                         SEQUENCE LISTING

<110>  Philogen S.p.A.
 
<120>  IL-12 antagonists with optimized linkers

<130>  PD43383

<160>  9     

<170>  PatentIn version 3.5

<210>  1
<211>  306
<212>  PRT
<213>  Homo sapiens

<400>  1

Ile Trp Glu Leu Lys Lys Asp Val Tyr Val Val Glu Leu Asp Trp Tyr 
1               5                   10                  15      


Pro Asp Ala Pro Gly Glu Met Val Val Leu Thr Cys Asp Thr Pro Glu 
            20                  25                  30          


Glu Asp Gly Ile Thr Trp Thr Leu Asp Gln Ser Ser Glu Val Leu Gly 
        35                  40                  45              


Ser Gly Lys Thr Leu Thr Ile Gln Val Lys Glu Phe Gly Asp Ala Gly 
    50                  55                  60                  


Gln Tyr Thr Cys His Lys Gly Gly Glu Val Leu Ser His Ser Leu Leu 
65                  70                  75                  80  


Leu Leu His Lys Lys Glu Asp Gly Ile Trp Ser Thr Asp Ile Leu Lys 
                85                  90                  95      


Asp Gln Lys Glu Pro Lys Asn Lys Thr Phe Leu Arg Cys Glu Ala Lys 
            100                 105                 110         


Asn Tyr Ser Gly Arg Phe Thr Cys Trp Trp Leu Thr Thr Ile Ser Thr 
        115                 120                 125             


Asp Leu Thr Phe Ser Val Lys Ser Ser Arg Gly Ser Ser Asp Pro Gln 
    130                 135                 140                 


Gly Val Thr Cys Gly Ala Ala Thr Leu Ser Ala Glu Arg Val Arg Gly 
145                 150                 155                 160 


Asp Asn Lys Glu Tyr Glu Tyr Ser Val Glu Cys Gln Glu Asp Ser Ala 
                165                 170                 175     


Cys Pro Ala Ala Glu Glu Ser Leu Pro Ile Glu Val Met Val Asp Ala 
            180                 185                 190         


Val His Lys Leu Lys Tyr Glu Asn Tyr Thr Ser Ser Phe Phe Ile Arg 
        195                 200                 205             


Asp Ile Ile Lys Pro Asp Pro Pro Lys Asn Leu Gln Leu Lys Pro Leu 
    210                 215                 220                 


Lys Asn Ser Arg Gln Val Glu Val Ser Trp Glu Tyr Pro Asp Thr Trp 
225                 230                 235                 240 


Ser Thr Pro His Ser Tyr Phe Ser Leu Thr Phe Cys Val Gln Val Gln 
                245                 250                 255     


Gly Lys Ser Lys Arg Glu Lys Lys Asp Arg Val Phe Thr Asp Lys Thr 
            260                 265                 270         


Ser Ala Thr Val Ile Cys Arg Lys Asn Ala Ser Ile Ser Val Arg Ala 
        275                 280                 285             


Gln Asp Arg Tyr Tyr Ser Ser Ser Trp Ser Glu Trp Ala Ser Val Pro 
    290                 295                 300                 


Cys Ser 
305     


<210>  2
<211>  15
<212>  PRT
<213>  artificial sequence

<220>
<223>  linker

<400>  2

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


<210>  3
<211>  197
<212>  PRT
<213>  Homo sapiens

<400>  3

Arg Asn Leu Pro Val Ala Thr Pro Asp Pro Gly Met Phe Pro Cys Leu 
1               5                   10                  15      


His His Ser Gln Asn Leu Leu Arg Ala Val Ser Asn Met Leu Gln Lys 
            20                  25                  30          


Ala Arg Gln Thr Leu Glu Phe Tyr Pro Cys Thr Ser Glu Glu Ile Asp 
        35                  40                  45              


His Glu Asp Ile Thr Lys Asp Lys Thr Ser Thr Val Glu Ala Cys Leu 
    50                  55                  60                  


Pro Leu Glu Leu Thr Lys Asn Glu Ser Cys Leu Asn Ser Arg Glu Thr 
65                  70                  75                  80  


Ser Phe Ile Thr Asn Gly Ser Cys Leu Ala Ser Arg Lys Thr Ser Phe 
                85                  90                  95      


Met Met Ala Leu Cys Leu Ser Ser Ile Tyr Glu Asp Leu Lys Met Tyr 
            100                 105                 110         


Gln Val Glu Phe Lys Thr Met Asn Ala Lys Leu Leu Met Asp Pro Lys 
        115                 120                 125             


Arg Gln Ile Phe Leu Asp Gln Asn Met Leu Ala Val Ile Asp Glu Leu 
    130                 135                 140                 


Met Gln Ala Leu Asn Phe Asn Ser Glu Thr Val Pro Gln Lys Ser Ser 
145                 150                 155                 160 


Leu Glu Glu Pro Asp Phe Tyr Lys Thr Lys Ile Lys Leu Cys Ile Leu 
                165                 170                 175     


Leu His Ala Phe Arg Ile Arg Ala Val Thr Ile Asp Arg Val Met Ser 
            180                 185                 190         


Tyr Leu Asn Ala Ser 
        195         


<210>  4
<211>  15
<212>  PRT
<213>  artificial sequence

<220>
<223>  linker

<400>  4

Gly Ser Ala Asp Gly Gly Ser Ser Ala Gly Gly Ser Asp Ala Gly 
1               5                   10                  15  


<210>  5
<211>  108
<212>  PRT
<213>  artificial sequence

<220>
<223>  antibody sequence (variable domain)

<400>  5

Glu Ile Val Leu Thr Gln Ser Pro Gly 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 Ser 
            20                  25                  30          


Phe Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu 
        35                  40                  45              


Ile Tyr Tyr Ala Ser Ser Arg Ala Thr Gly Ile Pro Asp Arg Phe Ser 
    50                  55                  60                  


Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Arg Leu Glu 
65                  70                  75                  80  


Pro Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Thr Gly Arg Ile Pro 
                85                  90                  95      


Pro Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys 
            100                 105             


<210>  6
<211>  5
<212>  PRT
<213>  artificial sequence

<220>
<223>  linker

<400>  6

Gly Ser Ser Gly Gly 
1               5   


<210>  7
<211>  116
<212>  PRT
<213>  artificial sequence

<220>
<223>  antibody sequence (variable domain)

<400>  7

Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 
1               5                   10                  15      


Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Phe 
            20                  25                  30          


Ser Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 
        35                  40                  45              


Ser Ser Ile Ser Gly Ser Ser Gly Thr 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 Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 
                85                  90                  95      


Ala Lys Pro Phe Pro Tyr Phe Asp Tyr Trp Gly Gln Gly Thr Leu Val 
            100                 105                 110         


Thr Val Ser Ser 
        115     


<210>  8
<211>  15
<212>  PRT
<213>  artificial sequence

<220>
<223>  linker

<400>  8

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


<210>  9
<211>  1006
<212>  PRT
<213>  artificial sequence

<220>
<223>  Immunoconjugate sequence

<400>  9

Ile Trp Glu Leu Lys Lys Asp Val Tyr Val Val Glu Leu Asp Trp Tyr 
1               5                   10                  15      


Pro Asp Ala Pro Gly Glu Met Val Val Leu Thr Cys Asp Thr Pro Glu 
            20                  25                  30          


Glu Asp Gly Ile Thr Trp Thr Leu Asp Gln Ser Ser Glu Val Leu Gly 
        35                  40                  45              


Ser Gly Lys Thr Leu Thr Ile Gln Val Lys Glu Phe Gly Asp Ala Gly 
    50                  55                  60                  


Gln Tyr Thr Cys His Lys Gly Gly Glu Val Leu Ser His Ser Leu Leu 
65                  70                  75                  80  


Leu Leu His Lys Lys Glu Asp Gly Ile Trp Ser Thr Asp Ile Leu Lys 
                85                  90                  95      


Asp Gln Lys Glu Pro Lys Asn Lys Thr Phe Leu Arg Cys Glu Ala Lys 
            100                 105                 110         


Asn Tyr Ser Gly Arg Phe Thr Cys Trp Trp Leu Thr Thr Ile Ser Thr 
        115                 120                 125             


Asp Leu Thr Phe Ser Val Lys Ser Ser Arg Gly Ser Ser Asp Pro Gln 
    130                 135                 140                 


Gly Val Thr Cys Gly Ala Ala Thr Leu Ser Ala Glu Arg Val Arg Gly 
145                 150                 155                 160 


Asp Asn Lys Glu Tyr Glu Tyr Ser Val Glu Cys Gln Glu Asp Ser Ala 
                165                 170                 175     


Cys Pro Ala Ala Glu Glu Ser Leu Pro Ile Glu Val Met Val Asp Ala 
            180                 185                 190         


Val His Lys Leu Lys Tyr Glu Asn Tyr Thr Ser Ser Phe Phe Ile Arg 
        195                 200                 205             


Asp Ile Ile Lys Pro Asp Pro Pro Lys Asn Leu Gln Leu Lys Pro Leu 
    210                 215                 220                 


Lys Asn Ser Arg Gln Val Glu Val Ser Trp Glu Tyr Pro Asp Thr Trp 
225                 230                 235                 240 


Ser Thr Pro His Ser Tyr Phe Ser Leu Thr Phe Cys Val Gln Val Gln 
                245                 250                 255     


Gly Lys Ser Lys Arg Glu Lys Lys Asp Arg Val Phe Thr Asp Lys Thr 
            260                 265                 270         


Ser Ala Thr Val Ile Cys Arg Lys Asn Ala Ser Ile Ser Val Arg Ala 
        275                 280                 285             


Gln Asp Arg Tyr Tyr Ser Ser Ser Trp Ser Glu Trp Ala Ser Val Pro 
    290                 295                 300                 


Cys Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly 
305                 310                 315                 320 


Ser Arg Asn Leu Pro Val Ala Thr Pro Asp Pro Gly Met Phe Pro Cys 
                325                 330                 335     


Leu His His Ser Gln Asn Leu Leu Arg Ala Val Ser Asn Met Leu Gln 
            340                 345                 350         


Lys Ala Arg Gln Thr Leu Glu Phe Tyr Pro Cys Thr Ser Glu Glu Ile 
        355                 360                 365             


Asp His Glu Asp Ile Thr Lys Asp Lys Thr Ser Thr Val Glu Ala Cys 
    370                 375                 380                 


Leu Pro Leu Glu Leu Thr Lys Asn Glu Ser Cys Leu Asn Ser Arg Glu 
385                 390                 395                 400 


Thr Ser Phe Ile Thr Asn Gly Ser Cys Leu Ala Ser Arg Lys Thr Ser 
                405                 410                 415     


Phe Met Met Ala Leu Cys Leu Ser Ser Ile Tyr Glu Asp Leu Lys Met 
            420                 425                 430         


Tyr Gln Val Glu Phe Lys Thr Met Asn Ala Lys Leu Leu Met Asp Pro 
        435                 440                 445             


Lys Arg Gln Ile Phe Leu Asp Gln Asn Met Leu Ala Val Ile Asp Glu 
    450                 455                 460                 


Leu Met Gln Ala Leu Asn Phe Asn Ser Glu Thr Val Pro Gln Lys Ser 
465                 470                 475                 480 


Ser Leu Glu Glu Pro Asp Phe Tyr Lys Thr Lys Ile Lys Leu Cys Ile 
                485                 490                 495     


Leu Leu His Ala Phe Arg Ile Arg Ala Val Thr Ile Asp Arg Val Met 
            500                 505                 510         


Ser Tyr Leu Asn Ala Ser Gly Ser Ala Asp Gly Gly Ser Ser Ala Gly 
        515                 520                 525             


Gly Ser Asp Ala Gly Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu 
    530                 535                 540                 


Val Gln Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe 
545                 550                 555                 560 


Thr Phe Ser Ser Phe Ser Met Ser Trp Val Arg Gln Ala Pro Gly Lys 
                565                 570                 575     


Gly Leu Glu Trp Val Ser Ser Ile Ser Gly Ser Ser Gly Thr Thr Tyr 
            580                 585                 590         


Tyr Ala Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser 
        595                 600                 605             


Lys Asn Thr Leu Tyr Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr 
    610                 615                 620                 


Ala Val Tyr Tyr Cys Ala Lys Pro Phe Pro Tyr Phe Asp Tyr Trp Gly 
625                 630                 635                 640 


Gln Gly Thr Leu Val Thr Val Ser Ser Gly Ser Ser Gly Gly Glu Ile 
                645                 650                 655     


Val Leu Thr Gln Ser Pro Gly Thr Leu Ser Leu Ser Pro Gly Glu Arg 
            660                 665                 670         


Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Val Ser Ser Ser Phe Leu 
        675                 680                 685             


Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu Ile Tyr 
    690                 695                 700                 


Tyr Ala Ser Ser Arg Ala Thr Gly Ile Pro Asp Arg Phe Ser Gly Ser 
705                 710                 715                 720 


Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Arg Leu Glu Pro Glu 
                725                 730                 735     


Asp Phe Ala Val Tyr Tyr Cys Gln Gln Thr Gly Arg Ile Pro Pro Thr 
            740                 745                 750         


Phe Gly Gln Gly Thr Lys Val Glu Ile Lys Ser Ser Ser Ser Gly Ser 
        755                 760                 765             


Ser Ser Ser Gly Ser Ser Ser Ser Gly Glu Val Gln Leu Leu Glu Ser 
    770                 775                 780                 


Gly Gly Gly Leu Val Gln Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala 
785                 790                 795                 800 


Ala Ser Gly Phe Thr Phe Ser Ser Phe Ser Met Ser Trp Val Arg Gln 
                805                 810                 815     


Ala Pro Gly Lys Gly Leu Glu Trp Val Ser Ser Ile Ser Gly Ser Ser 
            820                 825                 830         


Gly Thr Thr Tyr Tyr Ala Asp Ser Val Lys Gly Arg Phe Thr Ile Ser 
        835                 840                 845             


Arg Asp Asn Ser Lys Asn Thr Leu Tyr Leu Gln Met Asn Ser Leu Arg 
    850                 855                 860                 


Ala Glu Asp Thr Ala Val Tyr Tyr Cys Ala Lys Pro Phe Pro Tyr Phe 
865                 870                 875                 880 


Asp Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Gly Ser Ser 
                885                 890                 895     


Gly Gly Glu Ile Val Leu Thr Gln Ser Pro Gly Thr Leu Ser Leu Ser 
            900                 905                 910         


Pro Gly Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Val Ser 
        915                 920                 925             


Ser Ser Phe Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg 
    930                 935                 940                 


Leu Leu Ile Tyr Tyr Ala Ser Ser Arg Ala Thr Gly Ile Pro Asp Arg 
945                 950                 955                 960 


Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Arg 
                965                 970                 975     


Leu Glu Pro Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Thr Gly Arg 
            980                 985                 990         


Ile Pro Pro Thr Phe Gly Gln Gly  Thr Lys Val Glu Ile  Lys 
        995                 1000                 1005     


