                         SEQUENCE LISTING

<110>  F. Hoffman-La Roche AG
       Hoffman-La Roche Inc.
       Genentech Inc.       
 
<120>  Personalized treatment of ophthalmologic diseases

<130>  P35665-US

<150>  US 62/883,499
<151>  2019-08-06

<160>  27    

<170>  PatentIn version 3.5

<210>  1
<211>  14
<212>  PRT
<213>  Artificial

<220>
<223>  heavy chain CDR3H, <VEGF>ranibizumab

<400>  1

Tyr Pro Tyr Tyr Tyr Gly Thr Ser His Trp Tyr Phe Asp Val 
1               5                   10                  


<210>  2
<211>  17
<212>  PRT
<213>  Artificial

<220>
<223>  heavy chain CDR2H, <VEGF>ranibizumab

<400>  2

Trp Ile Asn Thr Tyr Thr Gly Glu Pro Thr Tyr Ala Ala Asp Phe Lys 
1               5                   10                  15      


Arg 
    


<210>  3
<211>  5
<212>  PRT
<213>  Artificial

<220>
<223>  heavy chain CDR1H, <VEGF>ranibizumab

<400>  3

His Tyr Gly Met Asn 
1               5   


<210>  4
<211>  9
<212>  PRT
<213>  Artificial

<220>
<223>  light chain CDR3L,  <VEGF>ranibizumab

<400>  4

Gln Gln Tyr Ser Thr Val Pro Trp Thr 
1               5                   


<210>  5
<211>  7
<212>  PRT
<213>  Artificial

<220>
<223>  light chain CDR2L,  <VEGF>ranibizumab

<400>  5

Phe Thr Ser Ser Leu His Ser 
1               5           


<210>  6
<211>  11
<212>  PRT
<213>  Artificial

<220>
<223>  light chain CDR1L,  <VEGF>ranibizumab

<400>  6

Ser Ala Ser Gln Asp Ile Ser Asn Tyr Leu Asn 
1               5                   10      


<210>  7
<211>  123
<212>  PRT
<213>  Artificial

<220>
<223>  heavy chain variable domain VH,  <VEGF>ranibizumab

<400>  7

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


Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Tyr Asp Phe Thr His Tyr 
            20                  25                  30          


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


Gly Trp Ile Asn Thr Tyr Thr Gly Glu Pro Thr Tyr Ala Ala Asp Phe 
    50                  55                  60                  


Lys Arg Arg Phe Thr Phe Ser Leu Asp Thr Ser Lys Ser Thr Ala Tyr 
65                  70                  75                  80  


Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 
                85                  90                  95      


Ala Lys Tyr Pro Tyr Tyr Tyr Gly Thr Ser His Trp Tyr Phe Asp Val 
            100                 105                 110         


Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser 
        115                 120             


<210>  8
<211>  107
<212>  PRT
<213>  Artificial

<220>
<223>  light chain variable domain VL,  <VEGF>ranibizumab

<400>  8

Asp Ile Gln Leu Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly 
1               5                   10                  15      


Asp Arg Val Thr Ile Thr Cys Ser Ala Ser Gln Asp Ile Ser Asn Tyr 
            20                  25                  30          


Leu Asn Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Val Leu Ile 
        35                  40                  45              


Tyr Phe Thr Ser Ser Leu His Ser Gly Val Pro Ser Arg Phe Ser Gly 
    50                  55                  60                  


Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro 
65                  70                  75                  80  


Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Tyr Ser Thr Val Pro Trp 
                85                  90                  95      


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


<210>  9
<211>  20
<212>  PRT
<213>  Artificial

<220>
<223>  heavy chain CDR3H, <ANG-2> Ang2i_LC10 variant

<400>  9

Ser Pro Asn Pro Tyr Tyr Tyr Asp Ser Ser Gly Tyr Tyr Tyr Pro Gly 
1               5                   10                  15      


Ala Phe Asp Ile 
            20  


<210>  10
<211>  17
<212>  PRT
<213>  Artificial

<220>
<223>  heavy chain CDR2H, <ANG-2> Ang2i_LC10 variant

<400>  10

Trp Ile Asn Pro Asn Ser Gly Gly Thr Asn Tyr Ala Gln Lys Phe Gln 
1               5                   10                  15      


Gly 
    


<210>  11
<211>  5
<212>  PRT
<213>  Artificial

<220>
<223>  heavy chain CDR1H, <ANG-2> Ang2i_LC10 variant

<400>  11

Gly Tyr Tyr Met His 
1               5   


<210>  12
<211>  11
<212>  PRT
<213>  Artificial

<220>
<223>  light chain CDR3L, <ANG-2> Ang2i_LC10 variant

<400>  12

Gln Val Trp Asp Ser Ser Ser Asp His Trp Val 
1               5                   10      


<210>  13
<211>  7
<212>  PRT
<213>  Artificial

<220>
<223>  light chain CDR2L, <ANG-2> Ang2i_LC10 variant

<400>  13

Asp Asp Ser Asp Arg Pro Ser 
1               5           


<210>  14
<211>  11
<212>  PRT
<213>  Artificial

<220>
<223>  light chain CDR1L, <ANG-2> Ang2i_LC10 variant

<400>  14

Gly Gly Asn Asn Ile Gly Ser Lys Ser Val His 
1               5                   10      


<210>  15
<211>  129
<212>  PRT
<213>  Artificial

<220>
<223>  heavy chain variable domain VH, <ANG-2> Ang2i_LC10 variant

<400>  15

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 Pro 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 Ser Pro Asn Pro Tyr Tyr Tyr Asp Ser Ser Gly Tyr Tyr Tyr 
            100                 105                 110         


Pro Gly Ala Phe Asp Ile Trp Gly Gln Gly Thr Met Val Thr Val Ser 
        115                 120                 125             


Ser 
    


<210>  16
<211>  110
<212>  PRT
<213>  Artificial

<220>
<223>  light chain variable domain VL, <ANG-2> Ang2i_LC10 variant

<400>  16

Ser Tyr Val Leu Thr Gln Pro Pro Ser Val Ser Val Ala Pro Gly Gln 
1               5                   10                  15      


Thr Ala Arg Ile Thr Cys Gly Gly Asn Asn Ile Gly Ser Lys Ser Val 
            20                  25                  30          


His Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Val Leu Val Val Tyr 
        35                  40                  45              


Asp Asp Ser Asp Arg Pro Ser Gly Ile Pro Glu Arg Phe Ser Gly Ser 
    50                  55                  60                  


Asn Ser Gly Asn Thr Ala Thr Leu Thr Ile Ser Arg Val Glu Ala Gly 
65                  70                  75                  80  


Asp Glu Ala Asp Tyr Tyr Cys Gln Val Trp Asp Ser Ser Ser Asp His 
                85                  90                  95      


Trp Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu Ser Ser 
            100                 105                 110 


<210>  17
<211>  451
<212>  PRT
<213>  Artificial

<220>
<223>  Heavy chain 1 of  <VEGF-ANG-2> CrossMAb IgG1 with AAA mutations 
       and P329G LALA mutations (VEGFang2-0016)

<400>  17

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


Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Tyr Asp Phe Thr His Tyr 
            20                  25                  30          


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


Gly Trp Ile Asn Thr Tyr Thr Gly Glu Pro Thr Tyr Ala Ala Asp Phe 
    50                  55                  60                  


Lys Arg Arg Phe Thr Phe Ser Leu Asp Thr Ser Lys Ser Thr Ala Tyr 
65                  70                  75                  80  


Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 
                85                  90                  95      


Ala Lys Tyr Pro Tyr Tyr Tyr Gly Thr Ser His Trp Tyr Phe Asp Val 
            100                 105                 110         


Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly 
        115                 120                 125             


Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly 
    130                 135                 140                 


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


Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe 
                165                 170                 175     


Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val 
            180                 185                 190         


Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val 
        195                 200                 205             


Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys 
    210                 215                 220                 


Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Ala 
225                 230                 235                 240 


Ala Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr 
                245                 250                 255     


Leu Met Ala Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val 
            260                 265                 270         


Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val 
        275                 280                 285             


Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser 
    290                 295                 300                 


Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu Ala Gln Asp Trp Leu 
305                 310                 315                 320 


Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Gly Ala 
                325                 330                 335     


Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro 
            340                 345                 350         


Gln Val Tyr Thr Leu Pro Pro Cys Arg Asp Glu Leu Thr Lys Asn Gln 
        355                 360                 365             


Val Ser Leu Trp Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala 
    370                 375                 380                 


Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr 
385                 390                 395                 400 


Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu 
                405                 410                 415     


Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser 
            420                 425                 430         


Val Met His Glu Ala Leu His Asn Ala Tyr Thr Gln Lys Ser Leu Ser 
        435                 440                 445             


Leu Ser Pro 
    450     


<210>  18
<211>  461
<212>  PRT
<213>  Artificial

<220>
<223>  Heavy chain 2 of  <VEGF-ANG-2> CrossMAb IgG1 with AAA mutations 
       and P329G LALA mutations (VEGFang2-0016)

<400>  18

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


Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr 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 Pro 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 Ser Pro Asn Pro Tyr Tyr Tyr Asp Ser Ser Gly Tyr Tyr Tyr 
            100                 105                 110         


Pro Gly Ala Phe Asp Ile Trp Gly Gln Gly Thr Met Val Thr Val Ser 
        115                 120                 125             


Ser Ala Ser Val Ala Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp 
    130                 135                 140                 


Glu Gln Leu Lys Ser Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn 
145                 150                 155                 160 


Phe Tyr Pro Arg Glu Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu 
                165                 170                 175     


Gln Ser Gly Asn Ser Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp 
            180                 185                 190         


Ser Thr Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr 
        195                 200                 205             


Glu Lys His Lys Val Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser 
    210                 215                 220                 


Ser Pro Val Thr Lys Ser Phe Asn Arg Gly Glu Cys Asp Lys Thr His 
225                 230                 235                 240 


Thr Cys Pro Pro Cys Pro Ala Pro Glu Ala Ala Gly Gly Pro Ser Val 
                245                 250                 255     


Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ala Ser Arg Thr 
            260                 265                 270         


Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu 
        275                 280                 285             


Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys 
    290                 295                 300                 


Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser 
305                 310                 315                 320 


Val Leu Thr Val Leu Ala Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys 
                325                 330                 335     


Cys Lys Val Ser Asn Lys Ala Leu Gly Ala Pro Ile Glu Lys Thr Ile 
            340                 345                 350         


Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Cys Thr Leu Pro 
        355                 360                 365             


Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu Ser Cys Ala 
    370                 375                 380                 


Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn 
385                 390                 395                 400 


Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser 
                405                 410                 415     


Asp Gly Ser Phe Phe Leu Val Ser Lys Leu Thr Val Asp Lys Ser Arg 
            420                 425                 430         


Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu 
        435                 440                 445             


His Asn Ala Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro 
    450                 455                 460     


<210>  19
<211>  214
<212>  PRT
<213>  Artificial

<220>
<223>  Light chain 1 of  <VEGF-ANG-2> CrossMAb IgG1 with AAA mutations 
       and P329G LALA mutations (VEGFang2-0016)

<400>  19

Asp Ile Gln Leu Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly 
1               5                   10                  15      


Asp Arg Val Thr Ile Thr Cys Ser Ala Ser Gln Asp Ile Ser Asn Tyr 
            20                  25                  30          


Leu Asn Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Val Leu Ile 
        35                  40                  45              


Tyr Phe Thr Ser Ser Leu His Ser Gly Val Pro Ser Arg Phe Ser Gly 
    50                  55                  60                  


Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro 
65                  70                  75                  80  


Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Tyr Ser Thr Val Pro Trp 
                85                  90                  95      


Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys Arg Thr Val Ala Ala 
            100                 105                 110         


Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly 
        115                 120                 125             


Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala 
    130                 135                 140                 


Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln 
145                 150                 155                 160 


Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser 
                165                 170                 175     


Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr 
            180                 185                 190         


Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser 
        195                 200                 205             


Phe Asn Arg Gly Glu Cys 
    210                 


<210>  20
<211>  213
<212>  PRT
<213>  Artificial

<220>
<223>  Light chain 2 of  <VEGF-ANG-2> CrossMAb IgG1 with AAA mutations 
       and P329G LALA mutations (VEGFang2-0016)

<400>  20

Ser Tyr Val Leu Thr Gln Pro Pro Ser Val Ser Val Ala Pro Gly Gln 
1               5                   10                  15      


Thr Ala Arg Ile Thr Cys Gly Gly Asn Asn Ile Gly Ser Lys Ser Val 
            20                  25                  30          


His Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Val Leu Val Val Tyr 
        35                  40                  45              


Asp Asp Ser Asp Arg Pro Ser Gly Ile Pro Glu Arg Phe Ser Gly Ser 
    50                  55                  60                  


Asn Ser Gly Asn Thr Ala Thr Leu Thr Ile Ser Arg Val Glu Ala Gly 
65                  70                  75                  80  


Asp Glu Ala Asp Tyr Tyr Cys Gln Val Trp Asp Ser Ser Ser Asp His 
                85                  90                  95      


Trp Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu Ser Ser Ala Ser 
            100                 105                 110         


Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr 
        115                 120                 125             


Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro 
    130                 135                 140                 


Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val 
145                 150                 155                 160 


His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser 
                165                 170                 175     


Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile 
            180                 185                 190         


Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys Lys Val 
        195                 200                 205             


Glu Pro Lys Ser Cys 
    210             


<210>  21
<211>  107
<212>  PRT
<213>  Homo sapiens

<400>  21

Arg Thr Val Ala Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu 
1               5                   10                  15      


Gln Leu Lys Ser Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe 
            20                  25                  30          


Tyr Pro Arg Glu Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln 
        35                  40                  45              


Ser Gly Asn Ser Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser 
    50                  55                  60                  


Thr Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu 
65                  70                  75                  80  


Lys His Lys Val Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser 
                85                  90                  95      


Pro Val Thr Lys Ser Phe Asn Arg Gly Glu Cys 
            100                 105         


<210>  22
<211>  105
<212>  PRT
<213>  homo sapiens

<400>  22

Gln Pro Lys Ala Ala Pro Ser Val Thr Leu Phe Pro Pro Ser Ser Glu 
1               5                   10                  15      


Glu Leu Gln Ala Asn Lys Ala Thr Leu Val Cys Leu Ile Ser Asp Phe 
            20                  25                  30          


Tyr Pro Gly Ala Val Thr Val Ala Trp Lys Ala Asp Ser Ser Pro Val 
        35                  40                  45              


Lys Ala Gly Val Glu Thr Thr Thr Pro Ser Lys Gln Ser Asn Asn Lys 
    50                  55                  60                  


Tyr Ala Ala Ser Ser Tyr Leu Ser Leu Thr Pro Glu Gln Trp Lys Ser 
65                  70                  75                  80  


His Arg Ser Tyr Ser Cys Gln Val Thr His Glu Gly Ser Thr Val Glu 
                85                  90                  95      


Lys Thr Val Ala Pro Thr Glu Cys Ser 
            100                 105 


<210>  23
<211>  328
<212>  PRT
<213>  Homo sapiens

<400>  23

Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys 
1               5                   10                  15      


Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr 
            20                  25                  30          


Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser 
        35                  40                  45              


Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser 
    50                  55                  60                  


Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr 
65                  70                  75                  80  


Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys 
                85                  90                  95      


Lys Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys 
            100                 105                 110         


Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro 
        115                 120                 125             


Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys 
    130                 135                 140                 


Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp 
145                 150                 155                 160 


Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu 
                165                 170                 175     


Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu 
            180                 185                 190         


His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn 
        195                 200                 205             


Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly 
    210                 215                 220                 


Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Asp Glu 
225                 230                 235                 240 


Leu Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr 
                245                 250                 255     


Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn 
            260                 265                 270         


Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe 
        275                 280                 285             


Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn 
    290                 295                 300                 


Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr 
305                 310                 315                 320 


Gln Lys Ser Leu Ser Leu Ser Pro 
                325             


<210>  24
<211>  191
<212>  PRT
<213>  Homo sapiens

<400>  24

Met Asn Phe Leu Leu Ser Trp Val His Trp Ser Leu Ala Leu Leu Leu 
1               5                   10                  15      


Tyr Leu His His Ala Lys Trp Ser Gln Ala Ala Pro Met Ala Glu Gly 
            20                  25                  30          


Gly Gly Gln Asn His His Glu Val Val Lys Phe Met Asp Val Tyr Gln 
        35                  40                  45              


Arg Ser Tyr Cys His Pro Ile Glu Thr Leu Val Asp Ile Phe Gln Glu 
    50                  55                  60                  


Tyr Pro Asp Glu Ile Glu Tyr Ile Phe Lys Pro Ser Cys Val Pro Leu 
65                  70                  75                  80  


Met Arg Cys Gly Gly Cys Cys Asn Asp Glu Gly Leu Glu Cys Val Pro 
                85                  90                  95      


Thr Glu Glu Ser Asn Ile Thr Met Gln Ile Met Arg Ile Lys Pro His 
            100                 105                 110         


Gln Gly Gln His Ile Gly Glu Met Ser Phe Leu Gln His Asn Lys Cys 
        115                 120                 125             


Glu Cys Arg Pro Lys Lys Asp Arg Ala Arg Gln Glu Asn Pro Cys Gly 
    130                 135                 140                 


Pro Cys Ser Glu Arg Arg Lys His Leu Phe Val Gln Asp Pro Gln Thr 
145                 150                 155                 160 


Cys Lys Cys Ser Cys Lys Asn Thr Asp Ser Arg Cys Lys Ala Arg Gln 
                165                 170                 175     


Leu Glu Leu Asn Glu Arg Thr Cys Arg Cys Asp Lys Pro Arg Arg 
            180                 185                 190     


<210>  25
<211>  496
<212>  PRT
<213>  Homo sapiens

<400>  25

Met Trp Gln Ile Val Phe Phe Thr Leu Ser Cys Asp Leu Val Leu Ala 
1               5                   10                  15      


Ala Ala Tyr Asn Asn Phe Arg Lys Ser Met Asp Ser Ile Gly Lys Lys 
            20                  25                  30          


Gln Tyr Gln Val Gln His Gly Ser Cys Ser Tyr Thr Phe Leu Leu Pro 
        35                  40                  45              


Glu Met Asp Asn Cys Arg Ser Ser Ser Ser Pro Tyr Val Ser Asn Ala 
    50                  55                  60                  


Val Gln Arg Asp Ala Pro Leu Glu Tyr Asp Asp Ser Val Gln Arg Leu 
65                  70                  75                  80  


Gln Val Leu Glu Asn Ile Met Glu Asn Asn Thr Gln Trp Leu Met Lys 
                85                  90                  95      


Leu Glu Asn Tyr Ile Gln Asp Asn Met Lys Lys Glu Met Val Glu Ile 
            100                 105                 110         


Gln Gln Asn Ala Val Gln Asn Gln Thr Ala Val Met Ile Glu Ile Gly 
        115                 120                 125             


Thr Asn Leu Leu Asn Gln Thr Ala Glu Gln Thr Arg Lys Leu Thr Asp 
    130                 135                 140                 


Val Glu Ala Gln Val Leu Asn Gln Thr Thr Arg Leu Glu Leu Gln Leu 
145                 150                 155                 160 


Leu Glu His Ser Leu Ser Thr Asn Lys Leu Glu Lys Gln Ile Leu Asp 
                165                 170                 175     


Gln Thr Ser Glu Ile Asn Lys Leu Gln Asp Lys Asn Ser Phe Leu Glu 
            180                 185                 190         


Lys Lys Val Leu Ala Met Glu Asp Lys His Ile Ile Gln Leu Gln Ser 
        195                 200                 205             


Ile Lys Glu Glu Lys Asp Gln Leu Gln Val Leu Val Ser Lys Gln Asn 
    210                 215                 220                 


Ser Ile Ile Glu Glu Leu Glu Lys Lys Ile Val Thr Ala Thr Val Asn 
225                 230                 235                 240 


Asn Ser Val Leu Gln Lys Gln Gln His Asp Leu Met Glu Thr Val Asn 
                245                 250                 255     


Asn Leu Leu Thr Met Met Ser Thr Ser Asn Ser Ala Lys Asp Pro Thr 
            260                 265                 270         


Val Ala Lys Glu Glu Gln Ile Ser Phe Arg Asp Cys Ala Glu Val Phe 
        275                 280                 285             


Lys Ser Gly His Thr Thr Asn Gly Ile Tyr Thr Leu Thr Phe Pro Asn 
    290                 295                 300                 


Ser Thr Glu Glu Ile Lys Ala Tyr Cys Asp Met Glu Ala Gly Gly Gly 
305                 310                 315                 320 


Gly Trp Thr Ile Ile Gln Arg Arg Glu Asp Gly Ser Val Asp Phe Gln 
                325                 330                 335     


Arg Thr Trp Lys Glu Tyr Lys Val Gly Phe Gly Asn Pro Ser Gly Glu 
            340                 345                 350         


Tyr Trp Leu Gly Asn Glu Phe Val Ser Gln Leu Thr Asn Gln Gln Arg 
        355                 360                 365             


Tyr Val Leu Lys Ile His Leu Lys Asp Trp Glu Gly Asn Glu Ala Tyr 
    370                 375                 380                 


Ser Leu Tyr Glu His Phe Tyr Leu Ser Ser Glu Glu Leu Asn Tyr Arg 
385                 390                 395                 400 


Ile His Leu Lys Gly Leu Thr Gly Thr Ala Gly Lys Ile Ser Ser Ile 
                405                 410                 415     


Ser Gln Pro Gly Asn Asp Phe Ser Thr Lys Asp Gly Asp Asn Asp Lys 
            420                 425                 430         


Cys Ile Cys Lys Cys Ser Gln Met Leu Thr Gly Gly Trp Trp Phe Asp 
        435                 440                 445             


Ala Cys Gly Pro Ser Asn Leu Asn Gly Met Tyr Tyr Pro Gln Arg Gln 
    450                 455                 460                 


Asn Thr Asn Lys Phe Asn Gly Ile Lys Trp Tyr Tyr Trp Lys Gly Ser 
465                 470                 475                 480 


Gly Tyr Ser Leu Lys Ala Thr Thr Met Met Ile Arg Pro Ala Asp Phe 
                485                 490                 495     


<210>  26
<211>  498
<212>  PRT
<213>  Homo sapiens

<400>  26

Met Thr Val Phe Leu Ser Phe Ala Phe Leu Ala Ala Ile Leu Thr His 
1               5                   10                  15      


Ile Gly Cys Ser Asn Gln Arg Arg Ser Pro Glu Asn Ser Gly Arg Arg 
            20                  25                  30          


Tyr Asn Arg Ile Gln His Gly Gln Cys Ala Tyr Thr Phe Ile Leu Pro 
        35                  40                  45              


Glu His Asp Gly Asn Cys Arg Glu Ser Thr Thr Asp Gln Tyr Asn Thr 
    50                  55                  60                  


Asn Ala Leu Gln Arg Asp Ala Pro His Val Glu Pro Asp Phe Ser Ser 
65                  70                  75                  80  


Gln Lys Leu Gln His Leu Glu His Val Met Glu Asn Tyr Thr Gln Trp 
                85                  90                  95      


Leu Gln Lys Leu Glu Asn Tyr Ile Val Glu Asn Met Lys Ser Glu Met 
            100                 105                 110         


Ala Gln Ile Gln Gln Asn Ala Val Gln Asn His Thr Ala Thr Met Leu 
        115                 120                 125             


Glu Ile Gly Thr Ser Leu Leu Ser Gln Thr Ala Glu Gln Thr Arg Lys 
    130                 135                 140                 


Leu Thr Asp Val Glu Thr Gln Val Leu Asn Gln Thr Ser Arg Leu Glu 
145                 150                 155                 160 


Ile Gln Leu Leu Glu Asn Ser Leu Ser Thr Tyr Lys Leu Glu Lys Gln 
                165                 170                 175     


Leu Leu Gln Gln Thr Asn Glu Ile Leu Lys Ile His Glu Lys Asn Ser 
            180                 185                 190         


Leu Leu Glu His Lys Ile Leu Glu Met Glu Gly Lys His Lys Glu Glu 
        195                 200                 205             


Leu Asp Thr Leu Lys Glu Glu Lys Glu Asn Leu Gln Gly Leu Val Thr 
    210                 215                 220                 


Arg Gln Thr Tyr Ile Ile Gln Glu Leu Glu Lys Gln Leu Asn Arg Ala 
225                 230                 235                 240 


Thr Thr Asn Asn Ser Val Leu Gln Lys Gln Gln Leu Glu Leu Met Asp 
                245                 250                 255     


Thr Val His Asn Leu Val Asn Leu Cys Thr Lys Glu Gly Val Leu Leu 
            260                 265                 270         


Lys Gly Gly Lys Arg Glu Glu Glu Lys Pro Phe Arg Asp Cys Ala Asp 
        275                 280                 285             


Val Tyr Gln Ala Gly Phe Asn Lys Ser Gly Ile Tyr Thr Ile Tyr Ile 
    290                 295                 300                 


Asn Asn Met Pro Glu Pro Lys Lys Val Phe Cys Asn Met Asp Val Asn 
305                 310                 315                 320 


Gly Gly Gly Trp Thr Val Ile Gln His Arg Glu Asp Gly Ser Leu Asp 
                325                 330                 335     


Phe Gln Arg Gly Trp Lys Glu Tyr Lys Met Gly Phe Gly Asn Pro Ser 
            340                 345                 350         


Gly Glu Tyr Trp Leu Gly Asn Glu Phe Ile Phe Ala Ile Thr Ser Gln 
        355                 360                 365             


Arg Gln Tyr Met Leu Arg Ile Glu Leu Met Asp Trp Glu Gly Asn Arg 
    370                 375                 380                 


Ala Tyr Ser Gln Tyr Asp Arg Phe His Ile Gly Asn Glu Lys Gln Asn 
385                 390                 395                 400 


Tyr Arg Leu Tyr Leu Lys Gly His Thr Gly Thr Ala Gly Lys Gln Ser 
                405                 410                 415     


Ser Leu Ile Leu His Gly Ala Asp Phe Ser Thr Lys Asp Ala Asp Asn 
            420                 425                 430         


Asp Asn Cys Met Cys Lys Cys Ala Leu Met Leu Thr Gly Gly Trp Trp 
        435                 440                 445             


Phe Asp Ala Cys Gly Pro Ser Asn Leu Asn Gly Met Phe Tyr Thr Ala 
    450                 455                 460                 


Gly Gln Asn His Gly Lys Leu Asn Gly Ile Lys Trp His Tyr Phe Lys 
465                 470                 475                 480 


Gly Pro Ser Tyr Ser Leu Arg Ser Thr Thr Met Met Ile Arg Pro Leu 
                485                 490                 495     


Asp Phe 
        


<210>  27
<211>  1124
<212>  PRT
<213>  Homo sapiens

<400>  27

Met Asp Ser Leu Ala Ser Leu Val Leu Cys Gly Val Ser Leu Leu Leu 
1               5                   10                  15      


Ser Gly Thr Val Glu Gly Ala Met Asp Leu Ile Leu Ile Asn Ser Leu 
            20                  25                  30          


Pro Leu Val Ser Asp Ala Glu Thr Ser Leu Thr Cys Ile Ala Ser Gly 
        35                  40                  45              


Trp Arg Pro His Glu Pro Ile Thr Ile Gly Arg Asp Phe Glu Ala Leu 
    50                  55                  60                  


Met Asn Gln His Gln Asp Pro Leu Glu Val Thr Gln Asp Val Thr Arg 
65                  70                  75                  80  


Glu Trp Ala Lys Lys Val Val Trp Lys Arg Glu Lys Ala Ser Lys Ile 
                85                  90                  95      


Asn Gly Ala Tyr Phe Cys Glu Gly Arg Val Arg Gly Glu Ala Ile Arg 
            100                 105                 110         


Ile Arg Thr Met Lys Met Arg Gln Gln Ala Ser Phe Leu Pro Ala Thr 
        115                 120                 125             


Leu Thr Met Thr Val Asp Lys Gly Asp Asn Val Asn Ile Ser Phe Lys 
    130                 135                 140                 


Lys Val Leu Ile Lys Glu Glu Asp Ala Val Ile Tyr Lys Asn Gly Ser 
145                 150                 155                 160 


Phe Ile His Ser Val Pro Arg His Glu Val Pro Asp Ile Leu Glu Val 
                165                 170                 175     


His Leu Pro His Ala Gln Pro Gln Asp Ala Gly Val Tyr Ser Ala Arg 
            180                 185                 190         


Tyr Ile Gly Gly Asn Leu Phe Thr Ser Ala Phe Thr Arg Leu Ile Val 
        195                 200                 205             


Arg Arg Cys Glu Ala Gln Lys Trp Gly Pro Glu Cys Asn His Leu Cys 
    210                 215                 220                 


Thr Ala Cys Met Asn Asn Gly Val Cys His Glu Asp Thr Gly Glu Cys 
225                 230                 235                 240 


Ile Cys Pro Pro Gly Phe Met Gly Arg Thr Cys Glu Lys Ala Cys Glu 
                245                 250                 255     


Leu His Thr Phe Gly Arg Thr Cys Lys Glu Arg Cys Ser Gly Gln Glu 
            260                 265                 270         


Gly Cys Lys Ser Tyr Val Phe Cys Leu Pro Asp Pro Tyr Gly Cys Ser 
        275                 280                 285             


Cys Ala Thr Gly Trp Lys Gly Leu Gln Cys Asn Glu Ala Cys His Pro 
    290                 295                 300                 


Gly Phe Tyr Gly Pro Asp Cys Lys Leu Arg Cys Ser Cys Asn Asn Gly 
305                 310                 315                 320 


Glu Met Cys Asp Arg Phe Gln Gly Cys Leu Cys Ser Pro Gly Trp Gln 
                325                 330                 335     


Gly Leu Gln Cys Glu Arg Glu Gly Ile Pro Arg Met Thr Pro Lys Ile 
            340                 345                 350         


Val Asp Leu Pro Asp His Ile Glu Val Asn Ser Gly Lys Phe Asn Pro 
        355                 360                 365             


Ile Cys Lys Ala Ser Gly Trp Pro Leu Pro Thr Asn Glu Glu Met Thr 
    370                 375                 380                 


Leu Val Lys Pro Asp Gly Thr Val Leu His Pro Lys Asp Phe Asn His 
385                 390                 395                 400 


Thr Asp His Phe Ser Val Ala Ile Phe Thr Ile His Arg Ile Leu Pro 
                405                 410                 415     


Pro Asp Ser Gly Val Trp Val Cys Ser Val Asn Thr Val Ala Gly Met 
            420                 425                 430         


Val Glu Lys Pro Phe Asn Ile Ser Val Lys Val Leu Pro Lys Pro Leu 
        435                 440                 445             


Asn Ala Pro Asn Val Ile Asp Thr Gly His Asn Phe Ala Val Ile Asn 
    450                 455                 460                 


Ile Ser Ser Glu Pro Tyr Phe Gly Asp Gly Pro Ile Lys Ser Lys Lys 
465                 470                 475                 480 


Leu Leu Tyr Lys Pro Val Asn His Tyr Glu Ala Trp Gln His Ile Gln 
                485                 490                 495     


Val Thr Asn Glu Ile Val Thr Leu Asn Tyr Leu Glu Pro Arg Thr Glu 
            500                 505                 510         


Tyr Glu Leu Cys Val Gln Leu Val Arg Arg Gly Glu Gly Gly Glu Gly 
        515                 520                 525             


His Pro Gly Pro Val Arg Arg Phe Thr Thr Ala Ser Ile Gly Leu Pro 
    530                 535                 540                 


Pro Pro Arg Gly Leu Asn Leu Leu Pro Lys Ser Gln Thr Thr Leu Asn 
545                 550                 555                 560 


Leu Thr Trp Gln Pro Ile Phe Pro Ser Ser Glu Asp Asp Phe Tyr Val 
                565                 570                 575     


Glu Val Glu Arg Arg Ser Val Gln Lys Ser Asp Gln Gln Asn Ile Lys 
            580                 585                 590         


Val Pro Gly Asn Leu Thr Ser Val Leu Leu Asn Asn Leu His Pro Arg 
        595                 600                 605             


Glu Gln Tyr Val Val Arg Ala Arg Val Asn Thr Lys Ala Gln Gly Glu 
    610                 615                 620                 


Trp Ser Glu Asp Leu Thr Ala Trp Thr Leu Ser Asp Ile Leu Pro Pro 
625                 630                 635                 640 


Gln Pro Glu Asn Ile Lys Ile Ser Asn Ile Thr His Ser Ser Ala Val 
                645                 650                 655     


Ile Ser Trp Thr Ile Leu Asp Gly Tyr Ser Ile Ser Ser Ile Thr Ile 
            660                 665                 670         


Arg Tyr Lys Val Gln Gly Lys Asn Glu Asp Gln His Val Asp Val Lys 
        675                 680                 685             


Ile Lys Asn Ala Thr Ile Thr Gln Tyr Gln Leu Lys Gly Leu Glu Pro 
    690                 695                 700                 


Glu Thr Ala Tyr Gln Val Asp Ile Phe Ala Glu Asn Asn Ile Gly Ser 
705                 710                 715                 720 


Ser Asn Pro Ala Phe Ser His Glu Leu Val Thr Leu Pro Glu Ser Gln 
                725                 730                 735     


Ala Pro Ala Asp Leu Gly Gly Gly Lys Met Leu Leu Ile Ala Ile Leu 
            740                 745                 750         


Gly Ser Ala Gly Met Thr Cys Leu Thr Val Leu Leu Ala Phe Leu Ile 
        755                 760                 765             


Ile Leu Gln Leu Lys Arg Ala Asn Val Gln Arg Arg Met Ala Gln Ala 
    770                 775                 780                 


Phe Gln Asn Val Arg Glu Glu Pro Ala Val Gln Phe Asn Ser Gly Thr 
785                 790                 795                 800 


Leu Ala Leu Asn Arg Lys Val Lys Asn Asn Pro Asp Pro Thr Ile Tyr 
                805                 810                 815     


Pro Val Leu Asp Trp Asn Asp Ile Lys Phe Gln Asp Val Ile Gly Glu 
            820                 825                 830         


Gly Asn Phe Gly Gln Val Leu Lys Ala Arg Ile Lys Lys Asp Gly Leu 
        835                 840                 845             


Arg Met Asp Ala Ala Ile Lys Arg Met Lys Glu Tyr Ala Ser Lys Asp 
    850                 855                 860                 


Asp His Arg Asp Phe Ala Gly Glu Leu Glu Val Leu Cys Lys Leu Gly 
865                 870                 875                 880 


His His Pro Asn Ile Ile Asn Leu Leu Gly Ala Cys Glu His Arg Gly 
                885                 890                 895     


Tyr Leu Tyr Leu Ala Ile Glu Tyr Ala Pro His Gly Asn Leu Leu Asp 
            900                 905                 910         


Phe Leu Arg Lys Ser Arg Val Leu Glu Thr Asp Pro Ala Phe Ala Ile 
        915                 920                 925             


Ala Asn Ser Thr Ala Ser Thr Leu Ser Ser Gln Gln Leu Leu His Phe 
    930                 935                 940                 


Ala Ala Asp Val Ala Arg Gly Met Asp Tyr Leu Ser Gln Lys Gln Phe 
945                 950                 955                 960 


Ile His Arg Asp Leu Ala Ala Arg Asn Ile Leu Val Gly Glu Asn Tyr 
                965                 970                 975     


Val Ala Lys Ile Ala Asp Phe Gly Leu Ser Arg Gly Gln Glu Val Tyr 
            980                 985                 990         


Val Lys Lys Thr Met Gly Arg Leu  Pro Val Arg Trp Met  Ala Ile Glu 
        995                 1000                 1005             


Ser Leu  Asn Tyr Ser Val Tyr  Thr Thr Asn Ser Asp  Val Trp Ser 
    1010                 1015                 1020             


Tyr Gly  Val Leu Leu Trp Glu  Ile Val Ser Leu Gly  Gly Thr Pro 
    1025                 1030                 1035             


Tyr Cys  Gly Met Thr Cys Ala  Glu Leu Tyr Glu Lys  Leu Pro Gln 
    1040                 1045                 1050             


Gly Tyr  Arg Leu Glu Lys Pro  Leu Asn Cys Asp Asp  Glu Val Tyr 
    1055                 1060                 1065             


Asp Leu  Met Arg Gln Cys Trp  Arg Glu Lys Pro Tyr  Glu Arg Pro 
    1070                 1075                 1080             


Ser Phe  Ala Gln Ile Leu Val  Ser Leu Asn Arg Met  Leu Glu Glu 
    1085                 1090                 1095             


Arg Lys  Thr Tyr Val Asn Thr  Thr Leu Tyr Glu Lys  Phe Thr Tyr 
    1100                 1105                 1110             


Ala Gly  Ile Asp Cys Ser Ala  Glu Glu Ala Ala 
    1115                 1120                 


