                         SEQUENCE LISTING

<110>  F. Hoffmann-La Roche AG
 
<120>  Method for improving VEGF-receptor blocking selectivity of an 
       anti-VEGF antibody

<130>  P35212-EP (MME)

<150>  EP17211032.2
<151>  2017-12-29

<160>  36    

<170>  PatentIn version 3.5

<210>  1
<211>  117
<212>  PRT
<213>  Artificial Sequence

<220>
<223>  VH domain of antibody VEGF-0089

<400>  1

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


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


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


Ser Ser Ile Gly Asn Gly Gly Gly Ile Tyr Thr Tyr Tyr Ala Asp Ser 
    50                  55                  60                  


Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu 
65                  70                  75                  80  


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


Cys Ala Lys Gly Asp Asn Leu Phe Asp Ser Trp Gly Pro Gly Thr Leu 
            100                 105                 110         


Val Thr Val Ser Ser 
        115         


<210>  2
<211>  106
<212>  PRT
<213>  Artificial Sequence

<220>
<223>  VL domain of antibodies VEGF-0089, VEGF-0113, VEGF-0114, 
       VEGF-P1AD8675, VEGF-P1AE3520, VEGF-P1AE3521, VEGF-0112, 
       VEGF-P1AE8674, VEGF-P1AE3519

<400>  2

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


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


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


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


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


Asp Val Ala Thr Tyr Tyr Cys Gln Gln Tyr Gln Asn Phe Pro Arg Thr 
                85                  90                  95      


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


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

<220>
<223>  H-CDR1 of antibodies VEGF-0089, VEGF-0113, VEGF-0114, 
       VEGF-P1AD8675, VEGF-P1AE3520, VEGF-P1AE3521, VEGF-0112, 
       VEGF-P1AE8674, VEGF-P1AE3519

<400>  3

Asn Tyr Ala Met Thr 
1               5   


<210>  4
<211>  18
<212>  PRT
<213>  Artificial Sequence

<220>
<223>  H-CDR2 of antibodies VEGF-0089, VEGF-P1AD8675, VEGF-P1AD8674

<400>  4

Ser Ile Gly Asn Gly Gly Gly Ile Tyr Thr Tyr Tyr Ala Asp Ser Val 
1               5                   10                  15      


Lys Gly 
        


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

<220>
<223>  H-CDR3 of antibodies VEGF-0089, VEGF-0113, VEGF-0114, 
       VEGF-P1AD8675, VEGF-P1AE3520, VEGF-P1AE3521, VEGF-0112, 
       VEGF-P1AE8674, VEGF-P1AE3519

<400>  5

Gly Asp Asn Leu Phe Asp Ser 
1               5           


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

<220>
<223>  L-CDR1 of antibodies VEGF-0089, VEGF-0113, VEGF-0114, 
       VEGF-P1AD8675, VEGF-P1AE3520, VEGF-P1AE3521, VEGF-0112, 
       VEGF-P1AE8674, VEGF-P1AE3519

<400>  6

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


<210>  7
<211>  11
<212>  PRT
<213>  Artificial Sequence

<220>
<223>  L-CDR2 of antibodies VEGF-0089, VEGF-0113, VEGF-0114, 
       VEGF-P1AD8675, VEGF-P1AE3520, VEGF-P1AE3521, VEGF-0112, 
       VEGF-P1AE8674, VEGF-P1AE3519

<400>  7

Ala Ser Thr Leu Gln Ser Gly Val Pro Ser Arg 
1               5                   10      


<210>  8
<211>  4
<212>  PRT
<213>  Artificial Sequence

<220>
<223>  L-CDR3 of antibodies VEGF-0089, VEGF-0113, VEGF-0114, 
       VEGF-P1AD8675, VEGF-P1AE3520, VEGF-P1AE3521, VEGF-0112, 
       VEGF-P1AE8674, VEGF-P1AE3519

<400>  8

Phe Pro Arg Thr 
1               


<210>  9
<211>  31
<212>  PRT
<213>  Artificial Sequence

<220>
<223>  H-FR3 of VEGF-0089, VEGF-0113,VEGF-0114, VEGF-0112

<400>  9

Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr Leu Gln Met 
1               5                   10                  15      


Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Ala Lys 
            20                  25                  30      


<210>  10
<211>  235
<212>  PRT
<213>  Artificial Sequence

<220>
<223>  heavy chain of VEGF-0089 Fab fragment

<400>  10

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


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


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


Ser Ser Ile Gly Asn Gly Gly Gly Ile Tyr Thr Tyr Tyr Ala Asp Ser 
    50                  55                  60                  


Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu 
65                  70                  75                  80  


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


Cys Ala Lys Gly Asp Asn Leu Phe Asp Ser Trp Gly Pro Gly Thr Leu 
            100                 105                 110         


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


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


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


Gly Thr Leu Thr Asn Gly Val Arg Thr Phe Pro Ser Val Arg Gln Ser 
                165                 170                 175     


Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Ser Val Thr Ser Ser Ser 
            180                 185                 190         


Gln Pro Val Thr Cys Asn Val Ala His Pro Ala Thr Asn Thr Lys Val 
        195                 200                 205             


Asp Lys Thr Val Ala Pro Ser Thr Cys Ser Glu Gln Lys Leu Ile Ser 
    210                 215                 220                 


Glu Glu Asp Leu Gly Ala Ala Glu Pro Glu Ala 
225                 230                 235 


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

<220>
<223>  light chain of VEGF-0089, VEGF-0113, VEGF-0114, VEGF-P1AD8675 Fab
       fragment

<400>  11

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


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


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


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


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


Asp Val Ala Thr Tyr Tyr Cys Gln Gln Tyr Gln Asn Phe Pro Arg Thr 
                85                  90                  95      


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


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


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


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


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


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


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


Asn Arg Gly Glu Cys 
    210             


<210>  12
<211>  117
<212>  PRT
<213>  Artificial Sequence

<220>
<223>  VH domain of antibody VEGF-0113

<400>  12

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


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


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


Ser Ser Ile Gly Asn Gly Pro Gly Ile Tyr Thr Tyr Tyr Ala Asp Ser 
    50                  55                  60                  


Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu 
65                  70                  75                  80  


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


Cys Ala Lys Gly Asp Asn Leu Phe Asp Ser Trp Gly Pro Gly Thr Leu 
            100                 105                 110         


Val Thr Val Ser Ser 
        115         


<210>  13
<211>  18
<212>  PRT
<213>  Artificial Sequence

<220>
<223>  H-CDR2 of antibody VEGF-0113, P1AE3520

<400>  13

Ser Ile Gly Asn Gly Pro Gly Ile Tyr Thr Tyr Tyr Ala Asp Ser Val 
1               5                   10                  15      


Lys Gly 
        


<210>  14
<211>  235
<212>  PRT
<213>  Artificial Sequence

<220>
<223>  heavy chain of VEGF-0113 Fab fragment

<400>  14

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


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


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


Ser Ser Ile Gly Asn Gly Pro Gly Ile Tyr Thr Tyr Tyr Ala Asp Ser 
    50                  55                  60                  


Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu 
65                  70                  75                  80  


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


Cys Ala Lys Gly Asp Asn Leu Phe Asp Ser Trp Gly Pro Gly Thr Leu 
            100                 105                 110         


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


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


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


Gly Thr Leu Thr Asn Gly Val Arg Thr Phe Pro Ser Val Arg Gln Ser 
                165                 170                 175     


Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Ser Val Thr Ser Ser Ser 
            180                 185                 190         


Gln Pro Val Thr Cys Asn Val Ala His Pro Ala Thr Asn Thr Lys Val 
        195                 200                 205             


Asp Lys Thr Val Ala Pro Ser Thr Cys Ser Glu Gln Lys Leu Ile Ser 
    210                 215                 220                 


Glu Glu Asp Leu Gly Ala Ala Glu Pro Glu Ala 
225                 230                 235 


<210>  15
<211>  116
<212>  PRT
<213>  Artificial Sequence

<220>
<223>  VH domain of antibody VEGF-0114

<400>  15

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


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


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


Ser Ser Ile Gly Ser Gly Gly Phe Tyr 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 Gly Asp Asn Leu Phe Asp Ser Trp Gly Pro Gly Thr Leu Val 
            100                 105                 110         


Thr Val Ser Ser 
        115     


<210>  16
<211>  17
<212>  PRT
<213>  Artificial Sequence

<220>
<223>  H-CDR2 of antibody VEGF-0114, VEGF-P1AE3521

<400>  16

Ser Ile Gly Ser Gly Gly Phe Tyr Thr Tyr Tyr Ala Asp Ser Val Lys 
1               5                   10                  15      


Gly 
    


<210>  17
<211>  234
<212>  PRT
<213>  Artificial Sequence

<220>
<223>  heavy chain of VEGF-0114 Fab fragment

<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 Phe Thr Phe Thr Asn Tyr 
            20                  25                  30          


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


Ser Ser Ile Gly Ser Gly Gly Phe Tyr 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 Gly Asp Asn Leu Phe Asp Ser Trp Gly Pro Gly Thr Leu Val 
            100                 105                 110         


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


Pro Cys Cys Gly Asp Thr Pro Ser Ser Thr Val Thr Leu Gly Cys Leu 
    130                 135                 140                 


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


Thr Leu Thr Asn Gly Val Arg Thr Phe Pro Ser Val Arg Gln Ser Ser 
                165                 170                 175     


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


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


Lys Thr Val Ala Pro Ser Thr Cys Ser Glu Gln Lys Leu Ile Ser Glu 
    210                 215                 220                 


Glu Asp Leu Gly Ala Ala Glu Pro Glu Ala 
225                 230                 


<210>  18
<211>  117
<212>  PRT
<213>  Artificial Sequence

<220>
<223>  VH domain of antibody VEGF-P1AD8675

<400>  18

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


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


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


Ser Ser Ile Gly Asn Gly Gly Gly Ile Tyr Thr Tyr Tyr Ala Asp Ser 
    50                  55                  60                  


Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Trp Lys Asn Thr Leu 
65                  70                  75                  80  


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


Cys Ala Lys Gly Asp Asn Leu Phe Asp Ser Trp Gly Pro Gly Thr Leu 
            100                 105                 110         


Val Thr Val Ser Ser 
        115         


<210>  19
<211>  31
<212>  PRT
<213>  Artificial Sequence

<220>
<223>  H-FR3 of antibody VEGF-P1AD8675, P1AE3520, VEGF-P1AE3521, 
       VEGF-P1AE3519

<400>  19

Phe Thr Ile Ser Arg Asp Asn Trp Lys Asn Thr Leu Tyr Leu Gln Met 
1               5                   10                  15      


Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Ala Lys 
            20                  25                  30      


<210>  20
<211>  220
<212>  PRT
<213>  Artificial Sequence

<220>
<223>  heavy chain of VEGF-P1AD8675 Fab fragment

<400>  20

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


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


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


Ser Ser Ile Gly Asn Gly Gly Gly Ile Tyr Thr Tyr Tyr Ala Asp Ser 
    50                  55                  60                  


Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Trp Lys Asn Thr Leu 
65                  70                  75                  80  


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


Cys Ala Lys Gly Asp Asn Leu Phe Asp Ser Trp Gly Pro Gly Thr Leu 
            100                 105                 110         


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


Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys 
    130                 135                 140                 


Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser 
145                 150                 155                 160 


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


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


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


Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys 
    210                 215                 220 


<210>  21
<211>  117
<212>  PRT
<213>  Artificial Sequence

<220>
<223>  VH domain of antibody VEGF-P1AE3520

<400>  21

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


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


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


Ser Ser Ile Gly Asn Gly Pro Gly Ile Tyr Thr Tyr Tyr Ala Asp Ser 
    50                  55                  60                  


Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Trp Lys Asn Thr Leu 
65                  70                  75                  80  


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


Cys Ala Lys Gly Asp Asn Leu Phe Asp Ser Trp Gly Pro Gly Thr Leu 
            100                 105                 110         


Val Thr Val Ser Ser 
        115         


<210>  22
<211>  235
<212>  PRT
<213>  Artificial Sequence

<220>
<223>  heavy chain of VEGF-P1AE3520 Fab fragment

<400>  22

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


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


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


Ser Ser Ile Gly Asn Gly Pro Gly Ile Tyr Thr Tyr Tyr Ala Asp Ser 
    50                  55                  60                  


Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Trp Lys Asn Thr Leu 
65                  70                  75                  80  


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


Cys Ala Lys Gly Asp Asn Leu Phe Asp Ser Trp Gly Pro Gly Thr Leu 
            100                 105                 110         


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


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


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


Gly Thr Leu Thr Asn Gly Val Arg Thr Phe Pro Ser Val Arg Gln Ser 
                165                 170                 175     


Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Ser Val Thr Ser Ser Ser 
            180                 185                 190         


Gln Pro Val Thr Cys Asn Val Ala His Pro Ala Thr Asn Thr Lys Val 
        195                 200                 205             


Asp Lys Thr Val Ala Pro Ser Thr Cys Ser Glu Gln Lys Leu Ile Ser 
    210                 215                 220                 


Glu Glu Asp Leu Gly Ala Ala Glu Pro Glu Ala 
225                 230                 235 


<210>  23
<211>  116
<212>  PRT
<213>  Artificial Sequence

<220>
<223>  VH domain of antibody VEGF-P1AE3521

<400>  23

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


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


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


Ser Ser Ile Gly Ser Gly Gly Phe Tyr Thr Tyr Tyr Ala Asp Ser Val 
    50                  55                  60                  


Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Trp 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 Gly Asp Asn Leu Phe Asp Ser Trp Gly Pro Gly Thr Leu Val 
            100                 105                 110         


Thr Val Ser Ser 
        115     


<210>  24
<211>  234
<212>  PRT
<213>  Artificial Sequence

<220>
<223>  heavy chain of VEGF-P1AE3521 Fab fragment

<400>  24

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


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


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


Ser Ser Ile Gly Ser Gly Gly Phe Tyr Thr Tyr Tyr Ala Asp Ser Val 
    50                  55                  60                  


Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Trp 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 Gly Asp Asn Leu Phe Asp Ser Trp Gly Pro Gly Thr Leu Val 
            100                 105                 110         


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


Pro Cys Cys Gly Asp Thr Pro Ser Ser Thr Val Thr Leu Gly Cys Leu 
    130                 135                 140                 


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


Thr Leu Thr Asn Gly Val Arg Thr Phe Pro Ser Val Arg Gln Ser Ser 
                165                 170                 175     


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


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


Lys Thr Val Ala Pro Ser Thr Cys Ser Glu Gln Lys Leu Ile Ser Glu 
    210                 215                 220                 


Glu Asp Leu Gly Ala Ala Glu Pro Glu Ala 
225                 230                 


<210>  25
<211>  117
<212>  PRT
<213>  Artificial Sequence

<220>
<223>  VH domain of antibody VEGF-0112

<400>  25

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


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


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


Ser Ser Ile Gly Ser Gly Gly Gly Ile Tyr Thr Tyr Tyr Ala Asp Ser 
    50                  55                  60                  


Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu 
65                  70                  75                  80  


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


Cys Ala Lys Gly Asp Asn Leu Phe Asp Ser Trp Gly Pro Gly Thr Leu 
            100                 105                 110         


Val Thr Val Ser Ser 
        115         


<210>  26
<211>  18
<212>  PRT
<213>  Artificial Sequence

<220>
<223>  H-CDR2 of antibody VEGF-0112 and VEGF-P1AE3519

<400>  26

Ser Ile Gly Ser Gly Gly Gly Ile Tyr Thr Tyr Tyr Ala Asp Ser Val 
1               5                   10                  15      


Lys Gly 
        


<210>  27
<211>  235
<212>  PRT
<213>  Artificial Sequence

<220>
<223>  heavy chain of VEGF-0112 Fab fragment

<400>  27

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


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


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


Ser Ser Ile Gly Ser Gly Gly Gly Ile Tyr Thr Tyr Tyr Ala Asp Ser 
    50                  55                  60                  


Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu 
65                  70                  75                  80  


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


Cys Ala Lys Gly Asp Asn Leu Phe Asp Ser Trp Gly Pro Gly Thr Leu 
            100                 105                 110         


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


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


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


Gly Thr Leu Thr Asn Gly Val Arg Thr Phe Pro Ser Val Arg Gln Ser 
                165                 170                 175     


Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Ser Val Thr Ser Ser Ser 
            180                 185                 190         


Gln Pro Val Thr Cys Asn Val Ala His Pro Ala Thr Asn Thr Lys Val 
        195                 200                 205             


Asp Lys Thr Val Ala Pro Ser Thr Cys Ser Glu Gln Lys Leu Ile Ser 
    210                 215                 220                 


Glu Glu Asp Leu Gly Ala Ala Glu Pro Glu Ala 
225                 230                 235 


<210>  28
<211>  117
<212>  PRT
<213>  Artificial Sequence

<220>
<223>  VH domain of antibody VEGF-P1AD8674

<400>  28

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


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


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


Ser Ser Ile Gly Asn Gly Gly Gly Ile Tyr Thr Tyr Tyr Ala Asp Ser 
    50                  55                  60                  


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


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


Cys Ala Lys Gly Asp Asn Leu Phe Asp Ser Trp Gly Pro Gly Thr Leu 
            100                 105                 110         


Val Thr Val Ser Ser 
        115         


<210>  29
<211>  31
<212>  PRT
<213>  Artificial Sequence

<220>
<223>  H-FR3 of antibody VEGF-P1AD8674

<400>  29

Phe Thr Ile Ser Arg Asn Asn Ala Glu Asn Thr Leu Tyr Leu Gln Met 
1               5                   10                  15      


Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Ala Lys 
            20                  25                  30      


<210>  30
<211>  220
<212>  PRT
<213>  Artificial Sequence

<220>
<223>  heavy chain of VEGF-P1AD8674 Fab fragment

<400>  30

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


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


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


Ser Ser Ile Gly Asn Gly Gly Gly Ile Tyr Thr Tyr Tyr Ala Asp Ser 
    50                  55                  60                  


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


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


Cys Ala Lys Gly Asp Asn Leu Phe Asp Ser Trp Gly Pro Gly Thr Leu 
            100                 105                 110         


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


Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys 
    130                 135                 140                 


Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser 
145                 150                 155                 160 


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


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


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


Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys 
    210                 215                 220 


<210>  31
<211>  117
<212>  PRT
<213>  Artificial Sequence

<220>
<223>  VH domain of antibody  VEGF-P1AE3519

<400>  31

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


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


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


Ser Ser Ile Gly Ser Gly Gly Gly Ile Tyr Thr Tyr Tyr Ala Asp Ser 
    50                  55                  60                  


Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Trp Lys Asn Thr Leu 
65                  70                  75                  80  


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


Cys Ala Lys Gly Asp Asn Leu Phe Asp Ser Trp Gly Pro Gly Thr Leu 
            100                 105                 110         


Val Thr Val Ser Ser 
        115         


<210>  32
<211>  235
<212>  PRT
<213>  Artificial Sequence

<220>
<223>  heavy chain of VEGF-P1AE3519 Fab fragment

<400>  32

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


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


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


Ser Ser Ile Gly Ser Gly Gly Gly Ile Tyr Thr Tyr Tyr Ala Asp Ser 
    50                  55                  60                  


Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Trp Lys Asn Thr Leu 
65                  70                  75                  80  


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


Cys Ala Lys Gly Asp Asn Leu Phe Asp Ser Trp Gly Pro Gly Thr Leu 
            100                 105                 110         


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


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


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


Gly Thr Leu Thr Asn Gly Val Arg Thr Phe Pro Ser Val Arg Gln Ser 
                165                 170                 175     


Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Ser Val Thr Ser Ser Ser 
            180                 185                 190         


Gln Pro Val Thr Cys Asn Val Ala His Pro Ala Thr Asn Thr Lys Val 
        195                 200                 205             


Asp Lys Thr Val Ala Pro Ser Thr Cys Ser Glu Gln Lys Leu Ile Ser 
    210                 215                 220                 


Glu Glu Asp Leu Gly Ala Ala Glu Pro Glu Ala 
225                 230                 235 


<210>  33
<211>  232
<212>  PRT
<213>  Homo sapiens

<400>  33

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 Lys Lys Ser Val 
    130                 135                 140                 


Arg Gly Lys Gly Lys Gly Gln Lys Arg Lys Arg Lys Lys Ser Arg Tyr 
145                 150                 155                 160 


Lys Ser Trp Ser Val Tyr Val Gly Ala Arg Cys Cys Leu Met Pro Trp 
                165                 170                 175     


Ser Leu Pro Gly Pro His Pro Cys Gly Pro Cys Ser Glu Arg Arg Lys 
            180                 185                 190         


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


Thr Asp Ser Arg Cys Lys Ala Arg Gln Leu Glu Leu Asn Glu Arg Thr 
    210                 215                 220                 


Cys Arg Cys Asp Lys Pro Arg Arg 
225                 230         


<210>  34
<211>  214
<212>  PRT
<213>  Artificial Sequence

<220>
<223>  heavy chain of Lucentis (ranibizumab)

<400>  34

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>  35
<211>  226
<212>  PRT
<213>  Artificial Sequence

<220>
<223>  light chain of Lucentis (ranibizumab)

<400>  35

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 
225     


<210>  36
<211>  121
<212>  PRT
<213>  Homo sapiens

<400>  36

Ala Pro Met Ala Glu Gly Gly Gly Gln Asn His His Glu Val Val Lys 
1               5                   10                  15      


Phe Met Asp Val Tyr Gln Arg Ser Tyr Cys His Pro Ile Glu Thr Leu 
            20                  25                  30          


Val Asp Ile Phe Gln Glu Tyr Pro Asp Glu Ile Glu Tyr Ile Phe Lys 
        35                  40                  45              


Pro Ser Cys Val Pro Leu Met Arg Cys Gly Gly Cys Cys Asn Asp Glu 
    50                  55                  60                  


Gly Leu Glu Cys Val Pro Thr Glu Glu Ser Asn Ile Thr Met Gln Ile 
65                  70                  75                  80  


Met Arg Ile Lys Pro His Gln Gly Gln His Ile Gly Glu Met Ser Phe 
                85                  90                  95      


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


Gln Glu Lys Cys Asp Lys Pro Arg Arg 
        115                 120     


