr Phe Met Cys Glu Tyr Ala Asp Glu Thr Ala 
                      100                 105                 110         
          Thr Ile Val Glu Phe Leu Asn Ala Trp Ile Thr Phe Ser Gln Ser Ile 
                  115                 120                 125             
          Ile Ser Thr Leu Thr 
              130             
          <![CDATA[<210>  258]]>
          <![CDATA[<211>  133]]>
          <![CDATA[<212>  PRT]]>
          <![CDATA[<213>  人工序列]]>
          <![CDATA[<220>]]>
          <![CDATA[<223>  合成：IL-2-T3A-L19A-Q22A-R38A-P65R-D84S-C125S]]>
          <![CDATA[<400>  258]]>
          Ala Pro Ala Ser Ser Ser Thr Lys Lys Thr Gln Leu Gln Leu Glu His 
          1               5                   10                  15      
          Leu Leu Ala Asp Leu Ala Met Ile Leu Asn Gly Ile Asn Asn Tyr Lys 
                      20                  25                  30          
          Asn Pro Lys Leu Thr Ala Met Leu Thr Phe Lys Phe Tyr Met Pro Lys 
                  35                  40                  45              
          Lys Ala Thr Glu Leu Lys His Leu Gln Cys Leu Glu Glu Glu Leu Lys 
              50                  55                  60                  
          Arg Leu Glu Glu Val Leu Asn Leu Ala Gln Ser Lys Asn Phe His Leu 
          65                  70                  75                  80  
          Arg Pro Arg Ser Leu Ile Ser Asn Ile Asn Val Ile Val Leu Glu Leu 
                          85                  90                  95      
          Lys Gly Ser Glu Thr Thr Phe Met Cys Glu Tyr Ala Asp Glu Thr Ala 
                      100                 105                 110         
          Thr Ile Val Glu Phe Leu Asn Arg Trp Ile Thr Phe Ser Gln Ser Ile 
                  115                 120                 125             
          Ile Ser Thr Leu Thr 
              130             
          <![CDATA[<210>  259]]>
          <![CDATA[<211>  133]]>
          <![CDATA[<212>  PRT]]>
          <![CDATA[<213>  人工序列]]>
          <![CDATA[<220>]]>
          <![CDATA[<223>  合成：IL-2-T3A-H16A-L19A-Q22A-R38A-P65R-C125S]]>
          <![CDATA[<400>  259]]>
          Ala Pro Ala Ser Ser Ser Thr Lys Lys Thr Gln Leu Gln Leu Glu Ala 
          1               5                   10                  15      
          Leu Leu Ala Asp Leu Ala Met Ile Leu Asn Gly Ile Asn Asn Tyr Lys 
                      20                  25                  30          
          Asn Pro Lys Leu Thr Ala Met Leu Thr Phe Lys Phe Tyr Met Pro Lys 
                  35                  40                  45              
          Lys Ala Thr Glu Leu Lys His Leu Gln Cys Leu Glu Glu Glu Leu Lys 
              50                  55                  60                  
          Arg Leu Glu Glu Val Leu Asn Leu Ala Gln Ser Lys Asn Phe His Leu 
          65                  70                  75                  80  
          Arg Pro Arg Asp Leu Ile Ser Asn Ile Asn Val Ile Val Leu Glu Leu 
                          85                  90                  95      
          Lys Gly Ser Glu Thr Thr Phe Met Cys Glu Tyr Ala Asp Glu Thr Ala 
                      100                 105                 110         
          Thr Ile Val Glu Phe Leu Asn Arg Trp Ile Thr Phe Ser Gln Ser Ile 
                  115                 120                 125             
          Ile Ser Thr Leu Thr 
              130             
          <![CDATA[<210>  260]]>
          <![CDATA[<211>  133]]>
          <![CDATA[<212>  PRT]]>
          <![CDATA[<213>  人工序列]]>
          <![CDATA[<220>]]>
          <![CDATA[<223>  合成：IL-2-T3A-L19A-Q22A-R38A-P65R-D84S-R120A-C125S]]>
          <![CDATA[<400>  260]]>
          Ala Pro Ala Ser Ser Ser Thr Lys Lys Thr Gln Leu Gln Leu Glu His 
          1               5                   10                  15      
          Leu Leu Ala Asp Leu Ala Met Ile Leu Asn Gly Ile Asn Asn Tyr Lys 
                      20                  25                  30          
          Asn Pro Lys Leu Thr Ala Met Leu Thr Phe Lys Phe Tyr Met Pro Lys 
                  35                  40                  45              
          Lys Ala Thr Glu Leu Lys His Leu Gln Cys Leu Glu Glu Glu Leu Lys 
              50                  55                  60                  
          Arg Leu Glu Glu Val Leu Asn Leu Ala Gln Ser Lys Asn Phe His Leu 
          65                  70                  75                  80  
          Arg Pro Arg Ser Leu Ile Ser Asn Ile Asn Val Ile Val Leu Glu Leu 
                          85                  90                  95      
          Lys Gly Ser Glu Thr Thr Phe Met Cys Glu Tyr Ala Asp Glu Thr Ala 
                      100                 105                 110         
          Thr Ile Val Glu Phe Leu Asn Ala Trp Ile Thr Phe Ser Gln Ser Ile 
                  115                 120                 125             
          Ile Ser Thr Leu Thr 
              130             
          <![CDATA[<210>  261]]>
          <![CDATA[<211>  133]]>
          <![CDATA[<212>  PRT]]>
          <![CDATA[<213>  人工序列]]>
          <![CDATA[<220>]]>
          <![CDATA[<223>  合成：IL-2-T3A-H16A-L19A-Q22A-R38A-P65R-R120A-C125S]]>
          <![CDATA[<400>  261]]>
          Ala Pro Ala Ser Ser Ser Thr Lys Lys Thr Gln Leu Gln Leu Glu Ala 
          1               5                   10                  15      
          Leu Leu Ala Asp Leu Ala Met Ile Leu Asn Gly Ile Asn Asn Tyr Lys 
                      20                  25                  30          
          Asn Pro Lys Leu Thr Ala Met Leu Thr Phe Lys Phe Tyr Met Pro Lys 
                  35                  40                  45              
          Lys Ala Thr Glu Leu Lys His Leu Gln Cys Leu Glu Glu Glu Leu Lys 
              50                  55                  60                  
          Arg Leu Glu Glu Val Leu Asn Leu Ala Gln Ser Lys Asn Phe His Leu 
          65                  70                  75                  80  
          Arg Pro Arg Asp Leu Ile Ser Asn Ile Asn Val Ile Val Leu Glu Leu 
                          85                  90                  95      
          Lys Gly Ser Glu Thr Thr Phe Met Cys Glu Tyr Ala Asp Glu Thr Ala 
                      100                 105                 110         
          Thr Ile Val Glu Phe Leu Asn Ala Trp Ile Thr Phe Ser Gln Ser Ile 
                  115                 120                 125             
          Ile Ser Thr Leu Thr 
              130             
          <![CDATA[<210>  262]]>
          <![CDATA[<211>  133]]>
          <![CDATA[<212>  PRT]]>
          <![CDATA[<213>  人工序列]]>
          <![CDATA[<220>]]>
          <![CDATA[<223>  合成：IL-2-T3A-H16A-E61R-P65R-D84S-C125S-I129A]]>
          <![CDATA[<400>  262]]>
          Ala Pro Ala Ser Ser Ser Thr Lys Lys Thr Gln Leu Gln Leu Glu Ala 
          1               5                   10                  15      
          Leu Leu Leu Asp Leu Gln Met Ile Leu Asn Gly Ile Asn Asn Tyr Lys 
                      20                  25                  30          
          Asn Pro Lys Leu Thr Arg Met Leu Thr Phe Lys Phe Tyr Met Pro Lys 
                  35                  40                  45              
          Lys Ala Thr Glu Leu Lys His Leu Gln Cys Leu Glu Arg Glu Leu Lys 
              50                  55                  60                  
          Arg Leu Glu Glu Val Leu Asn Leu Ala Gln Ser Lys Asn Phe His Leu 
          65                  70                  75                  80  
          Arg Pro Arg Ser Leu Ile Ser Asn Ile Asn Val Ile Val Leu Glu Leu 
                          85                  90                  95      
          Lys Gly Ser Glu Thr Thr Phe Met Cys Glu Tyr Ala Asp Glu Thr Ala 
                      100                 105                 110         
          Thr Ile Val Glu Phe Leu Asn Arg Trp Ile Thr Phe Ser Gln Ser Ile 
                  115                 120                 125             
          Ala Ser Thr Leu Thr 
              130             
          <![CDATA[<210>  263]]>
          <![CDATA[<211>  133]]>
          <![CDATA[<212>  PRT]]>
          <![CDATA[<213>  人工序列]]>
          <![CDATA[<220>]]>
          <![CDATA[<223>  合成：IL-2-T3A-H16A-E61R-P65R-D84S-C125S-I129H]]>
          <![CDATA[<400>  263]]>
          Ala Pro Ala Ser Ser Ser Thr Lys Lys Thr Gln Leu Gln Leu Glu Ala 
          1               5                   10                  15      
          Leu Leu Leu Asp Leu Gln Met Ile Leu Asn Gly Ile Asn Asn Tyr Lys 
                      20                  25                  30          
          Asn Pro Lys Leu Thr Arg Met Leu Thr Phe Lys Phe Tyr Met Pro Lys 
                  35                  40                  45              
          Lys Ala Thr Glu Leu Lys His Leu Gln Cys Leu Glu Arg Glu Leu Lys 
              50                  55                  60                  
          Arg Leu Glu Glu Val Leu Asn Leu Ala Gln Ser Lys Asn Phe His Leu 
          65                  70                  75                  80  
          Arg Pro Arg Ser Leu Ile Ser Asn Ile Asn Val Ile Val Leu Glu Leu 
                          85                  90                  95      
          Lys Gly Ser Glu Thr Thr Phe Met Cys Glu Tyr Ala Asp Glu Thr Ala 
                      100                 105                 110         
          Thr Ile Val Glu Phe Leu Asn Arg Trp Ile Thr Phe Ser Gln Ser Ile 
                  115                 120                 125             
          His Ser Thr Leu Thr 
              130             
          <![CDATA[<210>  264]]>
          <![CDATA[<211>  133]]>
          <![CDATA[<212>  PRT]]>
          <![CDATA[<213>  人工序列]]>
          <![CDATA[<220>]]>
          <![CDATA[<223>  合成：IL-2-T3A-H16A-E61R-P65R-D84S-C125S-I129R]]>
          <![CDATA[<400>  264]]>
          Ala Pro Ala Ser Ser Ser Thr Lys Lys Thr Gln Leu Gln Leu Glu Ala 
          1               5                   10                  15      
          Leu Leu Leu Asp Leu Gln Met Ile Leu Asn Gly Ile Asn Asn Tyr Lys 
                      20                  25                  30          
          Asn Pro Lys Leu Thr Arg Met Leu Thr Phe Lys Phe Tyr Met Pro Lys 
                  35                  40                  45              
          Lys Ala Thr Glu Leu Lys His Leu Gln Cys Leu Glu Arg Glu Leu Lys 
              50                  55                  60                  
          Arg Leu Glu Glu Val Leu Asn Leu Ala Gln Ser Lys Asn Phe His Leu 
          65                  70                  75                  80  
          Arg Pro Arg Ser Leu Ile Ser Asn Ile Asn Val Ile Val Leu Glu Leu 
                          85                  90                  95      
          Lys Gly Ser Glu Thr Thr Phe Met Cys Glu Tyr Ala Asp Glu Thr Ala 
                      100                 105                 110         
          Thr Ile Val Glu Phe Leu Asn Arg Trp Ile Thr Phe Ser Gln Ser Ile 
                  115                 120                 125             
          Arg Ser Thr Leu Thr 
              130             
          <![CDATA[<210>  265]]>
          <![CDATA[<211>  133]]>
          <![CDATA[<212>  PRT]]>
          <![CDATA[<213>  人工序列]]>
          <![CDATA[<220>]]>
          <![CDATA[<223>  合成：IL-2-T3A-H16A-E61R-P65R-D84S-C125S-I129S]]>
          <![CDATA[<400>  265]]>
          Ala Pro Ala Ser Ser Ser Thr Lys Lys Thr Gln Leu Gln Leu Glu Ala 
          1               5                   10                  15      
          Leu Leu Leu Asp Leu Gln Met Ile Leu Asn Gly Ile Asn Asn Tyr Lys 
                      20                  25                  30          
          Asn Pro Lys Leu Thr Arg Met Leu Thr Phe Lys Phe Tyr Met Pro Lys 
                  35                  40                  45              
          Lys Ala Thr Glu Leu Lys His Leu Gln Cys Leu Glu Arg Glu Leu Lys 
              50                  55                  60                  
          Arg Leu Glu Glu Val Leu Asn Leu Ala Gln Ser Lys Asn Phe His Leu 
          65                  70                  75                  80  
          Arg Pro Arg Ser Leu Ile Ser Asn Ile Asn Val Ile Val Leu Glu Leu 
                          85                  90                  95      
          Lys Gly Ser Glu Thr Thr Phe Met Cys Glu Tyr Ala Asp Glu Thr Ala 
                      100                 105                 110         
          Thr Ile Val Glu Phe Leu Asn Arg Trp Ile Thr Phe Ser Gln Ser Ile 
                  115                 120                 125             
          Ser Ser Thr Leu Thr 
              130             
          <![CDATA[<210>  266]]>
          <![CDATA[<211>  133]]>
          <![CDATA[<212>  PRT]]>
          <![CDATA[<213>  人工序列]]>
          <![CDATA[<220>]]>
          <![CDATA[<223>  合成：IL-2-T3A-H16A-E61R-P65R-D84S-C125C-Q126N]]>
          <![CDATA[<400>  266]]>
          Ala Pro Ala Ser Ser Ser Thr Lys Lys Thr Gln Leu Gln Leu Glu Ala 
          1               5                   10                  15      
          Leu Leu Leu Asp Leu Gln Met Ile Leu Asn Gly Ile Asn Asn Tyr Lys 
                      20                  25                  30          
          Asn Pro Lys Leu Thr Arg Met Leu Thr Phe Lys Phe Tyr Met Pro Lys 
                  35                  40                  45              
          Lys Ala Thr Glu Leu Lys His Leu Gln Cys Leu Glu Arg Glu Leu Lys 
              50                  55                  60                  
          Arg Leu Glu Glu Val Leu Asn Leu Ala Gln Ser Lys Asn Phe His Leu 
          65                  70                  75                  80  
          Arg Pro Arg Ser Leu Ile Ser Asn Ile Asn Val Ile Val Leu Glu Leu 
                          85                  90                  95      
          Lys Gly Ser Glu Thr Thr Phe Met Cys Glu Tyr Ala Asp Glu Thr Ala 
                      100                 105                 110         
          Thr Ile Val Glu Phe Leu Asn Arg Trp Ile Thr Phe Ser Asn Ser Ile 
                  115                 120                 125             
          Ile Ser Thr Leu Thr 
              130             
          <![CDATA[<210>  267]]>
          <![CDATA[<211>  133]]>
          <![CDATA[<212>  PRT]]>
          <![CDATA[<213>  人工序列]]>
          <![CDATA[<220>]]>
          <![CDATA[<223>  合成：IL-2-T3A-H16A-E61R-P65R-D84S-C125C-Q126Y]]>
          <![CDATA[<400>  267]]>
          Ala Pro Ala Ser Ser Ser Thr Lys Lys Thr Gln Leu Gln Leu Glu Ala 
          1               5                   10                  15      
          Leu Leu Leu Asp Leu Gln Met Ile Leu Asn Gly Ile Asn Asn Tyr Lys 
                      20                  25                  30          
          Asn Pro Lys Leu Thr Arg Met Leu Thr Phe Lys Phe Tyr Met Pro Lys 
                  35                  40                  45              
          Lys Ala Thr Glu Leu Lys His Leu Gln Cys Leu Glu Arg Glu Leu Lys 
              50                  55                  60                  
          Arg Leu Glu Glu Val Leu Asn Leu Ala Gln Ser Lys Asn Phe His Leu 
          65                  70                  75                  80  
          Arg Pro Arg Ser Leu Ile Ser Asn Ile Asn Val Ile Val Leu Glu Leu 
                          85                  90                  95      
          Lys Gly Ser Glu Thr Thr Phe Met Cys Glu Tyr Ala Asp Glu Thr Ala 
                      100                 105                 110         
          Thr Ile Val Glu Phe Leu Asn Arg Trp Ile Thr Phe Ser Tyr Ser Ile 
                  115                 120                 125             
          Ile Ser Thr Leu Thr 
              130             
          <![CDATA[<210>  268]]>
          <![CDATA[<211>  133]]>
          <![CDATA[<212>  PRT]]>
          <![CDATA[<213>  人工序列]]>
          <![CDATA[<220>]]>
          <![CDATA[<223>  合成：IL-2-T3A-H16A-E61R-P65R-D84S-C125C-S127N]]>
          <![CDATA[<400>  268]]>
          Ala Pro Ala Ser Ser Ser Thr Lys Lys Thr Gln Leu Gln Leu Glu Ala 
          1               5                   10                  15      
          Leu Leu Leu Asp Leu Gln Met Ile Leu Asn Gly Ile Asn Asn Tyr Lys 
                      20                  25                  30          
          Asn Pro Lys Leu Thr Arg Met Leu Thr Phe Lys Phe Tyr Met Pro Lys 
                  35                  40                  45              
          Lys Ala Thr Glu Leu Lys His Leu Gln Cys Leu Glu Arg Glu Leu Lys 
              50                  55                  60                  
          Arg Leu Glu Glu Val Leu Asn Leu Ala Gln Ser Lys Asn Phe His Leu 
          65                  70                  75                  80  
          Arg Pro Arg Ser Leu Ile Ser Asn Ile Asn Val Ile Val Leu Glu Leu 
                          85                  90                  95      
          Lys Gly Ser Glu Thr Thr Phe Met Cys Glu Tyr Ala Asp Glu Thr Ala 
                      100                 105                 110         
          Thr Ile Val Glu Phe Leu Asn Arg Trp Ile Thr Phe Ser Gln Asn Ile 
                  115                 120                 125             
          Ile Ser Thr Leu Thr 
              130             
          <![CDATA[<210>  269]]>
          <![CDATA[<211>  133]]>
          <![CDATA[<212>  PRT]]>
          <![CDATA[<213>  人工序列]]>
          <![CDATA[<220>]]>
          <![CDATA[<223>  合成：IL-2-T3A-H16A-E61R-P65R-D84S-C125C-S130P]]>
          <![CDATA[<400>  269]]>
          Ala Pro Ala Ser Ser Ser Thr Lys Lys Thr Gln Leu Gln Leu Glu Ala 
          1               5                   10                  15      
          Leu Leu Leu Asp Leu Gln Met Ile Leu Asn Gly Ile Asn Asn Tyr Lys 
                      20                  25                  30          
          Asn Pro Lys Leu Thr Arg Met Leu Thr Phe Lys Phe Tyr Met Pro Lys 
                  35                  40                  45              
          Lys Ala Thr Glu Leu Lys His Leu Gln Cys Leu Glu Arg Glu Leu Lys 
              50                  55                  60                  
          Arg Leu Glu Glu Val Leu Asn Leu Ala Gln Ser Lys Asn Phe His Leu 
          65                  70                  75                  80  
          Arg Pro Arg Ser Leu Ile Ser Asn Ile Asn Val Ile Val Leu Glu Leu 
                          85                  90                  95      
          Lys Gly Ser Glu Thr Thr Phe Met Cys Glu Tyr Ala Asp Glu Thr Ala 
                      100                 105                 110         
          Thr Ile Val Glu Phe Leu Asn Arg Trp Ile Thr Phe Ser Gln Ser Ile 
                  115                 120                 125             
          Ile Pro Thr Leu Thr 
              130             
          <![CDATA[<210>  270]]>
          <![CDATA[<211>  133]]>
          <![CDATA[<212>  PRT]]>
          <![CDATA[<213>  人工序列]]>
          <![CDATA[<220>]]>
          <![CDATA[<223>  合成：IL-2-T3A-H16A-E61R-P65R-D84Y-C125S]]>
          <![CDATA[<400>  270]]>
          Ala Pro Ala Ser Ser Ser Thr Lys Lys Thr Gln Leu Gln Leu Glu Ala 
          1               5                   10                  15      
          Leu Leu Leu Asp Leu Gln Met Ile Leu Asn Gly Ile Asn Asn Tyr Lys 
                      20                  25                  30          
          Asn Pro Lys Leu Thr Arg Met Leu Thr Phe Lys Phe Tyr Met Pro Lys 
                  35                  40                  45              
          Lys Ala Thr Glu Leu Lys His Leu Gln Cys Leu Glu Arg Glu Leu Lys 
              50                  55                  60                  
          Arg Leu Glu Glu Val Leu Asn Leu Ala Gln Ser Lys Asn Phe His Leu 
          65                  70                  75                  80  
          Arg Pro Arg Tyr Leu Ile Ser Asn Ile Asn Val Ile Val Leu Glu Leu 
                          85                  90                  95      
          Lys Gly Ser Glu Thr Thr Phe Met Cys Glu Tyr Ala Asp Glu Thr Ala 
                      100                 105                 110         
          Thr Ile Val Glu Phe Leu Asn Arg Trp Ile Thr Phe Ser Gln Ser Ile 
                  115                 120                 125             
          Ile Ser Thr Leu Thr 
              130             
          <![CDATA[<210>  271]]>
          <![CDATA[<211>  133]]>
          <![CDATA[<212>  PRT]]>
          <![CDATA[<213>  人工序列]]>
          <![CDATA[<220>]]>
          <![CDATA[<223>  合成：IL-2-T3A-H16A-M23T-E61R-P65R-D84Y-E95Q-C125S]]>
          <![CDATA[<400>  271]]>
          Ala Pro Ala Ser Ser Ser Thr Lys Lys Thr Gln Leu Gln Leu Glu Ala 
          1               5                   10                  15      
          Leu Leu Leu Asp Leu Gln Thr Ile Leu Asn Gly Ile Asn Asn Tyr Lys 
                      20                  25                  30          
          Asn Pro Lys Leu Thr Arg Met Leu Thr Phe Lys Phe Tyr Met Pro Lys 
                  35                  40                  45              
          Lys Ala Thr Glu Leu Lys His Leu Gln Cys Leu Glu Arg Glu Leu Lys 
              50                  55                  60                  
          Arg Leu Glu Glu Val Leu Asn Leu Ala Gln Ser Lys Asn Phe His Leu 
          65                  70                  75                  80  
          Arg Pro Arg Tyr Leu Ile Ser Asn Ile Asn Val Ile Val Leu Gln Leu 
                          85                  90                  95      
          Lys Gly Ser Glu Thr Thr Phe Met Cys Glu Tyr Ala Asp Glu Thr Ala 
                      100                 105                 110         
          Thr Ile Val Glu Phe Leu Asn Arg Trp Ile Thr Phe Ser Gln Ser Ile 
                  115                 120                 125             
          Ile Ser Thr Leu Thr 
              130             
          <![CDATA[<210>  272]]>
          <![CDATA[<211>  133]]>
          <![CDATA[<212>  PRT]]>
          <![CDATA[<213>  人工序列]]>
          <![CDATA[<220>]]>
          <![CDATA[<223>  合成：IL-2-T3A-H16A-L19N-E61R-P65R-D84Y-C125S]]>
          <![CDATA[<400>  272]]>
          Ala Pro Ala Ser Ser Ser Thr Lys Lys Thr Gln Leu Gln Leu Glu Ala 
          1               5                   10                  15      
          Leu Leu Asn Asp Leu Gln Met Ile Leu Asn Gly Ile Asn Asn Tyr Lys 
                      20                  25                  30          
          Asn Pro Lys Leu Thr Arg Met Leu Thr Phe Lys Phe Tyr Met Pro Lys 
                  35                  40                  45              
          Lys Ala Thr Glu Leu Lys His Leu Gln Cys Leu Glu Arg Glu Leu Lys 
              50                  55                  60                  
          Arg Leu Glu Glu Val Leu Asn Leu Ala Gln Ser Lys Asn Phe His Leu 
          65                  70                  75                  80  
          Arg Pro Arg Tyr Leu Ile Ser Asn Ile Asn Val Ile Val Leu Glu Leu 
                          85                  90                  95      
          Lys Gly Ser Glu Thr Thr Phe Met Cys Glu Tyr Ala Asp Glu Thr Ala 
                      100                 105                 110         
          Thr Ile Val Glu Phe Leu Asn Arg Trp Ile Thr Phe Ser Gln Ser Ile 
                  115                 120                 125             
          Ile Ser Thr Leu Thr 
              130             
          <![CDATA[<210>  273]]>
          <![CDATA[<211>  133]]>
          <![CDATA[<212>  PRT]]>
          <![CDATA[<213>  人工序列]]>
          <![CDATA[<220>]]>
          <![CDATA[<223>  合成：IL-2-T3A-H16A-L19N-M23T-E61R-P65R-D84Y-E95Q-C125S]]>
          <![CDATA[<400>  273]]>
          Ala Pro Ala Ser Ser Ser Thr Lys Lys Thr Gln Leu Gln Leu Glu Ala 
          1               5                   10                  15      
          Leu Leu Asn Asp Leu Gln Thr Ile Leu Asn Gly Ile Asn Asn Tyr Lys 
                      20                  25                  30          
          Asn Pro Lys Leu Thr Arg Met Leu Thr Phe Lys Phe Tyr Met Pro Lys 
                  35                  40                  45              
          Lys Ala Thr Glu Leu Lys His Leu Gln Cys Leu Glu Arg Glu Leu Lys 
              50                  55                  60                  
          Arg Leu Glu Glu Val Leu Asn Leu Ala Gln Ser Lys Asn Phe His Leu 
          65                  70                  75                  80  
          Arg Pro Arg Tyr Leu Ile Ser Asn Ile Asn Val Ile Val Leu Gln Leu 
                          85                  90                  95      
          Lys Gly Ser Glu Thr Thr Phe Met Cys Glu Tyr Ala Asp Glu Thr Ala 
                      100                 105                 110         
          Thr Ile Val Glu Phe Leu Asn Arg Trp Ile Thr Phe Ser Gln Ser Ile 
                  115                 120                 125             
          Ile Ser Thr Leu Thr 
              130             
          <![CDATA[<210>  274]]>
          <![CDATA[<211>  133]]>
          <![CDATA[<212>  PRT]]>
          <![CDATA[<213>  人工序列]]>
          <![CDATA[<220>]]>
          <![CDATA[<223>  合成：IL-2-T3A-H16A-E61R-P65R-D84Y-C125S-S127D]]>
          <![CDATA[<400>  274]]>
          Ala Pro Ala Ser Ser Ser Thr Lys Lys Thr Gln Leu Gln Leu Glu Ala 
          1               5                   10                  15      
          Leu Leu Leu Asp Leu Gln Met Ile Leu Asn Gly Ile Asn Asn Tyr Lys 
                      20                  25                  30          
          Asn Pro Lys Leu Thr Arg Met Leu Thr Phe Lys Phe Tyr Met Pro Lys 
                  35                  40                  45              
          Lys Ala Thr Glu Leu Lys His Leu Gln Cys Leu Glu Arg Glu Leu Lys 
              50                  55                  60                  
          Arg Leu Glu Glu Val Leu Asn Leu Ala Gln Ser Lys Asn Phe His Leu 
          65                  70                  75                  80  
          Arg Pro Arg Tyr Leu Ile Ser Asn Ile Asn Val Ile Val Leu Glu Leu 
                          85                  90                  95      
          Lys Gly Ser Glu Thr Thr Phe Met Cys Glu Tyr Ala Asp Glu Thr Ala 
                      100                 105                 110         
          Thr Ile Val Glu Phe Leu Asn Arg Trp Ile Thr Phe Ser Gln Asp Ile 
                  115                 120                 125             
          Ile Ser Thr Leu Thr 
              130             
          <![CDATA[<210>  275]]>
          <![CDATA[<211>  133]]>
          <![CDATA[<212>  PRT]]>
          <![CDATA[<213>  人工序列]]>
          <![CDATA[<220>]]>
          <![CDATA[<223>  合成：IL-2-T3A-H16A-M23T-E61R-P65R-D84Y-E95Q-C125S-S127D]]>
          <![CDATA[<400>  275]]>
          Ala Pro Ala Ser Ser Ser Thr Lys Lys Thr Gln Leu Gln Leu Glu Ala 
          1               5                   10                  15      
          Leu Leu Leu Asp Leu Gln Thr Ile Leu Asn Gly Ile Asn Asn Tyr Lys 
                      20                  25                  30          
          Asn Pro Lys Leu Thr Arg Met Leu Thr Phe Lys Phe Tyr Met Pro Lys 
                  35                  40                  45              
          Lys Ala Thr Glu Leu Lys His Leu Gln Cys Leu Glu Arg Glu Leu Lys 
              50                  55                  60                  
          Arg Leu Glu Glu Val Leu Asn Leu Ala Gln Ser Lys Asn Phe His Leu 
          65                  70                  75                  80  
          Arg Pro Arg Tyr Leu Ile Ser Asn Ile Asn Val Ile Val Leu Gln Leu 
                          85                  90                  95      
          Lys Gly Ser Glu Thr Thr Phe Met Cys Glu Tyr Ala Asp Glu Thr Ala 
                      100                 105                 110         
          Thr Ile Val Glu Phe Leu Asn Arg Trp Ile Thr Phe Ser Gln Asp Ile 
                  115                 120                 125             
          Ile Ser Thr Leu Thr 
              130             
          <![CDATA[<210>  276]]>
          <![CDATA[<211>  133]]>
          <![CDATA[<212>  PRT]]>
          <![CDATA[<213>  人工序列]]>
          <![CDATA[<220>]]>
          <![CDATA[<223>  合成：IL-2-T3A-H16A-L19N-E61R-P65R-D84Y-C125S-S127D]]>
          <![CDATA[<400>  276]]>
          Ala Pro Ala Ser Ser Ser Thr Lys Lys Thr Gln Leu Gln Leu Glu Ala 
          1               5                   10                  15      
          Leu Leu Asn Asp Leu Gln Met Ile Leu Asn Gly Ile Asn Asn Tyr Lys 
                      20                  25                  30          
          Asn Pro Lys Leu Thr Arg Met Leu Thr Phe Lys Phe Tyr Met Pro Lys 
                  35                  40                  45              
          Lys Ala Thr Glu Leu Lys His Leu Gln Cys Leu Glu Arg Glu Leu Lys 
              50                  55                  60                  
          Arg Leu Glu Glu Val Leu Asn Leu Ala Gln Ser Lys Asn Phe His Leu 
          65                  70                  75                  80  
          Arg Pro Arg Tyr Leu Ile Ser Asn Ile Asn Val Ile Val Leu Glu Leu 
                          85                  90                  95      
          Lys Gly Ser Glu Thr Thr Phe Met Cys Glu Tyr Ala Asp Glu Thr Ala 
                      100                 105                 110         
          Thr Ile Val Glu Phe Leu Asn Arg Trp Ile Thr Phe Ser Gln Asp Ile 
                  115                 120                 125             
          Ile Ser Thr Leu Thr 
              130             
          <![CDATA[<210>  277]]>
          <![CDATA[<211>  133]]>
          <![CDATA[<212>  PRT]]>
          <![CDATA[<213>  人工序列]]>
          <![CDATA[<220>]]>
          <![CDATA[<223>  合成：]]>
                 IL-2-T3A-H16A-L19N-M23T-E61R-P65R-D84Y-E95Q-C125S-S127D
          <![CDATA[<400>  277]]>
          Ala Pro Ala Ser Ser Ser Thr Lys Lys Thr Gln Leu Gln Leu Glu Ala 
          1               5                   10                  15      
          Leu Leu Asn Asp Leu Gln Thr Ile Leu Asn Gly Ile Asn Asn Tyr Lys 
                      20                  25                  30          
          Asn Pro Lys Leu Thr Arg Met Leu Thr Phe Lys Phe Tyr Met Pro Lys 
                  35                  40                  45              
          Lys Ala Thr Glu Leu Lys His Leu Gln Cys Leu Glu Arg Glu Leu Lys 
              50                  55                  60                  
          Arg Leu Glu Glu Val Leu Asn Leu Ala Gln Ser Lys Asn Phe His Leu 
          65                  70                  75                  80  
          Arg Pro Arg Tyr Leu Ile Ser Asn Ile Asn Val Ile Val Leu Gln Leu 
                          85                  90                  95      
          Lys Gly Ser Glu Thr Thr Phe Met Cys Glu Tyr Ala Asp Glu Thr Ala 
                      100                 105                 110         
          Thr Ile Val Glu Phe Leu Asn Arg Trp Ile Thr Phe Ser Gln Asp Ile 
                  115                 120                 125             
          Ile Ser Thr Leu Thr 
              130             
          <![CDATA[<210>  278]]>
          <![CDATA[<211>  132]]>
          <![CDATA[<212>  PRT]]>
          <![CDATA[<213>  人工序列]]>
          <![CDATA[<220>]]>
          <![CDATA[<223>  合成：IL-2-T3A-H16A-delta-F42-P65R-D84S-C125S]]>
          <![CDATA[<400>  278]]>
          Ala Pro Ala Ser Ser Ser Thr Lys Lys Thr Gln Leu Gln Leu Glu Ala 
          1               5                   10                  15      
          Leu Leu Leu Asp Leu Gln Met Ile Leu Asn Gly Ile Asn Asn Tyr Lys 
                      20                  25                  30          
          Asn Pro Lys Leu Thr Arg Met Leu Thr Lys Phe Tyr Met Pro Lys Lys 
                  35                  40                  45              
          Ala Thr Glu Leu Lys His Leu Gln Cys Leu Glu Glu Glu Leu Lys Arg 
              50                  55                  60                  
          Leu Glu Glu Val Leu Asn Leu Ala Gln Ser Lys Asn Phe His Leu Arg 
          65                  70                  75                  80  
          Pro Arg Ser Leu Ile Ser Asn Ile Asn Val Ile Val Leu Glu Leu Lys 
                          85                  90                  95      
          Gly Ser Glu Thr Thr Phe Met Cys Glu Tyr Ala Asp Glu Thr Ala Thr 
                      100                 105                 110         
          Ile Val Glu Phe Leu Asn Arg Trp Ile Thr Phe Ser Gln Ser Ile Ile 
                  115                 120                 125             
          Ser Thr Leu Thr 
              130         
          <![CDATA[<210>  279]]>
          <![CDATA[<211>  133]]>
          <![CDATA[<212>  PRT]]>
          <![CDATA[<213>  人工序列]]>
          <![CDATA[<220>]]>
          <![CDATA[<223>  合成：IL-2-T3A-H16A-K43E-Y45R-P65R-D84S-C125S]]>
          <![CDATA[<400>  279]]>
          Ala Pro Ala Ser Ser Ser Thr Lys Lys Thr Gln Leu Gln Leu Glu Ala 
          1               5                   10                  15      
          Leu Leu Leu Asp Leu Gln Met Ile Leu Asn Gly Ile Asn Asn Tyr Lys 
                      20                  25                  30          
          Asn Pro Lys Leu Thr Arg Met Leu Thr Phe Glu Phe Arg Met Pro Lys 
                  35                  40                  45              
          Lys Ala Thr Glu Leu Lys His Leu Gln Cys Leu Glu Glu Glu Leu Lys 
              50                  55                  60                  
          Arg Leu Glu Glu Val Leu Asn Leu Ala Gln Ser Lys Asn Phe His Leu 
          65                  70                  75                  80  
          Arg Pro Arg Ser Leu Ile Ser Asn Ile Asn Val Ile Val Leu Glu Leu 
                          85                  90                  95      
          Lys Gly Ser Glu Thr Thr Phe Met Cys Glu Tyr Ala Asp Glu Thr Ala 
                      100                 105                 110         
          Thr Ile Val Glu Phe Leu Asn Arg Trp Ile Thr Phe Ser Gln Ser Ile 
                  115                 120                 125             
          Ile Ser Thr Leu Thr 
              130             
          <![CDATA[<210>  280]]>
          <![CDATA[<211>  133]]>
          <![CDATA[<212>  PRT]]>
          <![CDATA[<213>  人工序列]]>
          <![CDATA[<220>]]>
          <![CDATA[<223>  合成：IL-2-T3A-H16A-K43E-P65R-D84S-C125S]]>
          <![CDATA[<400>  280]]>
          Ala Pro Ala Ser Ser Ser Thr Lys Lys Thr Gln Leu Gln Leu Glu Ala 
          1               5                   10                  15      
          Leu Leu Leu Asp Leu Gln Met Ile Leu Asn Gly Ile Asn Asn Tyr Lys 
                      20                  25                  30          
          Asn Pro Lys Leu Thr Arg Met Leu Thr Phe Glu Phe Tyr Met Pro Lys 
                  35                  40                  45              
          Lys Ala Thr Glu Leu Lys His Leu Gln Cys Leu Glu Glu Glu Leu Lys 
              50                  55                  60                  
          Arg Leu Glu Glu Val Leu Asn Leu Ala Gln Ser Lys Asn Phe His Leu 
          65                  70                  75                  80  
          Arg Pro Arg Ser Leu Ile Ser Asn Ile Asn Val Ile Val Leu Glu Leu 
                          85                  90                  95      
          Lys Gly Ser Glu Thr Thr Phe Met Cys Glu Tyr Ala Asp Glu Thr Ala 
                      100                 105                 110         
          Thr Ile Val Glu Phe Leu Asn Arg Trp Ile Thr Phe Ser Gln Ser Ile 
                  115                 120                 125             
          Ile Ser Thr Leu Thr 
              130             
          <![CDATA[<210>  281]]>
          <![CDATA[<211>  133]]>
          <![CDATA[<212>  PRT]]>
          <![CDATA[<213>  人工序列]]>
          <![CDATA[<220>]]>
          <![CDATA[<223>  合成：IL-2-T3A-H16A-P65R-D84S-I114F-C125S]]>
          <![CDATA[<400>  281]]>
          Ala Pro Ala Ser Ser Ser Thr Lys Lys Thr Gln Leu Gln Leu Glu Ala 
          1               5                   10                  15      
          Leu Leu Leu Asp Leu Gln Met Ile Leu Asn Gly Ile Asn Asn Tyr Lys 
                      20                  25                  30          
          Asn Pro Lys Leu Thr Arg Met Leu Thr Phe Lys Phe Tyr Met Pro Lys 
                  35                  40                  45              
          Lys Ala Thr Glu Leu Lys His Leu Gln Cys Leu Glu Glu Glu Leu Lys 
              50                  55                  60                  
          Arg Leu Glu Glu Val Leu Asn Leu Ala Gln Ser Lys Asn Phe His Leu 
          65                  70                  75                  80  
          Arg Pro Arg Ser Leu Ile Ser Asn Ile Asn Val Ile Val Leu Glu Leu 
                          85                  90                  95      
          Lys Gly Ser Glu Thr Thr Phe Met Cys Glu Tyr Ala Asp Glu Thr Ala 
                      100                 105                 110         
          Thr Phe Val Glu Phe Leu Asn Arg Trp Ile Thr Phe Ser Gln Ser Ile 
                  115                 120                 125             
          Ile Ser Thr Leu Thr 
              130             
          <![CDATA[<210>  282]]>
          <![CDATA[<211>  133]]>
          <![CDATA[<212>  PRT]]>
          <![CDATA[<213>  人工序列]]>
          <![CDATA[<220>]]>
          <![CDATA[<223>  合成：IL-2-T3A-H16A-F42R-P65R-D84S-C125S]]>
          <![CDATA[<400>  282]]>
          Ala Pro Ala Ser Ser Ser Thr Lys Lys Thr Gln Leu Gln Leu Glu Ala 
          1               5                   10                  15      
          Leu Leu Leu Asp Leu Gln Met Ile Leu Asn Gly Ile Asn Asn Tyr Lys 
                      20                  25                  30          
          Asn Pro Lys Leu Thr Arg Met Leu Thr Arg Lys Phe Tyr Met Pro Lys 
                  35                  40                  45              
          Lys Ala Thr Glu Leu Lys His Leu Gln Cys Leu Glu Glu Glu Leu Lys 
              50                  55                  60                  
          Arg Leu Glu Glu Val Leu Asn Leu Ala Gln Ser Lys Asn Phe His Leu 
          65                  70                  75                  80  
          Arg Pro Arg Ser Leu Ile Ser Asn Ile Asn Val Ile Val Leu Glu Leu 
                          85                  90                  95      
          Lys Gly Ser Glu Thr Thr Phe Met Cys Glu Tyr Ala Asp Glu Thr Ala 
                      100                 105                 110         
          Thr Ile Val Glu Phe Leu Asn Arg Trp Ile Thr Phe Ser Gln Ser Ile 
                  115                 120                 125             
          Ile Ser Thr Leu Thr 
              130             
          <![CDATA[<210>  283]]>
          <![CDATA[<211>  133]]>
          <![CDATA[<212>  PRT]]>
          <![CDATA[<213>  人工序列]]>
          <![CDATA[<220>]]>
          <![CDATA[<223>  合成：IL-2-T3A-K43E-Y45R-C125S]]>
          <![CDATA[<400>  283]]>
          Ala Pro Ala Ser Ser Ser Thr Lys Lys Thr Gln Leu Gln Leu Glu His 
          1               5                   10                  15      
          Leu Leu Leu Asp Leu Gln Met Ile Leu Asn Gly Ile Asn Asn Tyr Lys 
                      20                  25                  30          
          Asn Pro Lys Leu Thr Arg Met Leu Thr Phe Glu Phe Arg Met Pro Lys 
                  35                  40                  45              
          Lys Ala Thr Glu Leu Lys His Leu Gln Cys Leu Glu Glu Glu Leu Lys 
              50                  55                  60                  
          Pro Leu Glu Glu Val Leu Asn Leu Ala Gln Ser Lys Asn Phe His Leu 
          65                  70                  75                  80  
          Arg Pro Arg Asp Leu Ile Ser Asn Ile Asn Val Ile Val Leu Glu Leu 
                          85                  90                  95      
          Lys Gly Ser Glu Thr Thr Phe Met Cys Glu Tyr Ala Asp Glu Thr Ala 
                      100                 105                 110         
          Thr Ile Val Glu Phe Leu Asn Arg Trp Ile Thr Phe Ser Gln Ser Ile 
                  115                 120                 125             
          Ile Ser Thr Leu Thr 
              130             
          <![CDATA[<210>  284]]>
          <![CDATA[<211>  133]]>
          <![CDATA[<212>  PRT]]>
          <![CDATA[<213>  人工序列]]>
          <![CDATA[<220>]]>
          <![CDATA[<223>  合成：IL-2-T3A-E61R-C125S]]>
          <![CDATA[<400>  284]]>
          Ala Pro Ala Ser Ser Ser Thr Lys Lys Thr Gln Leu Gln Leu Glu His 
          1               5                   10                  15      
          Leu Leu Leu Asp Leu Gln Met Ile Leu Asn Gly Ile Asn Asn Tyr Lys 
                      20                  25                  30          
          Asn Pro Lys Leu Thr Arg Met Leu Thr Phe Lys Phe Tyr Met Pro Lys 
                  35                  40                  45              
          Lys Ala Thr Glu Leu Lys His Leu Gln Cys Leu Glu Arg Glu Leu Lys 
              50                  55                  60                  
          Pro Leu Glu Glu Val Leu Asn Leu Ala Gln Ser Lys Asn Phe His Leu 
          65                  70                  75                  80  
          Arg Pro Arg Asp Leu Ile Ser Asn Ile Asn Val Ile Val Leu Glu Leu 
                          85                  90                  95      
          Lys Gly Ser Glu Thr Thr Phe Met Cys Glu Tyr Ala Asp Glu Thr Ala 
                      100                 105                 110         
          Thr Ile Val Glu Phe Leu Asn Arg Trp Ile Thr Phe Ser Gln Ser Ile 
                  115                 120                 125             
          Ile Ser Thr Leu Thr 
              130             
          <![CDATA[<210>  285]]>
          <![CDATA[<211>  133]]>
          <![CDATA[<212>  PRT]]>
          <![CDATA[<213>  人工序列]]>
          <![CDATA[<220>]]>
          <![CDATA[<223>  合成：IL-2-T3A-I114F-C125S]]>
          <![CDATA[<400>  285]]>
          Ala Pro Ala Ser Ser Ser Thr Lys Lys Thr Gln Leu Gln Leu Glu His 
          1               5                   10                  15      
          Leu Leu Leu Asp Leu Gln Met Ile Leu Asn Gly Ile Asn Asn Tyr Lys 
                      20                  25                  30          
          Asn Pro Lys Leu Thr Arg Met Leu Thr Phe Lys Phe Tyr Met Pro Lys 
                  35                  40                  45              
          Lys Ala Thr Glu Leu Lys His Leu Gln Cys Leu Glu Glu Glu Leu Lys 
              50                  55                  60                  
          Pro Leu Glu Glu Val Leu Asn Leu Ala Gln Ser Lys Asn Phe His Leu 
          65                  70                  75                  80  
          Arg Pro Arg Asp Leu Ile Ser Asn Ile Asn Val Ile Val Leu Glu Leu 
                          85                  90                  95      
          Lys Gly Ser Glu Thr Thr Phe Met Cys Glu Tyr Ala Asp Glu Thr Ala 
                      100                 105                 110         
          Thr Phe Val Glu Phe Leu Asn Arg Trp Ile Thr Phe Ser Gln Ser Ile 
                  115                 120                 125             
          Ile Ser Thr Leu Thr 
              130             
          <![CDATA[<210>  286]]>
          <![CDATA[<211>  133]]>
          <![CDATA[<212>  PRT]]>
          <![CDATA[<213>  人工序列]]>
          <![CDATA[<220>]]>
          <![CDATA[<223>  合成：IL-2-T3A-K43E-C125S]]>
          <![CDATA[<400>  286]]>
          Ala Pro Ala Ser Ser Ser Thr Lys Lys Thr Gln Leu Gln Leu Glu His 
          1               5                   10                  15      
          Leu Leu Leu Asp Leu Gln Met Ile Leu Asn Gly Ile Asn Asn Tyr Lys 
                      20                  25                  30          
          Asn Pro Lys Leu Thr Arg Met Leu Thr Phe Glu Phe Tyr Met Pro Lys 
                  35                  40                  45              
          Lys Ala Thr Glu Leu Lys His Leu Gln Cys Leu Glu Glu Glu Leu Lys 
              50                  55                  60                  
          Pro Leu Glu Glu Val Leu Asn Leu Ala Gln Ser Lys Asn Phe His Leu 
          65                  70                  75                  80  
          Arg Pro Arg Asp Leu Ile Ser Asn Ile Asn Val Ile Val Leu Glu Leu 
                          85                  90                  95      
          Lys Gly Ser Glu Thr Thr Phe Met Cys Glu Tyr Ala Asp Glu Thr Ala 
                      100                 105                 110         
          Thr Ile Val Glu Phe Leu Asn Arg Trp Ile Thr Phe Ser Gln Ser Ile 
                  115                 120                 125             
          Ile Ser Thr Leu Thr 
              130             
          <![CDATA[<210>  287]]>
          <![CDATA[<211>  133]]>
          <![CDATA[<212>  PRT]]>
          <![CDATA[<213>  人工序列]]>
          <![CDATA[<220>]]>
          <![CDATA[<223>  合成：IL-2-T3A-P65R-I114F-C125S]]>
          <![CDATA[<400>  287]]>
          Ala Pro Ala Ser Ser Ser Thr Lys Lys Thr Gln Leu Gln Leu Glu His 
          1               5                   10                  15      
          Leu Leu Leu Asp Leu Gln Met Ile Leu Asn Gly Ile Asn Asn Tyr Lys 
                      20                  25                  30          
          Asn Pro Lys Leu Thr Arg Met Leu Thr Phe Lys Phe Tyr Met Pro Lys 
                  35                  40                  45              
          Lys Ala Thr Glu Leu Lys His Leu Gln Cys Leu Glu Glu Glu Leu Lys 
              50                  55                  60                  
          Arg Leu Glu Glu Val Leu Asn Leu Ala Gln Ser Lys Asn Phe His Leu 
          65                  70                  75                  80  
          Arg Pro Arg Asp Leu Ile Ser Asn Ile Asn Val Ile Val Leu Glu Leu 
                          85                  90                  95      
          Lys Gly Ser Glu Thr Thr Phe Met Cys Glu Tyr Ala Asp Glu Thr Ala 
                      100                 105                 110         
          Thr Phe Val Glu Phe Leu Asn Arg Trp Ile Thr Phe Ser Gln Ser Ile 
                  115                 120                 125             
          Ile Ser Thr Leu Thr 
              130             
          <![CDATA[<210>  288]]>
          <![CDATA[<211>  133]]>
          <![CDATA[<212>  PRT]]>
          <![CDATA[<213>  人工序列]]>
          <![CDATA[<220>]]>
          <![CDATA[<223>  合成：IL-2-T3A-K43E-P65R-C125S]]>
          <![CDATA[<400>  288]]>
          Ala Pro Ala Ser Ser Ser Thr Lys Lys Thr Gln Leu Gln Leu Glu His 
          1               5                   10                  15      
          Leu Leu Leu Asp Leu Gln Met Ile Leu Asn Gly Ile Asn Asn Tyr Lys 
                      20                  25                  30          
          Asn Pro Lys Leu Thr Arg Met Leu Thr Phe Glu Phe Tyr Met Pro Lys 
                  35                  40                  45              
          Lys Ala Thr Glu Leu Lys His Leu Gln Cys Leu Glu Glu Glu Leu Lys 
              50                  55                  60                  
          Arg Leu Glu Glu Val Leu Asn Leu Ala Gln Ser Lys Asn Phe His Leu 
          65                  70                  75                  80  
          Arg Pro Arg Asp Leu Ile Ser Asn Ile Asn Val Ile Val Leu Glu Leu 
                          85                  90                  95      
          Lys Gly Ser Glu Thr Thr Phe Met Cys Glu Tyr Ala Asp Glu Thr Ala 
                      100                 105                 110         
          Thr Ile Val Glu Phe Leu Asn Arg Trp Ile Thr Phe Ser Gln Ser Ile 
                  115                 120                 125             
          Ile Ser Thr Leu Thr 
              130             
          <![CDATA[<210>  289]]>
          <![CDATA[<211>  133]]>
          <![CDATA[<212>  PRT]]>
          <![CDATA[<213>  人工序列]]>
          <![CDATA[<220>]]>
          <![CDATA[<223>  合成：IL-2-T3A-K43E-Y45R-P65R-C125S]]>
          <![CDATA[<400>  289]]>
          Ala Pro Ala Ser Ser Ser Thr Lys Lys Thr Gln Leu Gln Leu Glu His 
          1               5                   10                  15      
          Leu Leu Leu Asp Leu Gln Met Ile Leu Asn Gly Ile Asn Asn Tyr Lys 
                      20                  25                  30          
          Asn Pro Lys Leu Thr Arg Met Leu Thr Phe Glu Phe Arg Met Pro Lys 
                  35                  40                  45              
          Lys Ala Thr Glu Leu Lys His Leu Gln Cys Leu Glu Glu Glu Leu Lys 
              50                  55                  60                  
          Arg Leu Glu Glu Val Leu Asn Leu Ala Gln Ser Lys Asn Phe His Leu 
          65                  70                  75                  80  
          Arg Pro Arg Asp Leu Ile Ser Asn Ile Asn Val Ile Val Leu Glu Leu 
                          85                  90                  95      
          Lys Gly Ser Glu Thr Thr Phe Met Cys Glu Tyr Ala Asp Glu Thr Ala 
                      100                 105                 110         
          Thr Ile Val Glu Phe Leu Asn Arg Trp Ile Thr Phe Ser Gln Ser Ile 
                  115                 120                 125             
          Ile Ser Thr Leu Thr 
              130             
          <![CDATA[<210>  290]]>
          <![CDATA[<211>  133]]>
          <![CDATA[<212>  PRT]]>
          <![CDATA[<213>  人工序列]]>
          <![CDATA[<220>]]>
          <![CDATA[<223>  合成：IL-2-T3A-R38A-C125S]]>
          <![CDATA[<400>  290]]>
          Ala Pro Ala Ser Ser Ser Thr Lys Lys Thr Gln Leu Gln Leu Glu His 
          1               5                   10                  15      
          Leu Leu Leu Asp Leu Gln Met Ile Leu Asn Gly Ile Asn Asn Tyr Lys 
                      20                  25                  30          
          Asn Pro Lys Leu Thr Ala Met Leu Thr Phe Lys Phe Tyr Met Pro Lys 
                  35                  40                  45              
          Lys Ala Thr Glu Leu Lys His Leu Gln Cys Leu Glu Glu Glu Leu Lys 
              50                  55                  60                  
          Pro Leu Glu Glu Val Leu Asn Leu Ala Gln Ser Lys Asn Phe His Leu 
          65                  70                  75                  80  
          Arg Pro Arg Asp Leu Ile Ser Asn Ile Asn Val Ile Val Leu Glu Leu 
                          85                  90                  95      
          Lys Gly Ser Glu Thr Thr Phe Met Cys Glu Tyr Ala Asp Glu Thr Ala 
                      100                 105                 110         
          Thr Ile Val Glu Phe Leu Asn Arg Trp Ile Thr Phe Ser Gln Ser Ile 
                  115                 120                 125             
          Ile Ser Thr Leu Thr 
              130             
          <![CDATA[<210>  291]]>
          <![CDATA[<211>  115]]>
          <![CDATA[<212>  PRT]]>
          <![CDATA[<213>  人工序列]]>
          <![CDATA[<220>]]>
          <![CDATA[<223>  合成：IL-15 WT]]>
          <![CDATA[<400>  291]]>
          Met Asn Trp Val Asn Val Ile Ser Asp Leu Lys Lys Ile Glu Asp Leu 
          1               5                   10                  15      
          Ile Gln Ser Met His Ile Asp Ala Thr Leu Tyr Thr Glu Ser Asp Val 
                      20                  25                  30          
          His Pro Ser Cys Lys Val Thr Ala Met Lys Cys Phe Leu Leu Glu Leu 
                  35                  40                  45              
          Gln Val Ile Ser Leu Glu Ser Gly Asp Ala Ser Ile His Asp Thr Val 
              50                  55                  60                  
          Glu Asn Leu Ile Ile Leu Ala Asn Asn Ser Leu Ser Ser Asn Gly Asn 
          65                  70                  75                  80  
          Val Thr Glu Ser Gly Cys Lys Glu Cys Glu Glu Leu Glu Glu Lys Asn 
                          85                  90                  95      
          Ile Lys Glu Phe Leu Gln Ser Phe Val His Ile Val Gln Met Phe Ile 
                      100                 105                 110         
          Asn Thr Ser 
                  115 
          <![CDATA[<210>  292]]>
          <![CDATA[<211>  223]]>
          <![CDATA[<212>  PRT]]>
          <![CDATA[<213>  人工序列]]>
          <![CDATA[<220>]]>
          <![CDATA[<223>  合成：Fc區xELL P329G杵]]>
          <![CDATA[<400>  292]]>
          Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Gly Gly Pro Ser 
          1               5                   10                  15      
          Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg 
                      20                  25                  30          
          Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro 
                  35                  40                  45              
          Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala 
              50                  55                  60                  
          Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val 
          65                  70                  75                  80  
          Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr 
                          85                  90                  95      
          Lys Cys Lys Val Ser Asn Lys Ala Leu Gly Ala Pro Ile Glu Lys Thr 
                      100                 105                 110         
          Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu 
                  115                 120                 125             
          Pro Pro Cys Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu Trp Cys 
              130                 135                 140                 
          Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser 
          145                 150                 155                 160 
          Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp 
                          165                 170                 175     
          Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser 
                      180                 185                 190         
          Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala 
                  195                 200                 205             
          Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly 
              210                 215                 220             
          <![CDATA[<210>  293]]>
          <![CDATA[<211>  223]]>
          <![CDATA[<212>  PRT]]>
          <![CDATA[<213>  人工序列]]>
          <![CDATA[<220>]]>
          <![CDATA[<223>  合成：Fc區xELL P329G, H435R臼]]>
          <![CDATA[<400>  293]]>
          Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Gly Gly Pro Ser 
          1               5                   10                  15      
          Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg 
                      20                  25                  30          
          Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro 
                  35                  40                  45              
          Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala 
              50                  55                  60                  
          Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val 
          65                  70                  75                  80  
          Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr 
                          85                  90                  95      
          Lys Cys Lys Val Ser Asn Lys Ala Leu Gly Ala Pro Ile Glu Lys Thr 
                      100                 105                 110         
          Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Cys Thr Leu 
                  115                 120                 125             
          Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu Ser Cys 
              130                 135                 140                 
          Ala Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser 
          145                 150                 155                 160 
          Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp 
                          165                 170                 175     
          Ser Asp Gly Ser Phe Phe Leu Val Ser Lys Leu Thr Val Asp Lys Ser 
                      180                 185                 190         
          Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala 
                  195                 200                 205             
          Leu His Asn Arg Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly 
              210                 215                 220             
          <![CDATA[<210>  294]]>
          <![CDATA[<211>  361]]>
          <![CDATA[<212>  PRT]]>
          <![CDATA[<213>  人工序列]]>
          <![CDATA[<220>]]>
          <![CDATA[<223>  合成：xELL-杵Fc  IL-2-RAS-T3G, C12]]>
          <![CDATA[<400>  294]]>
          Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Gly Gly Pro Ser 
          1               5                   10                  15      
          Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg 
                      20                  25                  30          
          Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro 
                  35                  40                  45              
          Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala 
              50                  55                  60                  
          Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val 
          65                  70                  75                  80  
          Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr 
                          85                  90                  95      
          Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr 
                      100                 105                 110         
          Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu 
                  115                 120                 125             
          Pro Pro Cys Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu Trp Cys 
              130                 135                 140                 
          Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser 
          145                 150                 155                 160 
          Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp 
                          165                 170                 175     
          Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser 
                      180                 185                 190         
          Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala 
                  195                 200                 205             
          Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Gly 
              210                 215                 220                 
          Ser Gly Gly Ser Ala Pro Gly Ser Ser Ser Thr Lys Lys Thr Gln Leu 
          225                 230                 235                 240 
          Gln Leu Glu Ala Leu Leu Leu Asp Leu Gln Met Ile Leu Asn Gly Ile 
                          245                 250                 255     
          Asn Asn Tyr Lys Asn Pro Lys Leu Thr Arg Met Leu Thr Phe Lys Phe 
                      260                 265                 270         
          Tyr Met Pro Lys Lys Ala Thr Glu Leu Lys His Leu Gln Cys Leu Glu 
                  275                 280                 285             
          Glu Glu Leu Lys Arg Leu Glu Glu Val Leu Asn Leu Ala Gln Ser Lys 
              290                 295                 300                 
          Asn Phe His Leu Arg Pro Arg Ser Leu Ile Ser Asn Ile Asn Val Ile 
          305                 310                 315                 320 
          Val Leu Glu Leu Lys Gly Ser Glu Thr Thr Phe Met Cys Glu Tyr Ala 
                          325                 330                 335     
          Asp Glu Thr Ala Thr Ile Val Glu Phe Leu Asn Arg Trp Ile Thr Phe 
                      340                 345                 350         
          Ser Gln Ser Ile Ile Ser Thr Leu Thr 
                  355                 360     
          <![CDATA[<210>  295]]>
          <![CDATA[<211>  358]]>
          <![CDATA[<212>  PRT]]>
          <![CDATA[<213>  人工序列]]>
          <![CDATA[<220>]]>
          <![CDATA[<223>  合成：gdTCR 5C8 VHH-xELL-臼T366S, L368A, Y407V, H435R Fc]]>
          <![CDATA[<400>  295]]>
          Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Ala Gly Gly 
          1               5                   10                  15      
          Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Arg Pro Phe Ser Asn Tyr 
                      20                  25                  30          
          Ala Met Gly Trp Phe Arg Gln Ala Pro Gly Lys Glu Arg Glu Phe Val 
                  35                  40                  45              
          Ala Ala Ile Ser Trp Ser Gly Gly Ser Thr Ser Tyr Ala Asp Ser Val 
              50                  55                  60                  
          Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Thr Val Tyr 
          65                  70                  75                  80  
          Leu Gln Met Asn Ser Pro Lys Pro Glu Asp Thr Ala Ile Tyr Tyr Cys 
                          85                  90                  95      
          Ala Ala Gln Phe Ser Gly Ala Asp Tyr Gly Phe Gly Arg Leu Gly Ile 
                      100                 105                 110         
          Arg Gly Tyr Glu Tyr Asp Tyr Trp Gly Gln Gly Thr Gln Val Thr Val 
                  115                 120                 125             
          Lys Pro Gly Gly Gly Gly Asp Lys Thr His Thr Cys Pro Pro Cys Pro 
              130                 135                 140                 
          Ala Pro Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp 
          145                 150                 155                 160 
          Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp 
                          165                 170                 175     
          Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly 
                      180                 185                 190         
          Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn 
                  195                 200                 205             
          Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp 
              210                 215                 220                 
          Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro 
          225                 230                 235                 240 
          Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu 
                          245                 250                 255     
          Pro Gln Val Cys Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn 
                      260                 265                 270         
          Gln Val Ser Leu Ser Cys Ala Val Lys Gly Phe Tyr Pro Ser Asp Ile 
                  275                 280                 285             
          Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr 
              290                 295                 300                 
          Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Val Ser Lys 
          305                 310                 315                 320 
          Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys 
                          325                 330                 335     
          Ser Val Met His Glu Ala Leu His Asn Arg Tyr Thr Gln Lys Ser Leu 
                      340                 345                 350         
          Ser Leu Ser Pro Gly Lys 
                  355             
          <![CDATA[<210>  296]]>
          <![CDATA[<211>  495]]>
          <![CDATA[<212>  PRT]]>
          <![CDATA[<213>  人工序列]]>
          <![CDATA[<220>]]>
          <![CDATA[<223>  合成：gdTCR 5C8 VHH-xELL-杵Fc-IL-2-T3A-H16A- ]]>
                 E61R-P65R-D84Y-C125S
          <![CDATA[<400>  296]]>
          Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Ala Gly Gly 
          1               5                   10                  15      
          Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Arg Pro Phe Ser Asn Tyr 
                      20                  25                  30          
          Ala Met Gly Trp Phe Arg Gln Ala Pro Gly Lys Glu Arg Glu Phe Val 
                  35                  40                  45              
          Ala Ala Ile Ser Trp Ser Gly Gly Ser Thr Ser Tyr Ala Asp Ser Val 
              50                  55                  60                  
          Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Thr Val Tyr 
          65                  70                  75                  80  
          Leu Gln Met Asn Ser Pro Lys Pro Glu Asp Thr Ala Ile Tyr Tyr Cys 
                          85                  90                  95      
          Ala Ala Gln Phe Ser Gly Ala Asp Tyr Gly Phe Gly Arg Leu Gly Ile 
                      100                 105                 110         
          Arg Gly Tyr Glu Tyr Asp Tyr Trp Gly Gln Gly Thr Gln Val Thr Val 
                  115                 120                 125             
          Lys Pro Gly Gly Gly Gly Asp Lys Thr His Thr Cys Pro Pro Cys Pro 
              130                 135                 140                 
          Ala Pro Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp 
          145                 150                 155                 160 
          Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp 
                          165                 170                 175     
          Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly 
                      180                 185                 190         
          Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn 
                  195                 200                 205             
          Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp 
              210                 215                 220                 
          Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro 
          225                 230                 235                 240 
          Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu 
                          245                 250                 255     
          Pro Gln Val Tyr Thr Leu Pro Pro Cys Arg Asp Glu Leu Thr Lys Asn 
                      260                 265                 270         
          Gln Val Ser Leu Trp Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile 
                  275                 280                 285             
          Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr 
              290                 295                 300                 
          Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys 
          305                 310                 315                 320 
          Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys 
                          325                 330                 335     
          Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu 
                      340                 345                 350         
          Ser Leu Ser Pro Gly Gly Ser Gly Gly Ser Ala Pro Ala Ser Ser Ser 
                  355                 360                 365             
          Thr Lys Lys Thr Gln Leu Gln Leu Glu Ala Leu Leu Leu Asp Leu Gln 
              370                 375                 380                 
          Met Ile Leu Asn Gly Ile Asn Asn Tyr Lys Asn Pro Lys Leu Thr Arg 
          385                 390                 395                 400 
          Met Leu Thr Phe Lys Phe Tyr Met Pro Lys Lys Ala Thr Glu Leu Lys 
                          405                 410                 415     
          His Leu Gln Cys Leu Glu Arg Glu Leu Lys Arg Leu Glu Glu Val Leu 
                      420                 425                 430         
          Asn Leu Ala Gln Ser Lys Asn Phe His Leu Arg Pro Arg Tyr Leu Ile 
                  435                 440                 445             
          Ser Asn Ile Asn Val Ile Val Leu Glu Leu Lys Gly Ser Glu Thr Thr 
              450                 455                 460                 
          Phe Met Cys Glu Tyr Ala Asp Glu Thr Ala Thr Ile Val Glu Phe Leu 
          465                 470                 475                 480 
          Asn Arg Trp Ile Thr Phe Ser Gln Ser Ile Ile Ser Thr Leu Thr 
                          485                 490                 495 
          <![CDATA[<210>  297]]>
          <![CDATA[<400>  297]]>
          000
          <![CDATA[<210>  298]]>
          <![CDATA[<211>  488]]>
          <![CDATA[<212>  PRT]]>
          <![CDATA[<213>  人工序列]]>
          <![CDATA[<220>]]>
          <![CDATA[<223>  合成：gdTCR 6C4 VHH-xELL-杵Fc-IL-2- T3A-H16A- ]]>
                 E61R-P65R-D84Y-C125S
          <![CDATA[<400>  298]]>
          Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Ala Gly Gly 
          1               5                   10                  15      
          Ser Leu Arg Leu Ser Cys Ala Val Ser Val Arg Thr Phe Ser Asp Tyr 
                      20                  25                  30          
          Arg Met Gly Trp Phe Arg Gln Ala Pro Gly Lys Glu Arg Glu Phe Val 
                  35                  40                  45              
          Ser Thr Ile Ser Trp Ser Gly Gly Leu Thr Tyr Tyr Ala Asp Ser Val 
              50                  55                  60                  
          Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 
          65                  70                  75                  80  
          Leu Gln Met Asn Ser Leu Lys Pro Glu Asp Thr Ala Val Tyr Tyr Cys 
                          85                  90                  95      
          Ala Ala Gly Gly Gly Tyr Ala Gly Gly Thr Tyr Tyr His Pro Glu Glu 
                      100                 105                 110         
          Trp Gly Gln Gly Thr Gln Val Thr Val Lys Pro Gly Gly Gly Gly Asp 
                  115                 120                 125             
          Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Gly Gly Pro Ser Val 
              130                 135                 140                 
          Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr 
          145                 150                 155                 160 
          Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu 
                          165                 170                 175     
          Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys 
                      180                 185                 190         
          Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser 
                  195                 200                 205             
          Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys 
              210                 215                 220                 
          Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile 
          225                 230                 235                 240 
          Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro 
                          245                 250                 255     
          Pro Cys Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu Trp Cys Leu 
                      260                 265                 270         
          Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn 
                  275                 280                 285             
          Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser 
              290                 295                 300                 
          Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg 
          305                 310                 315                 320 
          Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu 
                          325                 330                 335     
          His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Gly Ser 
                      340                 345                 350         
          Gly Gly Ser Ala Pro Ala Ser Ser Ser Thr Lys Lys Thr Gln Leu Gln 
                  355                 360                 365             
          Leu Glu Ala Leu Leu Leu Asp Leu Gln Met Ile Leu Asn Gly Ile Asn 
              370                 375                 380                 
          Asn Tyr Lys Asn Pro Lys Leu Thr Arg Met Leu Thr Phe Lys Phe Tyr 
          385                 390                 395                 400 
          Met Pro Lys Lys Ala Thr Glu Leu Lys His Leu Gln Cys Leu Glu Arg 
                          405                 410                 415     
          Glu Leu Lys Arg Leu Glu Glu Val Leu Asn Leu Ala Gln Ser Lys Asn 
                      420                 425                 430         
          Phe His Leu Arg Pro Arg Tyr Leu Ile Ser Asn Ile Asn Val Ile Val 
                  435                 440                 445             
          Leu Glu Leu Lys Gly Ser Glu Thr Thr Phe Met Cys Glu Tyr Ala Asp 
              450                 455                 460                 
          Glu Thr Ala Thr Ile Val Glu Phe Leu Asn Arg Trp Ile Thr Phe Ser 
          465                 470                 475                 480 
          Gln Ser Ile Ile Ser Thr Leu Thr 
                          485             
          <![CDATA[<210>  299]]>
          <![CDATA[<211>  351]]>
          <![CDATA[<212>  PRT]]>
          <![CDATA[<213>  人工序列]]>
          <![CDATA[<220>]]>
          <![CDATA[<223>  合成：gdTCR 6C4 VHH-xELL-臼T366S, L368A, Y407V H435R Fc]]>
          <![CDATA[<400>  299]]>
          Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Ala Gly Gly 
          1               5                   10                  15      
          Ser Leu Arg Leu Ser Cys Ala Val Ser Val Arg Thr Phe Ser Asp Tyr 
                      20                  25                  30          
          Arg Met Gly Trp Phe Arg Gln Ala Pro Gly Lys Glu Arg Glu Phe Val 
                  35                  40                  45              
          Ser Thr Ile Ser Trp Ser Gly Gly Leu Thr Tyr Tyr Ala Asp Ser Val 
              50                  55                  60                  
          Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 
          65                  70                  75                  80  
          Leu Gln Met Asn Ser Leu Lys Pro Glu Asp Thr Ala Val Tyr Tyr Cys 
                          85                  90                  95      
          Ala Ala Gly Gly Gly Tyr Ala Gly Gly Thr Tyr Tyr His Pro Glu Glu 
                      100                 105                 110         
          Trp Gly Gln Gly Thr Gln Val Thr Val Lys Pro Gly Gly Gly Gly Asp 
                  115                 120                 125             
          Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Gly Gly Pro Ser Val 
              130                 135                 140                 
          Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr 
          145                 150                 155                 160 
          Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu 
                          165                 170                 175     
          Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys 
                      180                 185                 190         
          Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser 
                  195                 200                 205             
          Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys 
              210                 215                 220                 
          Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile 
          225                 230                 235                 240 
          Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Cys Thr Leu Pro 
                          245                 250                 255     
          Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu Ser Cys Ala 
                      260                 265                 270         
          Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn 
                  275                 280                 285             
          Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser 
              290                 295                 300                 
          Asp Gly Ser Phe Phe Leu Val Ser Lys Leu Thr Val Asp Lys Ser Arg 
          305                 310                 315                 320 
          Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu 
                          325                 330                 335     
          His Asn Arg Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys 
                      340                 345                 350     
          <![CDATA[<210>  300]]>
          <![CDATA[<211>  345]]>
          <![CDATA[<212>  PRT]]>
          <![CDATA[<213>  人工序列]]>
          <![CDATA[<220>]]>
          <![CDATA[<223>  合成：410A9v1 (非靶向)VHH-xELL-臼T366S, L368A, Y407V]]>
                 H435R Fc
          <![CDATA[<400>  300]]>
          Glu Val Gln Leu Val Glu Ser Gly Gly Gly Glu Val Gln Pro Gly Gly 
          1               5                   10                  15      
          Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Ser Ile Asn Ser Ile Asn 
                      20                  25                  30          
          Val Met Glu Trp Tyr Arg Gln Ala Pro Gly Lys Glu Arg Asp Leu Val 
                  35                  40                  45              
          Ala Gly Ile Thr Ser Asp Gly Asp Thr Asn Tyr Ala Glu Ser Val Lys 
              50                  55                  60                  
          Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Thr Leu Tyr Leu 
          65                  70                  75                  80  
          Gln Met Ser Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Arg 
                          85                  90                  95      
          Ala Arg Asp Trp Gly Ser Leu Thr Asp Tyr Trp Gly Gln Gly Thr Leu 
                      100                 105                 110         
          Val Thr Val Lys Pro Gly Gly Gly Gly Asp Lys Thr His Thr Cys Pro 
                  115                 120                 125             
          Pro Cys Pro Ala Pro Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys 
              130                 135                 140                 
          Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val 
          145                 150                 155                 160 
          Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr 
                          165                 170                 175     
          Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu 
                      180                 185                 190         
          Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His 
                  195                 200                 205             
          Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys 
              210                 215                 220                 
          Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln 
          225                 230                 235                 240 
          Pro Arg Glu Pro Gln Val Cys Thr Leu Pro Pro Ser Arg Asp Glu Leu 
                          245                 250                 255     
          Thr Lys Asn Gln Val Ser Leu Ser Cys Ala Val Lys Gly Phe Tyr Pro 
                      260                 265                 270         
          Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn 
                  275                 280                 285             
          Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu 
              290                 295                 300                 
          Val Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val 
          305                 310                 315                 320 
          Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn Arg Tyr Thr Gln 
                          325                 330                 335     
          Lys Ser Leu Ser Leu Ser Pro Gly Lys 
                      340                 345 
          <![CDATA[<210>  301]]>
          <![CDATA[<211>  482]]>
          <![CDATA[<212>  PRT]]>
          <![CDATA[<213>  人工序列]]>
          <![CDATA[<220>]]>
          <![CDATA[<223>  合成：410A9v1 (非靶向) VHH- xELL-杵Fc- IL-2-T3A-H16A-]]>
                 E61R-P65R-D84Y-C125S
          <![CDATA[<400>  301]]>
          Glu Val Gln Leu Val Glu Ser Gly Gly Gly Glu Val Gln Pro Gly Gly 
          1               5                   10                  15      
          Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Ser Ile Asn Ser Ile Asn 
                      20                  25                  30          
          Val Met Glu Trp Tyr Arg Gln Ala Pro Gly Lys Glu Arg Asp Leu Val 
                  35                  40                  45              
          Ala Gly Ile Thr Ser Asp Gly Asp Thr Asn Tyr Ala Glu Ser Val Lys 
              50                  55                  60                  
          Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Thr Leu Tyr Leu 
          65                  70                  75                  80  
          Gln Met Ser Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Arg 
                          85                  90                  95      
          Ala Arg Asp Trp Gly Ser Leu Thr Asp Tyr Trp Gly Gln Gly Thr Leu 
                      100                 105                 110         
          Val Thr Val Lys Pro Gly Gly Gly Gly Asp Lys Thr His Thr Cys Pro 
                  115                 120                 125             
          Pro Cys Pro Ala Pro Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys 
              130                 135                 140                 
          Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val 
          145                 150                 155                 160 
          Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr 
                          165                 170                 175     
          Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu 
                      180                 185                 190         
          Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His 
                  195                 200                 205             
          Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys 
              210                 215                 220                 
          Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln 
          225                 230                 235                 240 
          Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Cys Arg Asp Glu Leu 
                          245                 250                 255     
          Thr Lys Asn Gln Val Ser Leu Trp Cys Leu Val Lys Gly Phe Tyr Pro 
                      260                 265                 270         
          Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn 
                  275                 280                 285             
          Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu 
              290                 295                 300                 
          Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val 
          305                 310                 315                 320 
          Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln 
                          325                 330                 335     
          Lys Ser Leu Ser Leu Ser Pro Gly Gly Ser Gly Gly Ser Ala Pro Ala 
                      340                 345                 350         
          Ser Ser Ser Thr Lys Lys Thr Gln Leu Gln Leu Glu Ala Leu Leu Leu 
                  355                 360                 365             
          Asp Leu Gln Met Ile Leu Asn Gly Ile Asn Asn Tyr Lys Asn Pro Lys 
              370                 375                 380                 
          Leu Thr Arg Met Leu Thr Phe Lys Phe Tyr Met Pro Lys Lys Ala Thr 
          385                 390                 395                 400 
          Glu Leu Lys His Leu Gln Cys Leu Glu Arg Glu Leu Lys Arg Leu Glu 
                          405                 410                 415     
          Glu Val Leu Asn Leu Ala Gln Ser Lys Asn Phe His Leu Arg Pro Arg 
                      420                 425                 430         
          Tyr Leu Ile Ser Asn Ile Asn Val Ile Val Leu Glu Leu Lys Gly Ser 
                  435                 440                 445             
          Glu Thr Thr Phe Met Cys Glu Tyr Ala Asp Glu Thr Ala Thr Ile Val 
              450                 455                 460                 
          Glu Phe Leu Asn Arg Trp Ile Thr Phe Ser Gln Ser Ile Ile Ser Thr 
          465                 470                 475                 480 
          Leu Thr
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
Figure 12_A0101_SEQ_0240
Figure 12_A0101_SEQ_0241
Figure 12_A0101_SEQ_0242
Figure 12_A0101_SEQ_0243
Figure 12_A0101_SEQ_0244
Figure 12_A0101_SEQ_0245
Figure 12_A0101_SEQ_0246
Figure 12_A0101_SEQ_0247
Figure 12_A0101_SEQ_0248
Figure 12_A0101_SEQ_0249
Figure 12_A0101_SEQ_0250
Figure 12_A0101_SEQ_0251
Figure 12_A0101_SEQ_0252
Figure 12_A0101_SEQ_0253
Figure 12_A0101_SEQ_0254
Figure 12_A0101_SEQ_0255
Figure 12_A0101_SEQ_0256
Figure 12_A0101_SEQ_0257
Figure 12_A0101_SEQ_0258
Figure 12_A0101_SEQ_0259
Figure 12_A0101_SEQ_0260
Figure 12_A0101_SEQ_0261
Figure 12_A0101_SEQ_0262
Figure 12_A0101_SEQ_0263
Figure 12_A0101_SEQ_0264
Figure 12_A0101_SEQ_0265
Figure 12_A0101_SEQ_0266
Figure 12_A0101_SEQ_0267
Figure 12_A0101_SEQ_0268
Figure 12_A0101_SEQ_0269
Figure 12_A0101_SEQ_0270
Figure 12_A0101_SEQ_0271
Figure 12_A0101_SEQ_0272
Figure 12_A0101_SEQ_0273
Figure 12_A0101_SEQ_0274
Figure 12_A0101_SEQ_0275
Figure 12_A0101_SEQ_0276
Figure 12_A0101_SEQ_0277
Figure 12_A0101_SEQ_0278
Figure 12_A0101_SEQ_0279
Figure 12_A0101_SEQ_0280
Figure 12_A0101_SEQ_0281
Figure 12_A0101_SEQ_0282
Figure 12_A0101_SEQ_0283
Figure 12_A0101_SEQ_0284
Figure 12_A0101_SEQ_0285
Figure 12_A0101_SEQ_0286
Figure 12_A0101_SEQ_0287
Figure 12_A0101_SEQ_0288
Figure 12_A0101_SEQ_0289
Figure 12_A0101_SEQ_0290
Figure 12_A0101_SEQ_0291
Figure 12_A0101_SEQ_0292
Figure 12_A0101_SEQ_0293
Figure 12_A0101_SEQ_0294
Figure 12_A0101_SEQ_0295
Figure 12_A0101_SEQ_0296
Figure 12_A0101_SEQ_0297
Figure 12_A0101_SEQ_0298
Figure 12_A0101_SEQ_0299
Figure 12_A0101_SEQ_0300
Figure 12_A0101_SEQ_0301
Figure 12_A0101_SEQ_0302
Figure 12_A0101_SEQ_0303
Figure 12_A0101_SEQ_0304
Figure 12_A0101_SEQ_0305
Figure 12_A0101_SEQ_0306
Figure 12_A0101_SEQ_0307
Figure 12_A0101_SEQ_0308
Figure 12_A0101_SEQ_0309
Figure 12_A0101_SEQ_0310
Figure 12_A0101_SEQ_0311
Figure 12_A0101_SEQ_0312
Figure 12_A0101_SEQ_0313
Figure 12_A0101_SEQ_0314
Figure 12_A0101_SEQ_0315
Figure 12_A0101_SEQ_0316
Figure 12_A0101_SEQ_0317
Figure 12_A0101_SEQ_0318
Figure 12_A0101_SEQ_0319
Figure 12_A0101_SEQ_0320
Figure 12_A0101_SEQ_0321
Figure 12_A0101_SEQ_0322
Figure 12_A0101_SEQ_0323
Figure 12_A0101_SEQ_0324
Figure 12_A0101_SEQ_0325
Figure 12_A0101_SEQ_0326
Figure 12_A0101_SEQ_0327
Figure 12_A0101_SEQ_0328
Figure 12_A0101_SEQ_0329
Figure 12_A0101_SEQ_0330
Figure 12_A0101_SEQ_0331
Figure 12_A0101_SEQ_0332
Figure 12_A0101_SEQ_0333
Figure 12_A0101_SEQ_0334
Figure 12_A0101_SEQ_0335
Figure 12_A0101_SEQ_0336
Figure 12_A0101_SEQ_0337
Figure 12_A0101_SEQ_0338
Figure 12_A0101_SEQ_0339
Figure 12_A0101_SEQ_0340
Figure 12_A0101_SEQ_0341
Figure 12_A0101_SEQ_0342
Figure 12_A0101_SEQ_0343
Figure 12_A0101_SEQ_0344
Figure 12_A0101_SEQ_0345
Figure 12_A0101_SEQ_0346
Figure 12_A0101_SEQ_0347
Figure 12_A0101_SEQ_0348

Claims (188)

  1. 一種包含經修飾IL-2之多肽，其中該經修飾IL-2包含D84Y取代。
  2. 如請求項1之多肽，其中相較於野生型IL-2，該經修飾IL-2對CD122之親和力降低。
  3. 如請求項1至2中任一項之多肽，其中該經修飾IL-2包含至少一個在選自以下之至少一個胺基酸位置處的取代：H16、L19、M23、N88及E95。
  4. 如請求項3之多肽，其中該經修飾IL-2包含胺基酸位置H16處之取代。
  5. 如請求項4之多肽，其中該取代係選自H16A、H16N、H16V及H16T。
  6. 如請求項1至5中任一項之多肽，其中該經修飾IL-2包含胺基酸位置L19處之取代。
  7. 如請求項6之多肽，其中該取代係選自L19A、L19P、L19Q、L19Y、L19N、L19S、L19T、L19V。
  8. 如請求項1至7中任一項之多肽，其中該經修飾IL-2包含胺基酸位置M23處之取代。
  9. 如請求項8之多肽，其中該取代係選自M23A、M23G、M23S、M23T、M23V、M23D、M23E、M23I、M23K、M23L、M23N、M23Q、M23R及M23Y。
  10. 如請求項1至9中任一項之多肽，其中該經修飾IL-2包含胺基酸位置N88處之取代。
  11. 如請求項10之多肽，其中該取代係選自N88T、N88A及N88S。
  12. 如請求項1至11中任一項之多肽，其中該經修飾IL-2包含胺基酸位置E95處之取代。
  13. 如請求項12之多肽，其中該取代係選自E95Q、E95G、E95T、E95V、E95P、E95H、E95N及E95Y。
  14. 如請求項1至13中任一項之多肽，其中相較於野生型IL-2，該經修飾IL-2包含至少一個降低對CD132之親和力之取代。
  15. 如請求項1至14中任一項之多肽，其中該經修飾IL-2包含至少一個在選自以下之至少一個胺基酸位置處的取代：Q22、R120、T123、Q126、S127、I129及S130。
  16. 如請求項15之多肽，其中該經修飾IL-2包含胺基酸位置Q22處之取代。
  17. 如請求項16之多肽，其中該取代係選自Q22A、Q22D、Q22G、Q22H、Q22K、Q22N、Q22R、Q22S、Q22T、Q22V及Q22Y。
  18. 如請求項15至17中任一項之多肽，其中該經修飾IL-2包含在胺基酸位置R120處之取代。
  19. 如請求項18之多肽，其中該取代係選自R120A、R120D、R120E、R120F、R120G、R120H、R120K、R120N、R120Q、R120S、R120V及R120Y。
  20. 如請求項15至19中任一項之多肽，其中該經修飾IL-2包含胺基酸位置T123處之取代。
  21. 如請求項20之多肽，其中該取代係選自T123D、T123E、T123H、T123K、T123N、T123Q及T123R。
  22. 如請求項15至21中任一項之多肽，其中該經修飾IL-2包含胺基酸位置Q126處之取代。
  23. 如請求項22之多肽，其中該取代係選自Q126N、Q126A及Q126Y。
  24. 如請求項15至23中任一項之多肽，其中該經修飾IL-2包含胺基酸位置S127處之取代。
  25. 如請求項24之多肽，其中該取代係選自S127D、S127E、S127H、S127K、S127N、S127P及S127R。
  26. 如請求項15至25中任一項之多肽，其中該經修飾IL-2包含胺基酸位置I129處之取代。
  27. 如請求項26之多肽，其中該取代係選自I129A、I129H、I129R及I129S。
  28. 如請求項15至27中任一項之多肽，其中該經修飾IL-2包含胺基酸位置S130處之取代。
  29. 如請求項28之多肽，其中該取代係選自S130E、S130K、S130N、S130P、S130Q及S130R。
  30. 一種包含經修飾IL-2之多肽，其中該經修飾IL-2包含至少一個在選自以下之至少一個胺基酸位置處的取代：Q22、R120、T123、S127及S130。
  31. 如請求項30之多肽，其中相較於野生型IL-2，該經修飾IL-2對CD132之親和力降低。
  32. 如請求項30至31中任一項之多肽，其中該經修飾IL-2包含胺基酸位置Q22處之取代。
  33. 如請求項32之多肽，其中該取代係選自Q22A、Q22D、Q22E、Q22G、Q22H、Q22K、Q22N、Q22P、Q22R、Q22S、Q22T、Q22V及Q22Y。
  34. 如請求項30至33中任一項之多肽，其中該經修飾IL-2包含胺基酸位置R120處之取代。
  35. 如請求項34之多肽，其中該取代係選自R120A、R120D、R120E、R120F、R120G、R120H、R120K、R120N、R120P、R120Q、R120S、R120V及R120Y。
  36. 如請求項30至35之多肽，其中該經修飾IL-2包含胺基酸位置T123處之取代。
  37. 如請求項36之多肽，其中該取代係選自T123D、T123E、T123H、T123K、T123N、T123Q及T123R。
  38. 如請求項30至37中任一項之多肽，其中該經修飾IL-2包含胺基酸位置S127處之取代。
  39. 如請求項38之多肽，其中該取代係選自S127D、S127E、S127H、S127K、S127N、S127P、S127Q及S127R。
  40. 如請求項30至39中任一項之多肽，其中該經修飾IL-2包含胺基酸位置S130處之取代。
  41. 如請求項40之多肽，其中該取代係選自S130D、S130E、S130H、S130K、S130N、S130P、S130Q及S130R。
  42. 如請求項30至41中任一項之多肽，其中相較於野生型IL-2，該經修飾IL-2包含至少一個降低對CD122之親和力之取代。
  43. 如請求項42之多肽，其中該經修飾IL-2包含至少一個在選自以下之至少一個胺基酸位置處的取代：H16、L19、M23、D84、N88及E95。
  44. 如請求項43之多肽，其中該經修飾IL-2包含胺基酸位置H16處之取代。
  45. 如請求項44之多肽，其中該取代係選自H16A、H16T、H16V及H16N。
  46. 如請求項43至45中任一項之多肽，其中該經修飾IL-2包含胺基酸位置L19處之取代。
  47. 如請求項46之多肽，其中該取代係選自L19A、L19P、L19Q、L19Y、L19N、L19S、L19T、L19V。
  48. 如請求項43至47中任一項之多肽，其中該經修飾IL-2包含胺基酸位置M23處之取代。
  49. 如請求項48之多肽，其中該取代係選自M23A、M23G、M23S、M23T、M23V、M23D、M23E、M23I、M23K、M23L、M23N、M23Q、M23R及M23Y。
  50. 如請求項43至49中任一項之多肽，其中該經修飾IL-2包含胺基酸位置D84處之取代。
  51. 如請求項50之多肽，其中該取代係選自D84S、D84G、D84A、D84T、D84V、D84Y及D84N。
  52. 如請求項43至51中任一項之多肽，其中該經修飾IL-2包含胺基酸位置N88處之取代。
  53. 如請求項52之多肽，其中該取代係選自N88T、N88A及N88S。
  54. 如請求項43至53中任一項之多肽，其中該經修飾IL-2包含胺基酸位置E95處之取代。
  55. 如請求項54之多肽，其中該取代係選自E95Q、E95G、E95T、E95V、E95P、E95H、E95N及E95Y。
  56. 如請求項1至55中任一項之多肽，其中相較於野生型IL-2，該經修飾IL-2包含至少一個降低對CD25之親和力之取代。
  57. 如請求項1至56中任一項之多肽，其中該經修飾IL-2包含至少一個在選自以下之至少一個胺基酸位置處的取代：K43、Y45、E61、I114、P65、F42、R38及L72，及/或其中該經修飾IL-2包含胺基酸F42之缺失。
  58. 如請求項57之多肽，其中該經修飾IL-2包含胺基酸F42處之取代或包含胺基酸F42之缺失。
  59. 如請求項58之多肽，其中該經修飾IL-2包含選自以下之胺基酸位置F42處之取代：F42K、F42A、F42R、F42G、F42S及F42T。
  60. 如請求項58之多肽，其中該經修飾IL-2包含胺基酸F42之缺失。
  61. 如請求項57至60中任一項之多肽，其中該經修飾IL-2包含胺基酸位置K43處之取代。
  62. 如請求項61之多肽，其中該取代係選自K43E及K43D。
  63. 如請求項57至62中任一項之多肽，其中該經修飾IL-2包含胺基酸位置Y45處之取代。
  64. 如請求項63之多肽，其中該取代係選自Y45R及Y45K。
  65. 如請求項57至64中任一項之多肽，其中該經修飾IL-2包含胺基酸位置E61處之取代。
  66. 如請求項65之多肽，其中該取代係選自E61R、E61G、E61H、E61N、E61P、E61S、E61T、E61Y、E61A、E61Q及E61K。
  67. 如請求項57至66中任一項之多肽，其中該經修飾IL-2包含胺基酸位置I114處之取代。
  68. 如請求項67之多肽，其中該取代為I114F、I114Y或I114W。
  69. 如請求項57至68中任一項之多肽，其中該經修飾IL-2包含胺基酸位置P65處之取代。
  70. 如請求項69之多肽，其中該取代係選自P65R、P65E、P65K、P65H、P65Y、P65Q、P65D及P65N。
  71. 如請求項57至70中任一項之多肽，其中該經修飾IL-2包含胺基酸位置R38處之取代。
  72. 如請求項71之多肽，其中該R38處之取代係選自R38A及R38G。
  73. 如請求項57至72中任一項之多肽，其中該經修飾IL-2包含胺基酸位置L72處之取代。
  74. 如請求項73之多肽，其中該L72處之取代為L72G。
  75. 如請求項1至74中任一項之多肽，其中該經修飾IL-2包含取代Q22A或取代R120A或取代Q22A及R120A。
  76. 如請求項1至75中任一項之多肽，其中該經修飾IL-2包含取代P65R及R38A或取代P65R及E61R。
  77. 如請求項1至76中任一項之多肽，其中該經修飾IL-2包含至少一個選自以下之取代：H16A、L19A、L19N、M23A、D84S或D84Y、N88S及E95Q。
  78. 如請求項1至77中任一項之多肽，其中該經修飾IL-2包含胺基酸位置P65、H16及D84處之取代。
  79. 如請求項78之多肽，其中該經修飾IL-2包含取代P65R、H16A及D84S；或取代P65R、H16A及D84Y。
  80. 如請求項1至79中任一項之多肽，其中該經修飾IL-2包含至少一個在選自T3及C125之至少一個胺基酸位置處的取代，及/或包含IL-2之前五個胺基酸之缺失。
  81. 如請求項80之多肽，其中該經修飾IL-2包含至少一個選自以下之取代：T3A、C125A、C125V及C125S。
  82. 如請求項81之多肽，其中該經修飾IL-2包含T3A及C125S取代，或T3A及C125V取代。
  83. 如請求項81之多肽，其中該經修飾IL-2包含IL-2之前五個胺基酸之缺失及C125S取代或C125V取代。
  84. 如前述請求項中任一項之多肽，其中該經修飾IL-2包含一組選自以下之取代：[T3A、H16A、E61R、P65R、D84Y、C125S]、[T3A、H16A、M23T、E61R、P65R、D84Y、E95Q、C125S]、[T3A、H16A、L19N、E61R、P65R、D84Y、C125S]、[T3A、H16A、L19N、M23T、E61R、P65R、D84Y、E95Q、C125S]、[T3A、H16A、E61R、P65R、D84Y、C125S、S127D]、[T3A、H16A、M23T、E61R、P65R、D84Y、E95Q、C125S、S127D]、[T3A、H16A、L19N、E61R、P65R、D84Y、C125S、S127D]及[T3A、H16A、L19N、M23T、E61R、P65R、D84Y、E95Q、C125S、S127D]。
  85. 一種包含經修飾IL-2之經修飾多肽，其中該經修飾IL-2包含一組選自以下之取代：[T3A、H16A、E61R、P65R、D84Y、C125S]、[T3A、H16A、M23T、E61R、P65R、D84Y、E95Q、C125S]、[T3A、H16A、L19N、E61R、P65R、D84Y、C125S]、[T3A、H16A、L19N、M23T、E61R、P65R、D84Y、E95Q、C125S]、[T3A、H16A、E61R、P65R、D84Y、C125S、S127D]、[T3A、H16A、M23T、E61R、P65R、D84Y、E95Q、C125S、S127D]、[T3A、H16A、L19N、E61R、P65R、D84Y、C125S、S127D]及[T3A、H16A、L19N、M23T、E61R、P65R、D84Y、E95Q、C125S、S127D]。
  86. 如前述請求項中任一項之多肽，其中該經修飾IL-2包含指定取代，且不包含任何額外取代。
  87. 如前述請求項中任一項之多肽，其中該經修飾IL-2為經修飾之人類IL-2。
  88. 如前述請求項中任一項之多肽，其中該等胺基酸位置對應於SEQ ID NO: 1中之胺基酸位置。
  89. 如前述請求項中任一項之多肽，其中該經修飾IL-2包含與SEQ ID NO: 84至少90%、91%、92%、93%、94%、95%、96%、97%、98%或99%一致且包含選自SEQ ID NO: 105至290之胺基酸序列之對應取代的胺基酸序列。
  90. 如前述請求項中任一項之多肽，其中該經修飾IL-2包含與選自SEQ ID NO: 270至277之胺基酸序列至少90%、91%、92%、93%、94%、95%、96%、97%、98%、99%或100%一致的胺基酸序列且包含取代D84Y。
  91. 如前述請求項中任一項之多肽，其中該經修飾IL-2包含選自SEQ ID NO: 105至290之胺基酸序列。
  92. 如前述請求項中任一項之多肽，其中該經修飾IL-2包含選自SEQ ID NO: 270至277之胺基酸序列。
  93. 如前述請求項中任一項之多肽，其中該多肽包含Fc區。
  94. 如請求項93之多肽，其中該經修飾IL-2與該Fc區之N端或C端融合。
  95. 如請求項93或請求項94之多肽，其中該Fc區包含Kabat胺基酸位置T366處之取代。
  96. 如請求項95之多肽，其中該Fc區包含T366W取代。
  97. 如請求項93或請求項94之多肽，其中該Fc區包含至少一個在選自T366、L368及Y407之至少一個Kabat胺基酸位置處的取代。
  98. 如請求項108之多肽，其中該Fc區包含T366S、L368A及Y407V突變。
  99. 如請求項93至98中任一項之多肽，其中該Fc區包含選自S354及Y349之Kabat位置處的取代。
  100. 如請求項99之多肽，其中該Fc區包含S354C或Y349C取代。
  101. 如請求項93至100中任一項之多肽，其中該Fc區包含Kabat胺基酸位置H435處之取代。
  102. 如請求項101之多肽，其中該Fc區包含選自H435R及H435K之取代。
  103. 如請求項93至102中任一項之多肽，其中該Fc區包含至少一個在選自M252及M428之至少一個Kabat胺基酸位置處的取代。
  104. 如請求項103之多肽，其中該Fc區包含M252Y及M428V取代。
  105. 如請求項93至104中任一項之多肽，其中該Fc區包含Kabat胺基酸E233、L234及L235之缺失。
  106. 如請求項93至104中任一項之多肽，其中該Fc區包含至少一個在選自L234、L235及P329之至少一個胺基酸位置處的取代。
  107. 如請求項106之多肽，其中該Fc區包含L234A、L235A及P329G取代。
  108. 如請求項93至107中任一項之多肽，其中該Fc區包含與選自SEQ ID NO: 47至83、292及293之胺基酸序列至少90%、91%、92%、93%、94%、95%、96%、97%、98%、99%或100%一致的胺基酸序列。
  109. 如請求項93至108中任一項之多肽，其中該Fc區為重鏈恆定區之一部分。
  110. 如請求項109之多肽，其中該重鏈恆定區為IgG恆定區。
  111. 如請求項110之多肽，其中該重鏈恆定區為IgG1、IgG2、IgG3或IgG4恆定區。
  112. 如請求項93至111中任一項之多肽，其中該經修飾IL-2與該Fc區或重鏈恆定區之C端融合。
  113. 如請求項112之多肽，其中該經修飾IL-2經由包含1至20個胺基酸之連接子而與該Fc區或重鏈恆定區之C端融合。
  114. 如請求項113之多肽，其中該連接子包含甘胺酸胺基酸。
  115. 如請求項114之多肽，其中該連接子包含甘胺酸及絲胺酸胺基酸。
  116. 如請求項113至115中任一項之多肽，其中該連接子中之大部分或所有該等胺基酸為甘胺酸及絲胺酸。
  117. 如請求項93至116中任一項之多肽，其中該多肽包含選自SEQ ID NO: 105至290之胺基酸序列及選自SEQ ID NO: 48、64、292及293之胺基酸序列。
  118. 如前述請求項中任一項之多肽，其中該多肽包含至少一個抗原結合域。
  119. 如請求項118之多肽，其中該多肽包含兩個、三個或四個抗原結合域。
  120. 如請求項118或請求項119之多肽，其中至少一個抗原結合域特異性結合於T細胞抗原或自然殺手細胞抗原。
  121. 如請求項118至120中任一項之多肽，其中至少一個抗原結合域特異性結合於CD4 +T細胞抗原或CD8 +T細胞抗原。
  122. 如請求項121之多肽，其中該至少一個抗原結合域特異性結合於經活化CD4 +T細胞或經活化CD8 +T細胞上之抗原。
  123. 如請求項118至122中任一項之多肽，其中至少一個抗原結合域為促效劑。
  124. 如請求項118至122中任一項之多肽，其中該抗原結合域為拮抗劑。
  125. 如請求項118至124中任一項之多肽，其中至少一個抗原結合域特異性結合於PD-1、CTLA-4、LAG3、TIM3、4-1BB、OX40、GITR、CD8a、CD8b、CD4、NKp30、NKG2A、TIGIT、TGFβR1、TGFβR2、Fas、NKG2D、NKp46、PD-L1、CD107a、ICOS、TNFR2、CD16a或γδTCR。
  126. 如請求項118至124中任一項之多肽，其中至少一個抗原結合域特異性結合於PD-1。
  127. 如請求項118至126中任一項之多肽，其中至少一個抗原結合域為人類或人類化抗原結合域。
  128. 如請求項127之多肽，其中各抗原結合域獨立地為人類或人類化抗原結合域。
  129. 如請求項118至128中任一項之多肽，其中至少一個抗原結合域包含VHH域。
  130. 如請求項129之多肽，其中各抗原結合域包含VHH域。
  131. 如請求項118至128中任一項之多肽，其中至少一個抗原結合域包含VH域及VL域。
  132. 如請求項131之多肽，其中至少一個抗原結合域包含選自以下之抗體之VH域及VL域：派立珠單抗(pembrolizumab)、納武單抗(nivolumab)、AMP-514、TSR-042、STI-A1110、伊匹單抗(ipilimumab)、曲美單抗(tremelimumab)、烏瑞魯單抗(urelumab)、烏圖木單抗(utomilumab)、阿特珠單抗(atezolizumab)及德瓦魯單抗(durvalumab)。
  133. 如請求項131或132之多肽，其中該至少一個抗原結合域包含單鏈Fv (scFv)。
  134. 如請求項131或132之多肽，其中該多肽包含重鏈恆定區，其中該VH域與該重鏈恆定區融合，且其中該VL域與該VH域締合。
  135. 如請求項134之多肽，其中該VL域與輕鏈恆定區融合。
  136. 如請求項135之多肽，其中該輕鏈恆定區係選自κ及λ。
  137. 如請求項118至136中任一項之多肽，其中該等抗原結合域中之每一者係相同。
  138. 如請求項118至137中任一項之多肽，其中該等抗原結合域中之每一者特異性結合於相同抗原。
  139. 如請求項118至136中任一項之多肽，其中該等抗原結合域中之至少一者特異性結合於與其他抗原結合域中之至少一者不同的抗原。
  140. 如請求項139之多肽，其中至少一個抗原結合域特異性結合於PD-1，且至少一個其他抗原結合域特異性結合於除PD-1以外之T細胞抗原或自然殺手細胞抗原。
  141. 如請求項118至140中任一項之多肽，其中至少一個抗原結合域結合於PD-1、CTLA-4、LAG3、TIM3、4-1BB、OX40、GITR、CD8a、CD8b、CD4、NKp30、NKG2A、TIGIT、TGFβR1、TGFβR2、Fas、NKG2D、NKp46、PD-L1、CD107a、ICOS、TNFR2、CD16a、DNAM1或γδTCR (Vγ9、Vγ2、Vδ1)。
  142. 如請求項93至141中任一項之多肽，其中該多肽在生理條件下形成均二聚體。
  143. 如前述請求項中任一項之多肽，其中該經修飾IL-2以比人類野生型IL-2對該IL-2R之親和力低至少2倍、3倍、4倍、5倍、6倍、7倍、8倍、9倍、至少10倍、至少20倍、至少30倍、至少50倍或至少100倍的親和力結合人類IL-2R。
  144. 一種複合物，其包含第一多肽及第二多肽，其中該第一多肽為如前述請求項中任一項之多肽。
  145. 如請求項144之複合物，其中該第一多肽包含第一Fc區，且該第二多肽包含第二Fc區。
  146. 如請求項144或請求項145之複合物，其中各Fc區為選自人類IgG1、IgG2、IgG3及IgG4之同型。
  147. 如請求項146之複合物，其中各Fc區為人類IgG1。
  148. 如請求項144至147中任一項之複合物，其中各Fc區包含胺基酸E233、L234及L235之缺失。
  149. 如請求項144至148中任一項之複合物，其中各Fc區包含H435R或H435K突變。
  150. 如請求項155至160中任一項之複合物，其中該Fc區包含突變M252Y及M428L或突變M252Y及M428V。
  151. 如請求項144至150中任一項之複合物，其中該第一Fc區或該第二Fc區包含T366W突變，且其他Fc區包含突變T366S、L368A及Y407V。
  152. 如請求項151之複合物，其中該第一Fc區或該第二Fc區包含S354C突變。
  153. 如請求項144至152中任一項之複合物，其中各Fc區獨立地包含與選自SEQ ID NO: 47至83、292及293之胺基酸序列至少90%、91%、92%、93%、94%、95%、96%、97%、98%、99%或100%一致的胺基酸序列。
  154. 如請求項144至153中任一項之複合物，其中該第二多肽不包含經修飾IL-2。
  155. 如請求項144至154中任一項之複合物，其中該第一多肽包含至少一個抗原結合域。
  156. 如請求項144至155中任一項之複合物，其中該第二多肽包含至少一個抗原結合域。
  157. 如請求項144至156中任一項之複合物，其中該第一多肽包含第一抗原結合域、Fc區及經修飾IL-2。
  158. 如請求項157之複合物，其中該第一抗原結合域與該Fc區之N端融合，且該經修飾IL-2與該Fc區之C端融合。
  159. 如請求項157或請求項158之複合物，其中該第二多肽包含第二抗原結合域及Fc區。
  160. 如請求項159之複合物，其中該第一抗原結合域及該第二抗原結合域相同或不同。
  161. 如請求項160之複合物，其中： a)     該第一抗原結合域及該第二抗原結合域兩者均結合PD-1； b)     該第一抗原結合域結合PD-1，且該第二抗原結合域結合LAG3； c)     該第一抗原結合域結合PD-1，且該第二抗原結合域結合CTLA-4； d)     該第一抗原結合域結合PD-1，且該第二抗原結合域結合4-1BB； e)     該第一抗原結合域結合PD-1，且該第二抗原結合域結合OX40； f)     該第一抗原結合域結合PD-1，且該第二抗原結合域結合GITR； g)     該第一抗原結合域結合PD-1，且該第二抗原結合域結合CD8a； h)     該第一抗原結合域結合PD-1，且該第二抗原結合域結合CD8b； i)     該第一抗原結合域結合PD-1，且該第二抗原結合域結合CD4； j)     該第一抗原結合域結合PD-1，且該第二抗原結合域結合NKp30； k)     該第一抗原結合域結合PD-1，且該第二抗原結合域結合NKG2A； l)     該第一抗原結合域結合PD-1，且該第二抗原結合域結合TIGIT； m)    該第一抗原結合域結合PD-1，且該第二抗原結合域結合NKG2D； n)     該第一抗原結合域結合PD-1，且該第二抗原結合域結合TGFBR2； o)     該第一抗原結合域結合PD-1，且該第二抗原結合域結合Fas； p)     該第一抗原結合域結合PD-1，且該第二抗原結合域結合CD107a； q)     該第一抗原結合域結合PD-1，且該第二抗原結合域結合NKp46； r)     該第一抗原結合域結合CD8a，且該第二抗原結合域結合TGFRβR2； s)     該第一抗原結合域結合CD8a，且該第二抗原結合域結合Fas； t)     該第一抗原結合域結合NKG2D，且該第二抗原結合域結合TGFRβR2； u)     該第一抗原結合域結合NKG2D，且該第二抗原結合域結合Fas； v)     該第一抗原結合域結合NKG2A，且該第二抗原結合域結合TGFRβR2； w)    該第一抗原結合域結合NKG2A，且該第二抗原結合域結合Fas； x)     該第一抗原結合域結合NKp46，且該第二抗原結合域結合TGFRβR2； y)     該第一抗原結合域結合NKp46，且該第二抗原結合域結合Fas； z)     該第一抗原結合域結合CTLA-4，且該第二抗原結合域結合LAG3； aa)    該第一抗原結合域結合CTLA-4，且該第二抗原結合域結合Tim3； bb)   該第一抗原結合域結合CTLA-4，且該第二抗原結合域結合OX40； cc)    該第一抗原結合域結合CTLA-4，且該第二抗原結合域結合GITR； dd)   該第一抗原結合域結合CTLA-4，且該第二抗原結合域結合CD107a； ee)    該第一抗原結合域結合CTLA-4，且該第二抗原結合域結合NKp46； ff)    該第一抗原結合域結合ICOS，且該第二抗原結合域結合TNFR2； gg)   該第一抗原結合域結合γδTCR，且該第二抗原結合域結合NKG2D； hh)   該第一抗原結合域結合γδTCR，且該第二抗原結合域結合DNAM1； ii)     該第一抗原結合域結合γδTCR，且該第二抗原結合域結合TIGIT； jj)     該第一抗原結合域結合γδTCR，且該第二抗原結合域結合4-1BB； kk)   該第一抗原結合域結合γδTCR，且該第二抗原結合域結合Fas； ll)     該第一抗原結合域結合γδTCR，且該第二抗原結合域結合NKG2A；或 mm)  該第一抗原結合域結合γδTCR，且該第二抗原結合域結合CD16a。
  162. 如請求項144至161中任一項之複合物，其中該經修飾IL-2以比人類野生型IL-2對該IL-2R之親和力低至少2倍、3倍、4倍、5倍、6倍、7倍、8倍、9倍、至少10倍、至少20倍、至少30倍、至少50倍或至少100倍的親和力結合人類IL-2R。
  163. 一種醫藥組合物，其包含如請求項1至154中任一項之多肽或如請求項144至162中任一項之複合物及醫藥學上可接受之載劑。
  164. 一種經分離核酸，其編碼如請求項1至143中任一項之多肽或如請求項144至162中任一項之複合物。
  165. 一種表現載體，其包含如請求項164之核酸。
  166. 一種經分離宿主細胞，其包含如請求項164之核酸或如請求項165之表現載體。
  167. 一種經分離宿主細胞，其表現如請求項1至143中任一項之多肽或如請求項144至162中任一項之複合物。
  168. 一種產生如請求項1至143中任一項之多肽或如請求項144至162中任一項之複合物的方法，其包含在適合表現該多肽或複合物之條件下培育如請求項166或請求項167之宿主細胞。
  169. 如請求項168之方法，其進一步包含分離該多肽或複合物。
  170. 一種增加CD4+及/或CD8+ T細胞增殖之方法，其包含使T細胞與如請求項1至143中任一項之多肽或如請求項144至162中任一項之複合物接觸。
  171. 如請求項170之方法，其中該等CD4+及/或CD8+ T細胞係在活體外。
  172. 如請求項170之方法，其中該等CD4+及/或CD8+ T細胞係在活體內。
  173. 如請求項170至172中任一項之方法，其中該增加為至少1.5倍、至少2倍、至少3倍或至少5倍。
  174. 一種增加NK細胞增殖之方法，其包含使NK細胞與如請求項1至143中任一項之多肽或如請求項144至162中任一項之複合物接觸。
  175. 如請求項174之方法，其中該增加為至少1.5倍、至少2倍、至少3倍或至少5倍。
  176. 一種治療癌症之方法，其包含向患有癌症之受試者投與醫藥學上有效量的如請求項1至143中任一項之多肽或如請求項144至162中任一項之複合物或如請求項163之醫藥組合物。
  177. 如請求項176之方法，其中該癌症係選自基底細胞癌；膽道癌；膀胱癌；骨癌；大腦及中樞神經系統癌症；乳癌；腹膜癌；子宮頸癌；絨毛膜癌；結腸及直腸癌症；結締組織癌；消化系統癌症；子宮內膜癌；食道癌；眼癌；頭頸癌；胃癌(gastric cancer)；胃腸癌；神經膠母細胞瘤；肝癌瘤；肝腫瘤；上皮細胞內贅瘤；腎臟癌或腎癌；喉癌；肝癌；肺癌；小細胞肺癌；非小細胞肺癌；肺腺癌；肺鱗狀癌(squamous carcinoma of the lung)；黑色素瘤；骨髓瘤；神經母細胞瘤；口腔癌；卵巢癌；胰臟癌；前列腺癌；視網膜母細胞瘤；橫紋肌肉瘤；直腸癌；呼吸系統癌症；唾液腺癌；肉瘤；皮膚癌；鱗狀細胞癌；胃癌(stomach cancer)；睾丸癌；甲狀腺癌；子宮或子宮內膜癌；泌尿系統癌症；外陰癌；淋巴瘤；霍奇金氏淋巴瘤(Hodgkin's lymphoma)；非霍奇金氏淋巴瘤(non-Hodgkin's lymphoma)；B細胞淋巴瘤；低級/濾泡性非霍奇金氏淋巴瘤(NHL)；小淋巴球性(SL) NHL；中級/濾泡性NHL；中級瀰漫性NHL；高級免疫母細胞性NHL；高級淋巴母細胞性NHL；高級小無裂細胞NHL；腫塊性病變NHL；套細胞淋巴瘤；AIDS相關淋巴瘤；瓦爾登斯特倫氏巨球蛋白血症(Waldenstrom's macroglobulinemia)；慢性淋巴球性白血病(CLL)；急性淋巴母細胞性白血病(ALL)；毛細胞白血病；及慢性骨髓母細胞性白血病。
  178. 如請求項176或177之方法，其進一步包含投與額外治療劑。
  179. 如請求項178之方法，其中該額外治療劑為抗癌劑。
  180. 如請求項179之方法，其中該抗癌劑係選自化學治療劑、抗癌生物製劑、放射療法、CAR-T療法及溶瘤病毒。
  181. 如請求項179或請求項180之方法，其中該額外治療劑為抗癌生物製劑。
  182. 如請求項181之方法，其中該抗癌生物製劑為抑制PD-1及/或PD-L1之藥劑。
  183. 如請求項181之方法，其中該抗癌生物製劑為抑制VISTA、gpNMB、B7H3、B7H4、HHLA2、CTLA4或TIGIT之藥劑。
  184. 如請求項179至183中任一項之方法，其中該抗癌劑為抗體。
  185. 如請求項181之方法，其中該抗癌生物製劑為細胞介素。
  186. 如請求項179之方法，其中該抗癌劑為CAR-T療法。
  187. 如請求項179之方法，其中該抗癌劑為溶瘤病毒。
  188. 如請求項176至187中任一項之方法，其進一步包含腫瘤切除及/或放射療法。
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