                         б

<110>  ԴƼ޹˾
 
<120>  һ˫εĸϸ;

<130>  IEC180029PCT

<150>  CN 201711374615.0
<151>  2017-12-19

<160>  22    

<170>  PatentIn version 3.5

<210>  1
<211>  209
<212>  PRT
<213>  ˹

<220>
<223>  ҰFGF21ȫ

<400>  1

Met Asp Ser Asp Glu Thr Gly Phe Glu His Ser Gly Leu Trp Val Ser 
1               5                   10                  15      


Val Leu Ala Gly Leu Leu Leu Gly Ala Cys Gln Ala His Pro Ile Pro 
            20                  25                  30          


Asp Ser Ser Pro Leu Leu Gln Phe Gly Gly Gln Val Arg Gln Arg Tyr 
        35                  40                  45              


Leu Tyr Thr Asp Asp Ala Gln Gln Thr Glu Ala His Leu Glu Ile Arg 
    50                  55                  60                  


Glu Asp Gly Thr Val Gly Gly Ala Ala Asp Gln Ser Pro Glu Ser Leu 
65                  70                  75                  80  


Leu Gln Leu Lys Ala Leu Lys Pro Gly Val Ile Gln Ile Leu Gly Val 
                85                  90                  95      


Lys Thr Ser Arg Phe Leu Cys Gln Arg Pro Asp Gly Ala Leu Tyr Gly 
            100                 105                 110         


Ser Leu His Phe Asp Pro Glu Ala Cys Ser Phe Arg Glu Leu Leu Leu 
        115                 120                 125             


Glu Asp Gly Tyr Asn Val Tyr Gln Ser Glu Ala His Gly Leu Pro Leu 
    130                 135                 140                 


His Leu Pro Gly Asn Lys Ser Pro His Arg Asp Pro Ala Pro Arg Gly 
145                 150                 155                 160 


Pro Ala Arg Phe Leu Pro Leu Pro Gly Leu Pro Pro Ala Leu Pro Glu 
                165                 170                 175     


Pro Pro Gly Ile Leu Ala Pro Gln Pro Pro Asp Val Gly Ser Ser Asp 
            180                 185                 190         


Pro Leu Ser Met Val Gly Pro Ser Gln Gly Arg Ser Pro Ser Tyr Ala 
        195                 200                 205             


Ser 
    


<210>  2
<211>  205
<212>  PRT
<213>  ˹

<220>
<223>  FGF21v

<400>  2

Met Asp Ser Asp Glu Thr Gly Phe Glu His Ser Gly Leu Trp Val Ser 
1               5                   10                  15      


Val Leu Ala Gly Leu Leu Leu Gly Ala Cys Gln Ala Asp Ser Ser Pro 
            20                  25                  30          


Leu Leu Gln Phe Gly Gly Gln Val Arg Gln Arg Tyr Leu Tyr Thr Asp 
        35                  40                  45              


Asp Ala Gln Gln Thr Glu Ala His Leu Glu Ile Arg Glu Asp Gly Thr 
    50                  55                  60                  


Val Gly Gly Ala Ala Asp Gln Ser Pro Glu Ser Leu Leu Gln Leu Lys 
65                  70                  75                  80  


Ala Leu Lys Pro Gly Val Ile Gln Ile Leu Gly Val Lys Thr Ser Arg 
                85                  90                  95      


Phe Leu Cys Gln Arg Pro Asp Gly Ala Leu Tyr Gly Ser Leu His Phe 
            100                 105                 110         


Asp Pro Glu Ala Cys Ser Phe Arg Glu Leu Leu Leu Glu Asp Gly Tyr 
        115                 120                 125             


Asn Val Tyr Gln Ser Glu Ala His Gly Leu Pro Leu His Cys Pro Gly 
    130                 135                 140                 


Asn Lys Ser Pro His Arg Asp Pro Ala Pro Arg Gly Pro Cys Arg Phe 
145                 150                 155                 160 


Leu Pro Leu Pro Gly Leu Pro Pro Ala Leu Pro Glu Pro Pro Gly Ile 
                165                 170                 175     


Leu Ala Pro Gln Pro Pro Asp Val Gly Ser Ser Asp Pro Leu Ala Met 
            180                 185                 190         


Val Gly Pro Ser Gln Gly Arg Ser Pro Ser Tyr Ala Ser 
        195                 200                 205 


<210>  3
<211>  615
<212>  DNA
<213>  ˹

<220>
<223>  FGF21v

<400>  3
atggactcgg acgagaccgg gttcgagcac tcaggactgt gggtttctgt gctggctggt       60

cttctgctgg gagcctgcca ggcagactcc agtcctctcc tgcaattcgg gggccaagtc      120

cggcagcggt acctctacac agatgatgcc cagcagacag aagcccacct ggagatcagg      180

gaggatggga cggtgggggg cgctgctgac cagagccccg aaagtctcct gcagctgaaa      240

gccttgaagc cgggagttat tcaaatcttg ggagtcaaga catccaggtt cctgtgccag      300

cggccagatg gggccctgta tggatcgctc cactttgacc ctgaggcctg cagcttccgg      360

gagctgcttc ttgaggacgg atacaatgtt taccagtccg aagcccacgg cctcccgctg      420

cactgcccag ggaacaagtc cccacaccgg gaccctgcac cccgaggacc atgccgcttc      480

ctgccactac caggcctgcc ccccgcactc ccggagccac ccggaatcct ggccccccag      540

ccccccgatg tgggctcctc ggaccctctg gccatggtgg gaccttccca gggccgaagc      600

cccagctacg cttcc                                                       615


<210>  4
<211>  31
<212>  PRT
<213>  ˹

<220>
<223>  ҰGLP-1(7-37)OH

<400>  4

His Ala Glu Gly Thr Phe Thr Ser Asp Val Ser Ser Tyr Leu Glu Gly 
1               5                   10                  15      


Gln Ala Ala Lys Glu Phe Ile Ala Trp Leu Val Lys Gly Arg Gly 
            20                  25                  30      


<210>  5
<211>  31
<212>  PRT
<213>  ˹

<220>
<223>  GLP-1v

<400>  5

His Gly Glu Gly Thr Phe Thr Ser Asp Val Ser Ser Tyr Leu Glu Glu 
1               5                   10                  15      


Gln Ala Ala Lys Glu Phe Ile Ala Trp Leu Val Lys Gly Gly Gly 
            20                  25                  30      


<210>  6
<211>  93
<212>  DNA
<213>  ˹

<220>
<223>  GLP-1v

<400>  6
catggcgaag ggacctttac cagtgatgta agttcttatt tggaagagca agctgccaag       60

gaattcattg cttggctggt gaaaggcggc gga                                    93


<210>  7
<211>  228
<212>  PRT
<213>  ˹

<220>
<223>  IgG4 Fc 

<400>  7

Glu Ser Lys Tyr Gly Pro Pro Cys Pro Pro Cys Pro Ala Pro Glu Ala 
1               5                   10                  15      


Ala Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr 
            20                  25                  30          


Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val 
        35                  40                  45              


Ser Gln Glu Asp Pro Glu Val Gln Phe Asn Trp Tyr Val Asp Gly Val 
    50                  55                  60                  


Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Phe Asn Ser 
65                  70                  75                  80  


Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu 
                85                  90                  95      


Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Gly Leu Pro Ser 
            100                 105                 110         


Ser Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro 
        115                 120                 125             


Gln Val Tyr Thr Leu Pro Pro Ser Gln Glu Glu Met Thr Lys Asn Gln 
    130                 135                 140                 


Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala 
145                 150                 155                 160 


Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr 
                165                 170                 175     


Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Arg Leu 
            180                 185                 190         


Thr Val Asp Lys Ser Arg Trp Gln Glu Gly Asn Val Phe Ser Cys Ser 
        195                 200                 205             


Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser 
    210                 215                 220                 


Leu Ser Leu Gly 
225             


<210>  8
<211>  687
<212>  DNA
<213>  ˹

<220>
<223>  IgG4 Fc 

<400>  8
gagtccaaat atggtccccc atgcccaccc tgcccagcac ctgaggccgc cgggggacca       60

tcagtcttcc tgttcccccc aaaacccaag gacactctca tgatctcccg gacccctgag      120

gtcacgtgcg tggtggtgga cgtgagccag gaagaccccg aggtccagtt caactggtac      180

gtggatggcg tggaggtgca taatgccaag acaaagccgc gggaggagca gttcaacagc      240

acgtaccgtg tggtcagcgt cctcaccgtc ctgcaccagg actggctgaa cggcaaggag      300

tacaagtgca aggtctccaa caaaggcctc ccgtcctcca tcgagaaaac catctccaaa      360

gccaaagggc agccccgaga gccacaggtg tacaccctgc ccccatccca ggaggagatg      420

accaagaacc aggtcagcct gacctgcctg gtcaaaggct tctaccccag cgacatcgcc      480

gtggagtggg aaagcaatgg gcagccggag aacaactaca agaccacgcc tcccgtgctg      540

gactccgacg gctccttctt cctctacagc aggctaaccg tggacaagag caggtggcag      600

gaggggaatg tcttctcatg ctccgtgatg catgaggctc tgcacaacca ctacacacag      660

aagagcctct ccctgtctct gggttga                                          687


<210>  9
<211>  15
<212>  PRT
<213>  ˹

<220>
<223>  Linker

<400>  9

Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser 
1               5                   10                  15  


<210>  10
<211>  276
<212>  PRT
<213>  ˹

<220>
<223>  GLP1-Fc

<400>  10

His Gly Glu Gly Thr Phe Thr Ser Asp Val Ser Ser Tyr Leu Glu Glu 
1               5                   10                  15      


Gln Ala Ala Lys Glu Phe Ile Ala Trp Leu Val Lys Gly Gly Gly Gly 
            20                  25                  30          


Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Ala Glu 
        35                  40                  45              


Ser Lys Tyr Gly Pro Pro Cys Pro Ser Cys Pro Ala Pro Glu Phe Leu 
    50                  55                  60                  


Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu 
65                  70                  75                  80  


Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser 
                85                  90                  95      


Gln Glu Asp Pro Glu Val Gln Phe Asn Trp Tyr Val Asp Gly Val Glu 
            100                 105                 110         


Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Phe Asn Ser Thr 
        115                 120                 125             


Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn 
    130                 135                 140                 


Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Gly Leu Pro Ser Ser 
145                 150                 155                 160 


Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln 
                165                 170                 175     


Val Tyr Thr Leu Pro Pro Ser Gln Glu Glu Met Thr Lys Asn Gln Val 
            180                 185                 190         


Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val 
        195                 200                 205             


Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro 
    210                 215                 220                 


Pro Val Leu Asp Ser Asp Gly Ser Phe Ala Ala Tyr Ser Arg Leu Thr 
225                 230                 235                 240 


Val Asp Lys Ser Arg Trp Gln Glu Gly Asn Val Phe Ser Cys Ser Val 
                245                 250                 255     


Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu 
            260                 265                 270         


Ser Pro Gly Lys 
        275     


<210>  11
<211>  831
<212>  DNA
<213>  ˹

<220>
<223>  GLP1-Fc

<400>  11
catggcgaag ggacctttac cagtgatgta agttcttatt tggaagagca agctgccaag       60

gaattcattg cttggctggt gaaaggcggc ggaggcggag gcggaagcgg aggcggagga      120

agcggcggtg gcggcagcgc tgagtccaaa tatggtcccc catgcccatc atgcccagca      180

cctgagttcc tggggggacc atcagtcttc ctgttccccc caaaacccaa ggacactctc      240

atgatctccc ggacccctga ggtcacgtgc gtggtggtgg acgtgagcca ggaagacccc      300

gaggtccagt tcaactggta cgtggatggc gtggaggtgc ataatgccaa gacaaagccg      360

cgggaggagc agttcaacag cacgtaccgt gtggtcagcg tcctcaccgt cctgcaccag      420

gactggctga acggcaagga gtacaagtgc aaggtctcca acaaaggcct cccgtcctcc      480

atcgagaaaa ccatctccaa agccaaaggg cagccccgag agccacaggt gtacaccctg      540

cccccatccc aggaggagat gaccaagaac caggtcagcc tgacctgcct ggtcaaaggc      600

ttctacccca gcgacatcgc cgtggagtgg gagagcaatg ggcagccgga gaacaactac      660

aagaccacgc ctcccgtgct ggactccgac ggctccttcg ccgcatacag caggctaacc      720

gtggacaaga gcaggtggca ggaggggaat gtcttctcat gctccgtgat gcatgaggct      780

ctgcacaacc actacacaca gaagagcctc tccctgtctc cgggtaaatg a               831


<210>  12
<211>  18
<212>  PRT
<213>  ˹

<220>
<223>  T2A

<400>  12

Glu Gly Arg Gly Ser Leu Leu Thr Cys Gly Asp Val Glu Glu Asn Pro 
1               5                   10                  15      


Gly Pro 
        


<210>  13
<211>  54
<212>  DNA
<213>  ˹

<220>
<223>  T2A

<400>  13
gagggcagag gaagtctgct aacatgcggt gacgtcgagg agaatcctgg acct             54


<210>  14
<211>  519
<212>  PRT
<213>  ˹

<220>
<223>  FGF21-GLP1-Fc

<400>  14

Met Asp Ser Asp Glu Thr Gly Phe Glu His Ser Gly Leu Trp Val Ser 
1               5                   10                  15      


Val Leu Ala Gly Leu Leu Leu Gly Ala Cys Gln Ala Asp Ser Ser Pro 
            20                  25                  30          


Leu Leu Gln Phe Gly Gly Gln Val Arg Gln Arg Tyr Leu Tyr Thr Asp 
        35                  40                  45              


Asp Ala Gln Gln Thr Glu Ala His Leu Glu Ile Arg Glu Asp Gly Thr 
    50                  55                  60                  


Val Gly Gly Ala Ala Asp Gln Ser Pro Glu Ser Leu Leu Gln Leu Lys 
65                  70                  75                  80  


Ala Leu Lys Pro Gly Val Ile Gln Ile Leu Gly Val Lys Thr Ser Arg 
                85                  90                  95      


Phe Leu Cys Gln Arg Pro Asp Gly Ala Leu Tyr Gly Ser Leu His Phe 
            100                 105                 110         


Asp Pro Glu Ala Cys Ser Phe Arg Glu Leu Leu Leu Glu Asp Gly Tyr 
        115                 120                 125             


Asn Val Tyr Gln Ser Glu Ala His Gly Leu Pro Leu His Cys Pro Gly 
    130                 135                 140                 


Asn Lys Ser Pro His Arg Asp Pro Ala Pro Arg Gly Pro Cys Arg Phe 
145                 150                 155                 160 


Leu Pro Leu Pro Gly Leu Pro Pro Ala Leu Pro Glu Pro Pro Gly Ile 
                165                 170                 175     


Leu Ala Pro Gln Pro Pro Asp Val Gly Ser Ser Asp Pro Leu Ala Met 
            180                 185                 190         


Val Gly Pro Ser Gln Gly Arg Ser Pro Ser Tyr Ala Ser Glu Gly Arg 
        195                 200                 205             


Gly Ser Leu Leu Thr Cys Gly Asp Val Glu Glu Asn Pro Gly Pro Met 
    210                 215                 220                 


Arg Ala Leu Leu Ala Arg Leu Leu Leu Cys Val Leu Val Val Ser Asp 
225                 230                 235                 240 


Ser Lys Gly His Gly Glu Gly Thr Phe Thr Ser Asp Val Ser Ser Tyr 
                245                 250                 255     


Leu Glu Glu Gln Ala Ala Lys Glu Phe Ile Ala Trp Leu Val Lys Gly 
            260                 265                 270         


Gly Gly Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly 
        275                 280                 285             


Ser Ala Glu Ser Lys Tyr Gly Pro Pro Cys Pro Ser Cys Pro Ala Pro 
    290                 295                 300                 


Glu Phe Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys 
305                 310                 315                 320 


Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val 
                325                 330                 335     


Asp Val Ser Gln Glu Asp Pro Glu Val Gln Phe Asn Trp Tyr Val Asp 
            340                 345                 350         


Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Phe 
        355                 360                 365             


Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp 
    370                 375                 380                 


Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Gly Leu 
385                 390                 395                 400 


Pro Ser Ser Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg 
                405                 410                 415     


Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Gln Glu Glu Met Thr Lys 
            420                 425                 430         


Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp 
        435                 440                 445             


Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys 
    450                 455                 460                 


Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Ala Ala Tyr Ser 
465                 470                 475                 480 


Arg Leu Thr Val Asp Lys Ser Arg Trp Gln Glu Gly Asn Val Phe Ser 
                485                 490                 495     


Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser 
            500                 505                 510         


Leu Ser Leu Ser Pro Gly Lys 
        515                 


<210>  15
<211>  1560
<212>  DNA
<213>  ˹

<220>
<223>  FGF21-GLP1-Fc

<400>  15
atggactcgg acgagaccgg gttcgagcac tcaggactgt gggtttctgt gctggctggt       60

cttctgctgg gagcctgcca ggcagactcc agtcctctcc tgcaattcgg gggccaagtc      120

cggcagcggt acctctacac agatgatgcc cagcagacag aagcccacct ggagatcagg      180

gaggatggga cggtgggggg cgctgctgac cagagccccg aaagtctcct gcagctgaaa      240

gccttgaagc cgggagttat tcaaatcttg ggagtcaaga catccaggtt cctgtgccag      300

cggccagatg gggccctgta tggatcgctc cactttgacc ctgaggcctg cagcttccgg      360

gagctgcttc ttgaggacgg atacaatgtt taccagtccg aagcccacgg cctcccgctg      420

cactgcccag ggaacaagtc cccacaccgg gaccctgcac cccgaggacc atgccgcttc      480

ctgccactac caggcctgcc ccccgcactc ccggagccac ccggaatcct ggccccccag      540

ccccccgatg tgggctcctc ggaccctctg gccatggtgg gaccttccca gggccgaagc      600

cccagctacg cttccgaggg cagaggaagt ctgctaacat gcggtgacgt cgaggagaat      660

cctggaccta tgagagccct gctggcgcgc ctgcttctct gcgtcctggt cgtgagcgac      720

tccaaaggcc atggcgaagg gacctttacc agtgatgtaa gttcttattt ggaagagcaa      780

gctgccaagg aattcattgc ttggctggtg aaaggcggcg gaggcggagg cggaagcgga      840

ggcggaggaa gcggcggtgg cggcagcgct gagtccaaat atggtccccc atgcccatca      900

tgcccagcac ctgagttcct ggggggacca tcagtcttcc tgttcccccc aaaacccaag      960

gacactctca tgatctcccg gacccctgag gtcacgtgcg tggtggtgga cgtgagccag     1020

gaagaccccg aggtccagtt caactggtac gtggatggcg tggaggtgca taatgccaag     1080

acaaagccgc gggaggagca gttcaacagc acgtaccgtg tggtcagcgt cctcaccgtc     1140

ctgcaccagg actggctgaa cggcaaggag tacaagtgca aggtctccaa caaaggcctc     1200

ccgtcctcca tcgagaaaac catctccaaa gccaaagggc agccccgaga gccacaggtg     1260

tacaccctgc ccccatccca ggaggagatg accaagaacc aggtcagcct gacctgcctg     1320

gtcaaaggct tctaccccag cgacatcgcc gtggagtggg agagcaatgg gcagccggag     1380

aacaactaca agaccacgcc tcccgtgctg gactccgacg gctccttcgc cgcatacagc     1440

aggctaaccg tggacaagag caggtggcag gaggggaatg tcttctcatg ctccgtgatg     1500

catgaggctc tgcacaacca ctacacacag aagagcctct ccctgtctcc gggtaaatga     1560


<210>  16
<211>  33
<212>  DNA
<213>  ˹

<220>
<223>  

<400>  16
cgcggatccg ccaccatgga ctcggacgag acc                                    33


<210>  17
<211>  28
<212>  DNA
<213>  ˹

<220>
<223>  

<400>  17
acgcgtcgac tcatttaccc ggagacag                                          28


<210>  18
<211>  20
<212>  DNA
<213>  ˹

<220>
<223>  

<400>  18
cactgtgacc tcgcagatcc                                                   20


<210>  19
<211>  20
<212>  DNA
<213>  ˹

<220>
<223>  

<400>  19
ataggcagct tctccgcatc                                                   20


<210>  20
<211>  18
<212>  DNA
<213>  ˹

<220>
<223>  

<400>  20
cctggcaccc agcacaat                                                     18


<210>  21
<211>  18
<212>  DNA
<213>  ˹

<220>
<223>  

<400>  21
gggccggact cgtcatac                                                     18


<210>  22
<211>  20
<212>  PRT
<213>  ˹

<220>
<223>  ź

<400>  22

Met Arg Ala Leu Leu Ala Arg Leu Leu Leu Cys Val Leu Val Val Ser 
1               5                   10                  15      


Asp Ser Lys Gly 
            20  


