                         SEQUENCE LISTING

<110>  Iovance Biotherapeutics, Inc.
       RITTHIPICHAI, Krit
       JUILLERAT, Alexandre
       BOYNE, Alex
 
<120>  CISH GENE EDITING OF TUMOR INFILTRATING LYMPHOCYTES AND USES OF 
       SAME IN IMMUNOTHERAPY

<130>  116983-5082-WO

<140>  PCT/US22/21356
<141>  2022-03-22

<150>  US 63/165,066
<151>  2021-03-23

<160>  175   

<170>  PatentIn version 3.5

<210>  1
<211>  450
<212>  PRT
<213>  Artificial Sequence

<220>
<223>  Muromonab heavy chain

<400>  1

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


Ser Val Lys Met Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Arg Tyr 
            20                  25                  30          


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


Gly Tyr Ile Asn Pro Ser Arg Gly Tyr Thr Asn Tyr Asn Gln Lys Phe 
    50                  55                  60                  


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


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


Ala Arg Tyr Tyr Asp Asp His Tyr Cys Leu Asp Tyr Trp Gly Gln Gly 
            100                 105                 110         


Thr Thr Leu Thr Val Ser Ser Ala Lys Thr Thr Ala Pro Ser Val Tyr 
        115                 120                 125             


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


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


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


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


Thr Trp Pro Ser Gln Ser Ile Thr Cys Asn Val Ala His Pro Ala Ser 
        195                 200                 205             


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


Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly 
225                 230                 235                 240 


Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile 
                245                 250                 255     


Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu 
            260                 265                 270         


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


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


Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys 
305                 310                 315                 320 


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


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


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


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


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


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


Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His 
            420                 425                 430         


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


Gly Lys 
    450 


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

<220>
<223>  Muromonab light chain

<400>  2

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


Glu Lys Val Thr Met Thr Cys Ser Ala Ser Ser Ser Val Ser Tyr Met 
            20                  25                  30          


Asn Trp Tyr Gln Gln Lys Ser Gly Thr Ser Pro Lys Arg Trp Ile Tyr 
        35                  40                  45              


Asp Thr Ser Lys Leu Ala Ser Gly Val Pro Ala His Phe Arg Gly Ser 
    50                  55                  60                  


Gly Ser Gly Thr Ser Tyr Ser Leu Thr Ile Ser Gly Met Glu Ala Glu 
65                  70                  75                  80  


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


Phe Gly Ser Gly Thr Lys Leu Glu Ile Asn Arg Ala Asp Thr Ala Pro 
            100                 105                 110         


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


Ala Ser Val Val Cys Phe Leu Asn Asn Phe Tyr Pro Lys Asp Ile Asn 
    130                 135                 140                 


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


Ser Trp Thr Asp Gln Asp Ser Lys Asp Ser Thr Tyr Ser Met Ser Ser 
                165                 170                 175     


Thr Leu Thr Leu Thr Lys Asp Glu Tyr Glu Arg His Asn Ser Tyr Thr 
            180                 185                 190         


Cys Glu Ala Thr His Lys Thr Ser Thr Ser Pro Ile Val Lys Ser Phe 
        195                 200                 205             


Asn Arg Asn Glu Cys 
    210             


<210>  3
<211>  134
<212>  PRT
<213>  Artificial Sequence

<220>
<223>  recombinant human IL-2 (rhIL-2)

<400>  3

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


His Leu Leu Leu Asp Leu Gln Met Ile Leu Asn Gly Ile Asn Asn Tyr 
            20                  25                  30          


Lys Asn Pro Lys Leu Thr Arg Met Leu Thr Phe Lys Phe Tyr Met Pro 
        35                  40                  45              


Lys Lys Ala Thr Glu Leu Lys His Leu Gln Cys Leu Glu Glu Glu Leu 
    50                  55                  60                  


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


Leu Arg Pro Arg Asp Leu Ile Ser Asn Ile Asn Val Ile Val Leu Glu 
                85                  90                  95      


Leu Lys Gly Ser Glu Thr Thr Phe Met Cys Glu Tyr Ala Asp Glu Thr 
            100                 105                 110         


Ala Thr Ile Val Glu Phe Leu Asn Arg Trp Ile Thr Phe Cys Gln Ser 
        115                 120                 125             


Ile Ile Ser Thr Leu Thr 
    130                 


<210>  4
<211>  132
<212>  PRT
<213>  Artificial Sequence

<220>
<223>  Aldesleukin

<400>  4

Pro Thr Ser Ser Ser Thr Lys Lys Thr Gln Leu Gln Leu Glu His Leu 
1               5                   10                  15      


Leu Leu Asp Leu Gln Met Ile Leu Asn Gly Ile Asn Asn Tyr Lys Asn 
            20                  25                  30          


Pro Lys Leu Thr Arg Met Leu Thr Phe Lys Phe Tyr Met Pro Lys Lys 
        35                  40                  45              


Ala Thr Glu Leu Lys His Leu Gln Cys Leu Glu Glu Glu Leu Lys Pro 
    50                  55                  60                  


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


Pro Arg Asp Leu Ile Ser Asn Ile Asn Val Ile Val Leu Glu Leu Lys 
                85                  90                  95      


Gly Ser Glu Thr Thr Phe Met Cys Glu Tyr Ala Asp Glu Thr Ala Thr 
            100                 105                 110         


Ile Val Glu Phe Leu Asn Arg Trp Ile Thr Phe Ser Gln Ser Ile Ile 
        115                 120                 125             


Ser Thr Leu Thr 
    130         


<210>  5
<211>  130
<212>  PRT
<213>  Artificial Sequence

<220>
<223>  recombinant human IL-4 

(rhIL-4)

<400>  5

Met His Lys Cys Asp Ile Thr Leu Gln Glu Ile Ile Lys Thr Leu Asn 
1               5                   10                  15      


Ser Leu Thr Glu Gln Lys Thr Leu Cys Thr Glu Leu Thr Val Thr Asp 
            20                  25                  30          


Ile Phe Ala Ala Ser Lys Asn Thr Thr Glu Lys Glu Thr Phe Cys Arg 
        35                  40                  45              


Ala Ala Thr Val Leu Arg Gln Phe Tyr Ser His His Glu Lys Asp Thr 
    50                  55                  60                  


Arg Cys Leu Gly Ala Thr Ala Gln Gln Phe His Arg His Lys Gln Leu 
65                  70                  75                  80  


Ile Arg Phe Leu Lys Arg Leu Asp Arg Asn Leu Trp Gly Leu Ala Gly 
                85                  90                  95      


Leu Asn Ser Cys Pro Val Lys Glu Ala Asn Gln Ser Thr Leu Glu Asn 
            100                 105                 110         


Phe Leu Glu Arg Leu Lys Thr Ile Met Arg Glu Lys Tyr Ser Lys Cys 
        115                 120                 125             


Ser Ser 
    130 


<210>  6
<211>  153
<212>  PRT
<213>  Artificial Sequence

<220>
<223>  recombinant human IL-7

(rhIL-7)

<400>  6

Met Asp Cys Asp Ile Glu Gly Lys Asp Gly Lys Gln Tyr Glu Ser Val 
1               5                   10                  15      


Leu Met Val Ser Ile Asp Gln Leu Leu Asp Ser Met Lys Glu Ile Gly 
            20                  25                  30          


Ser Asn Cys Leu Asn Asn Glu Phe Asn Phe Phe Lys Arg His Ile Cys 
        35                  40                  45              


Asp Ala Asn Lys Glu Gly Met Phe Leu Phe Arg Ala Ala Arg Lys Leu 
    50                  55                  60                  


Arg Gln Phe Leu Lys Met Asn Ser Thr Gly Asp Phe Asp Leu His Leu 
65                  70                  75                  80  


Leu Lys Val Ser Glu Gly Thr Thr Ile Leu Leu Asn Cys Thr Gly Gln 
                85                  90                  95      


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


Ser Leu Glu Glu Asn Lys Ser Leu Lys Glu Gln Lys Lys Leu Asn Asp 
        115                 120                 125             


Leu Cys Phe Leu Lys Arg Leu Leu Gln Glu Ile Lys Thr Cys Trp Asn 
    130                 135                 140                 


Lys Ile Leu Met Gly Thr Lys Glu His 
145                 150             


<210>  7
<211>  115
<212>  PRT
<213>  Artificial Sequence

<220>
<223>  recombinant human IL-15 

(rhIL-15)

<400>  7

Met Asn Trp Val Asn Val Ile Ser Asp Leu Lys Lys Ile Glu Asp Leu 
1               5                   10                  15      


Ile Gln Ser Met His Ile Asp Ala Thr Leu Tyr Thr Glu Ser Asp Val 
            20                  25                  30          


His Pro Ser Cys Lys Val Thr Ala Met Lys Cys Phe Leu Leu Glu Leu 
        35                  40                  45              


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


Glu Asn Leu Ile Ile Leu Ala Asn Asn Ser Leu Ser Ser Asn Gly Asn 
65                  70                  75                  80  


Val Thr Glu Ser Gly Cys Lys Glu Cys Glu Glu Leu Glu Glu Lys Asn 
                85                  90                  95      


Ile Lys Glu Phe Leu Gln Ser Phe Val His Ile Val Gln Met Phe Ile 
            100                 105                 110         


Asn Thr Ser 
        115 


<210>  8
<211>  132
<212>  PRT
<213>  Artificial Sequence

<220>
<223>  recombinant human IL-21 

(rhIL-21)

<400>  8

Met Gln Asp Arg His Met Ile Arg Met Arg Gln Leu Ile Asp Ile Val 
1               5                   10                  15      


Asp Gln Leu Lys Asn Tyr Val Asn Asp Leu Val Pro Glu Phe Leu Pro 
            20                  25                  30          


Ala Pro Glu Asp Val Glu Thr Asn Cys Glu Trp Ser Ala Phe Ser Cys 
        35                  40                  45              


Phe Gln Lys Ala Gln Leu Lys Ser Ala Asn Thr Gly Asn Asn Glu Arg 
    50                  55                  60                  


Ile Ile Asn Val Ser Ile Lys Lys Leu Lys Arg Lys Pro Pro Ser Thr 
65                  70                  75                  80  


Asn Ala Gly Arg Arg Gln Lys His Arg Leu Thr Cys Pro Ser Cys Asp 
                85                  90                  95      


Ser Tyr Glu Lys Lys Pro Pro Lys Glu Phe Leu Glu Arg Phe Lys Ser 
            100                 105                 110         


Leu Leu Gln Lys Met Ile His Gln His Leu Ser Ser Arg Thr His Gly 
        115                 120                 125             


Ser Glu Asp Ser 
    130         


<210>  9

<400>  9
000

<210>  10

<400>  10
000

<210>  11

<400>  11
000

<210>  12

<400>  12
000

<210>  13

<400>  13
000

<210>  14

<400>  14
000

<210>  15

<400>  15
000

<210>  16

<400>  16
000

<210>  17

<400>  17
000

<210>  18

<400>  18
000

<210>  19

<400>  19
000

<210>  20

<400>  20
000

<210>  21

<400>  21
000

<210>  22

<400>  22
000

<210>  23

<400>  23
000

<210>  24

<400>  24
000

<210>  25

<400>  25
000

<210>  26

<400>  26
000

<210>  27

<400>  27
000

<210>  28

<400>  28
000

<210>  29

<400>  29
000

<210>  30

<400>  30
000

<210>  31

<400>  31
000

<210>  32

<400>  32
000

<210>  33

<400>  33
000

<210>  34

<400>  34
000

<210>  35

<400>  35
000

<210>  36

<400>  36
000

<210>  37

<400>  37
000

<210>  38

<400>  38
000

<210>  39

<400>  39
000

<210>  40

<400>  40
000

<210>  41

<400>  41
000

<210>  42

<400>  42
000

<210>  43

<400>  43
000

<210>  44

<400>  44
000

<210>  45

<400>  45
000

<210>  46

<400>  46
000

<210>  47

<400>  47
000

<210>  48

<400>  48
000

<210>  49

<400>  49
000

<210>  50

<400>  50
000

<210>  51

<400>  51
000

<210>  52

<400>  52
000

<210>  53

<400>  53
000

<210>  54

<400>  54
000

<210>  55

<400>  55
000

<210>  56

<400>  56
000

<210>  57

<400>  57
000

<210>  58

<400>  58
000

<210>  59

<400>  59
000

<210>  60

<400>  60
000

<210>  61

<400>  61
000

<210>  62

<400>  62
000

<210>  63

<400>  63
000

<210>  64

<400>  64
000

<210>  65

<400>  65
000

<210>  66

<400>  66
000

<210>  67

<400>  67
000

<210>  68

<400>  68
000

<210>  69

<400>  69
000

<210>  70

<400>  70
000

<210>  71

<400>  71
000

<210>  72

<400>  72
000

<210>  73

<400>  73
000

<210>  74

<400>  74
000

<210>  75

<400>  75
000

<210>  76

<400>  76
000

<210>  77

<400>  77
000

<210>  78

<400>  78
000

<210>  79

<400>  79
000

<210>  80

<400>  80
000

<210>  81

<400>  81
000

<210>  82

<400>  82
000

<210>  83

<400>  83
000

<210>  84

<400>  84
000

<210>  85

<400>  85
000

<210>  86

<400>  86
000

<210>  87

<400>  87
000

<210>  88

<400>  88
000

<210>  89

<400>  89
000

<210>  90

<400>  90
000

<210>  91

<400>  91
000

<210>  92

<400>  92
000

<210>  93

<400>  93
000

<210>  94

<400>  94
000

<210>  95

<400>  95
000

<210>  96

<400>  96
000

<210>  97

<400>  97
000

<210>  98

<400>  98
000

<210>  99

<400>  99
000

<210>  100

<400>  100
000

<210>  101

<400>  101
000

<210>  102

<400>  102
000

<210>  103

<400>  103
000

<210>  104

<400>  104
000

<210>  105

<400>  105
000

<210>  106

<400>  106
000

<210>  107

<400>  107
000

<210>  108

<400>  108
000

<210>  109

<400>  109
000

<210>  110

<400>  110
000

<210>  111

<400>  111
000

<210>  112

<400>  112
000

<210>  113

<400>  113
000

<210>  114

<400>  114
000

<210>  115

<400>  115
000

<210>  116

<400>  116
000

<210>  117

<400>  117
000

<210>  118

<400>  118
000

<210>  119

<400>  119
000

<210>  120

<400>  120
000

<210>  121

<400>  121
000

<210>  122

<400>  122
000

<210>  123

<400>  123
000

<210>  124

<400>  124
000

<210>  125

<400>  125
000

<210>  126

<400>  126
000

<210>  127
<211>  49
<212>  DNA
<213>  Artificial Sequence

<220>
<223>  Target PD-1 Sequence

<400>  127
ttctccccag ccctgctcgt ggtgaccgaa ggggacaacg ccaccttca                   49


<210>  128
<211>  49
<212>  DNA
<213>  Artificial Sequence

<220>
<223>  Target PD-1 Sequence

<400>  128
tacctctgtg gggccatctc cctggccccc aaggcgcaga tcaaagaga                   49


<210>  129
<211>  530
<212>  PRT
<213>  Artificial Sequence

<220>
<223>  530

       PRT

Artificial Sequence

synthetic construct Repeat PD-1-left

<400>  129

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


Gln Ala Leu Glu Thr Val Gln Arg Leu Leu Pro Val Leu Cys Gln Ala 
            20                  25                  30          


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


Gly Lys Gln Ala Leu Glu Thr Val Gln Arg Leu Leu Pro Val Leu Cys 
    50                  55                  60                  


Gln Ala His Gly Leu Thr Pro Gln Gln Val Val Ala Ile Ala Ser Asn 
65                  70                  75                  80  


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


Leu Cys Gln Ala His Gly Leu Thr Pro Glu Gln Val Val Ala Ile Ala 
            100                 105                 110         


Ser His Asp Gly Gly Lys Gln Ala Leu Glu Thr Val Gln Arg Leu Leu 
        115                 120                 125             


Pro Val Leu Cys Gln Ala His Gly Leu Thr Pro Glu Gln Val Val Ala 
    130                 135                 140                 


Ile Ala Ser His Asp Gly Gly Lys Gln Ala Leu Glu Thr Val Gln Arg 
145                 150                 155                 160 


Leu Leu Pro Val Leu Cys Gln Ala His Gly Leu Thr Pro Glu Gln Val 
                165                 170                 175     


Val Ala Ile Ala Ser His Asp Gly Gly Lys Gln Ala Leu Glu Thr Val 
            180                 185                 190         


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


Gln Val Val Ala Ile Ala Ser His Asp Gly Gly Lys Gln Ala Leu Glu 
    210                 215                 220                 


Thr Val Gln Arg Leu Leu Pro Val Leu Cys Gln Ala His Gly Leu Thr 
225                 230                 235                 240 


Pro Glu Gln Val Val Ala Ile Ala Ser Asn Ile Gly Gly Lys Gln Ala 
                245                 250                 255     


Leu Glu Thr Val Gln Ala Leu Leu Pro Val Leu Cys Gln Ala His Gly 
            260                 265                 270         


Leu Thr Pro Gln Gln Val Val Ala Ile Ala Ser Asn Asn Gly Gly Lys 
        275                 280                 285             


Gln Ala Leu Glu Thr Val Gln Arg Leu Leu Pro Val Leu Cys Gln Ala 
    290                 295                 300                 


His Gly Leu Thr Pro Glu Gln Val Val Ala Ile Ala Ser His Asp Gly 
305                 310                 315                 320 


Gly Lys Gln Ala Leu Glu Thr Val Gln Arg Leu Leu Pro Val Leu Cys 
                325                 330                 335     


Gln Ala His Gly Leu Thr Pro Glu Gln Val Val Ala Ile Ala Ser His 
            340                 345                 350         


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


Leu Cys Gln Ala His Gly Leu Thr Pro Glu Gln Val Val Ala Ile Ala 
    370                 375                 380                 


Ser His Asp Gly Gly Lys Gln Ala Leu Glu Thr Val Gln Arg Leu Leu 
385                 390                 395                 400 


Pro Val Leu Cys Gln Ala His Gly Leu Thr Pro Gln Gln Val Val Ala 
                405                 410                 415     


Ile Ala Ser Asn Gly Gly Gly Lys Gln Ala Leu Glu Thr Val Gln Arg 
            420                 425                 430         


Leu Leu Pro Val Leu Cys Gln Ala His Gly Leu Thr Pro Gln Gln Val 
        435                 440                 445             


Val Ala Ile Ala Ser Asn Asn Gly Gly Lys Gln Ala Leu Glu Thr Val 
    450                 455                 460                 


Gln Arg Leu Leu Pro Val Leu Cys Gln Ala His Gly Leu Thr Pro Glu 
465                 470                 475                 480 


Gln Val Val Ala Ile Ala Ser His Asp Gly Gly Lys Gln Ala Leu Glu 
                485                 490                 495     


Thr Val Gln Arg Leu Leu Pro Val Leu Cys Gln Ala His Gly Leu Thr 
            500                 505                 510         


Pro Gln Gln Val Val Ala Ile Ala Ser Asn Gly Gly Gly Arg Pro Ala 
        515                 520                 525             


Leu Glu 
    530 


<210>  130
<211>  529
<212>  PRT
<213>  Artificial Sequence

<220>
<223>  529

       PRT

Artificial Sequence

synthetic construct Repeat PD-1-right

<400>  130

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


Gln Ala Leu Glu Thr Val Gln Arg Leu Leu Pro Val Leu Cys Gln Ala 
            20                  25                  30          


His Gly Leu Thr Pro Glu Gln Val Val Ala Ile Ala Ser Asn Ile Gly 
        35                  40                  45              


Gly Lys Gln Ala Leu Glu Thr Val Gln Ala Leu Leu Pro Val Leu Cys 
    50                  55                  60                  


Gln Ala His Gly Leu Thr Pro Glu Gln Val Val Ala Ile Ala Ser Asn 
65                  70                  75                  80  


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


Leu Cys Gln Ala His Gly Leu Thr Pro Gln Gln Val Val Ala Ile Ala 
            100                 105                 110         


Ser Asn Asn Gly Gly Lys Gln Ala Leu Glu Thr Val Gln Arg Leu Leu 
        115                 120                 125             


Pro Val Leu Cys Gln Ala His Gly Leu Thr Pro Gln Gln Val Val Ala 
    130                 135                 140                 


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


Leu Leu Pro Val Leu Cys Gln Ala His Gly Leu Thr Pro Gln Gln Val 
                165                 170                 175     


Val Ala Ile Ala Ser Asn Gly Gly Gly Lys Gln Ala Leu Glu Thr Val 
            180                 185                 190         


Gln Arg Leu Leu Pro Val Leu Cys Gln Ala His Gly Leu Thr Pro Gln 
        195                 200                 205             


Gln Val Val Ala Ile Ala Ser Asn Asn Gly Gly Lys Gln Ala Leu Glu 
    210                 215                 220                 


Thr Val Gln Arg Leu Leu Pro Val Leu Cys Gln Ala His Gly Leu Thr 
225                 230                 235                 240 


Pro Gln Gln Val Val Ala Ile Ala Ser Asn Asn Gly Gly Lys Gln Ala 
                245                 250                 255     


Leu Glu Thr Val Gln Arg Leu Leu Pro Val Leu Cys Gln Ala His Gly 
            260                 265                 270         


Leu Thr Pro Glu Gln Val Val Ala Ile Ala Ser Asn Gly Gly Lys Gln 
        275                 280                 285             


Ala Leu Glu Thr Val Gln Arg Leu Leu Pro Val Leu Cys Gln Ala His 
    290                 295                 300                 


Gly Leu Thr Pro Gln Gln Val Val Ala Ile Ala Ser Asn Asn Gly Gly 
305                 310                 315                 320 


Lys Gln Ala Leu Glu Thr Val Gln Arg Leu Leu Pro Val Leu Cys Gln 
                325                 330                 335     


Ala His Gly Leu Thr Pro Gln Gln Val Val Ala Ile Ala Ser Asn Gly 
            340                 345                 350         


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


Cys Gln Ala His Gly Leu Thr Pro Gln Gln Val Val Ala Ile Ala Ser 
    370                 375                 380                 


Asn Gly Gly Gly Lys Gln Ala Leu Glu Thr Val Gln Arg Leu Leu Pro 
385                 390                 395                 400 


Val Leu Cys Gln Ala His Gly Leu Thr Pro Gln Gln Val Val Ala Ile 
                405                 410                 415     


Ala Ser Asn Asn Gly Gly Lys Gln Ala Leu Glu Thr Val Gln Arg Leu 
            420                 425                 430         


Leu Pro Val Leu Cys Gln Ala His Gly Leu Thr Pro Gln Gln Val Val 
        435                 440                 445             


Ala Ile Ala Ser Asn Gly Gly Gly Lys Gln Ala Leu Glu Thr Val Gln 
    450                 455                 460                 


Arg Leu Leu Pro Val Leu Cys Gln Ala His Gly Leu Thr Pro Glu Gln 
465                 470                 475                 480 


Val Val Ala Ile Ala Ser His Asp Gly Gly Lys Gln Ala Leu Glu Thr 
                485                 490                 495     


Val Gln Arg Leu Leu Pro Val Leu Cys Gln Ala His Gly Leu Thr Pro 
            500                 505                 510         


Gln Gln Val Val Ala Ile Ala Ser Asn Gly Gly Gly Arg Pro Ala Leu 
        515                 520                 525             


Glu 
    


<210>  131
<211>  530
<212>  PRT
<213>  Artificial Sequence

<220>
<223>  530

       PRT

Artificial Sequence

synthetic construct Repeat PD-1-left

<400>  131

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


Gln Ala Leu Glu Thr Val Gln Ala Leu Leu Pro Val Leu Cys Gln Ala 
            20                  25                  30          


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


Gly Lys Gln Ala Leu Glu Thr Val Gln Arg Leu Leu Pro Val Leu Cys 
    50                  55                  60                  


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


Asp Gly Gly Lys Gln Ala Leu Glu Thr Val Gln Arg Leu Leu Pro Val 
                85                  90                  95      


Leu Cys Gln Ala His Gly Leu Thr Pro Gln Gln Val Val Ala Ile Ala 
            100                 105                 110         


Ser Asn Gly Gly Gly Lys Gln Ala Leu Glu Thr Val Gln Arg Leu Leu 
        115                 120                 125             


Pro Val Leu Cys Gln Ala His Gly Leu Thr Pro Glu Gln Val Val Ala 
    130                 135                 140                 


Ile Ala Ser His Asp Gly Gly Lys Gln Ala Leu Glu Thr Val Gln Arg 
145                 150                 155                 160 


Leu Leu Pro Val Leu Cys Gln Ala His Gly Leu Thr Pro Gln Gln Val 
                165                 170                 175     


Val Ala Ile Ala Ser Asn Gly Gly Gly Lys Gln Ala Leu Glu Thr Val 
            180                 185                 190         


Gln Arg Leu Leu Pro Val Leu Cys Gln Ala His Gly Leu Thr Pro Gln 
        195                 200                 205             


Gln Val Val Ala Ile Ala Ser Asn Asn Gly Gly Lys Gln Ala Leu Glu 
    210                 215                 220                 


Thr Val Gln Arg Leu Leu Pro Val Leu Cys Gln Ala His Gly Leu Thr 
225                 230                 235                 240 


Pro Gln Gln Val Val Ala Ile Ala Ser Asn Gly Gly Gly Lys Gln Ala 
                245                 250                 255     


Leu Glu Thr Val Gln Arg Leu Leu Pro Val Leu Cys Gln Ala His Gly 
            260                 265                 270         


Leu Thr Pro Gln Gln Val Val Ala Ile Ala Ser Asn Asn Gly Gly Lys 
        275                 280                 285             


Gln Ala Leu Glu Thr Val Gln Arg Leu Leu Pro Val Leu Cys Gln Ala 
    290                 295                 300                 


His Gly Leu Thr Pro Gln Gln Val Val Ala Ile Ala Ser Asn Asn Gly 
305                 310                 315                 320 


Gly Lys Gln Ala Leu Glu Thr Val Gln Arg Leu Leu Pro Val Leu Cys 
                325                 330                 335     


Gln Ala His Gly Leu Thr Pro Gln Gln Val Val Ala Ile Ala Ser Asn 
            340                 345                 350         


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


Leu Cys Gln Ala His Gly Leu Thr Pro Gln Gln Val Val Ala Ile Ala 
    370                 375                 380                 


Ser Asn Asn Gly Gly Lys Gln Ala Leu Glu Thr Val Gln Arg Leu Leu 
385                 390                 395                 400 


Pro Val Leu Cys Gln Ala His Gly Leu Thr Pro Glu Gln Val Val Ala 
                405                 410                 415     


Ile Ala Ser His Asp Gly Gly Lys Gln Ala Leu Glu Thr Val Gln Arg 
            420                 425                 430         


Leu Leu Pro Val Leu Cys Gln Ala His Gly Leu Thr Pro Glu Gln Val 
        435                 440                 445             


Val Ala Ile Ala Ser His Asp Gly Gly Lys Gln Ala Leu Glu Thr Val 
    450                 455                 460                 


Gln Arg Leu Leu Pro Val Leu Cys Gln Ala His Gly Leu Thr Pro Glu 
465                 470                 475                 480 


Gln Val Val Ala Ile Ala Ser Asn Ile Gly Gly Lys Gln Ala Leu Glu 
                485                 490                 495     


Thr Val Gln Ala Leu Leu Pro Val Leu Cys Gln Ala His Gly Leu Thr 
            500                 505                 510         


Pro Gln Gln Val Val Ala Ile Ala Ser Asn Gly Gly Gly Arg Pro Ala 
        515                 520                 525             


Leu Glu 
    530 


<210>  132
<211>  529
<212>  PRT
<213>  Artificial Sequence

<220>
<223>  529

       PRT

Artificial Sequence

synthetic construct Repeat PD-1-right

<400>  132

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


Gln Ala Leu Glu Thr Val Gln Arg Leu Leu Pro Val Leu Cys Gln Ala 
            20                  25                  30          


His Gly Leu Thr Pro Gln Gln Val Val Ala Ile Ala Ser Asn Gly Gly 
        35                  40                  45              


Gly Lys Gln Ala Leu Glu Thr Val Gln Arg Leu Leu Pro Val Leu Cys 
    50                  55                  60                  


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


Asp Gly Gly Lys Gln Ala Leu Glu Thr Val Gln Arg Leu Leu Pro Val 
                85                  90                  95      


Leu Cys Gln Ala His Gly Leu Thr Pro Gln Gln Val Val Ala Ile Ala 
            100                 105                 110         


Ser Asn Gly Gly Gly Lys Gln Ala Leu Glu Thr Val Gln Arg Leu Leu 
        115                 120                 125             


Pro Val Leu Cys Gln Ala His Gly Leu Thr Pro Gln Gln Val Val Ala 
    130                 135                 140                 


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


Leu Leu Pro Val Leu Cys Gln Ala His Gly Leu Thr Pro Gln Gln Val 
                165                 170                 175     


Val Ala Ile Ala Ser Asn Gly Gly Gly Lys Gln Ala Leu Glu Thr Val 
            180                 185                 190         


Gln Arg Leu Leu Pro Val Leu Cys Gln Ala His Gly Leu Thr Pro Gln 
        195                 200                 205             


Gln Val Val Ala Ile Ala Ser Asn Asn Gly Gly Lys Gln Ala Leu Glu 
    210                 215                 220                 


Thr Val Gln Arg Leu Leu Pro Val Leu Cys Gln Ala His Gly Leu Thr 
225                 230                 235                 240 


Pro Glu Gln Val Val Ala Ile Ala Ser Asn Ile Gly Gly Lys Gln Ala 
                245                 250                 255     


Leu Glu Thr Val Gln Ala Leu Leu Pro Val Leu Cys Gln Ala His Gly 
            260                 265                 270         


Leu Thr Pro Gln Gln Val Val Ala Ile Ala Ser Asn Gly Gly Gly Lys 
        275                 280                 285             


Gln Ala Leu Glu Thr Val Gln Arg Leu Leu Pro Val Leu Cys Gln Ala 
    290                 295                 300                 


His Gly Leu Thr Pro Glu Gln Val Val Ala Ile Ala Ser His Asp Gly 
305                 310                 315                 320 


Gly Lys Gln Ala Leu Glu Thr Val Gln Arg Leu Leu Pro Val Leu Cys 
                325                 330                 335     


Gln Ala His Gly Leu Thr Pro Gln Gln Val Val Ala Ile Ala Ser Asn 
            340                 345                 350         


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


Leu Cys Gln Ala His Gly Leu Thr Pro Gln Gln Val Val Ala Ile Ala 
    370                 375                 380                 


Ser Asn Asn Gly Gly Lys Gln Ala Leu Glu Thr Val Gln Arg Leu Leu 
385                 390                 395                 400 


Pro Val Leu Cys Gln Ala His Gly Leu Thr Pro Glu Gln Val Val Ala 
                405                 410                 415     


Ile Ala Ser Asn Gly Gly Lys Gln Ala Leu Glu Thr Val Gln Arg Leu 
            420                 425                 430         


Leu Pro Val Leu Cys Gln Ala His Gly Leu Thr Pro Gln Gln Val Val 
        435                 440                 445             


Ala Ile Ala Ser Asn Asn Gly Gly Lys Gln Ala Leu Glu Thr Val Gln 
    450                 455                 460                 


Arg Leu Leu Pro Val Leu Cys Gln Ala His Gly Leu Thr Pro Glu Gln 
465                 470                 475                 480 


Val Val Ala Ile Ala Ser His Asp Gly Gly Lys Gln Ala Leu Glu Thr 
                485                 490                 495     


Val Gln Arg Leu Leu Pro Val Leu Cys Gln Ala His Gly Leu Thr Pro 
            500                 505                 510         


Gln Gln Val Val Ala Ile Ala Ser Asn Gly Gly Gly Arg Pro Ala Leu 
        515                 520                 525             


Glu 
    


<210>  133
<211>  2814
<212>  DNA
<213>  Artificial Sequence

<220>
<223>  2814

       DNA

Artificial Sequence

synthetic construct PD-1-left TALEN 133

<400>  133
atgggcgatc ctaaaaagaa acgtaaggtc atcgattacc catacgatgt tccagattac       60

gctatcgata tcgccgatct acgcacgctc ggctacagcc agcagcaaca ggagaagatc      120

aaaccgaagg ttcgttcgac agtggcgcag caccacgagg cactggtcgg ccacgggttt      180

acacacgcgc acatcgttgc gttaagccaa cacccggcag cgttagggac cgtcgctgtc      240

aagtatcagg acatgatcgc agcgttgcca gaggcgacac acgaagcgat cgttggcgtc      300

ggcaaacagt ggtccggcgc acgcgctctg gaggccttgc tcacggtggc gggagagttg      360

agaggtccac cgttacagtt ggacacaggc caacttctca agattgcaaa acgtggcggc      420

gtgaccgcag tggaggcagt gcatgcatgg cgcaatgcac tgacgggtgc cccgctcaac      480

ttgacccccc agcaggtggt ggccatcgcc agcaatggcg gtggcaagca ggcgctggag      540

acggtccagc ggctgttgcc ggtgctgtgc caggcccacg gcttgacccc ggagcaggtg      600

gtggccatcg ccagccacga tggcggcaag caggcgctgg agacggtcca gcggctgttg      660

ccggtgctgt gccaggccca cggcttgacc ccccagcagg tggtggccat cgccagcaat      720

ggcggtggca agcaggcgct ggagacggtc cagcggctgt tgccggtgct gtgccaggcc      780

cacggcttga ccccggagca ggtggtggcc atcgccagcc acgatggcgg caagcaggcg      840

ctggagacgg tccagcggct gttgccggtg ctgtgccagg cccacggctt gaccccggag      900

caggtggtgg ccatcgccag ccacgatggc ggcaagcagg cgctggagac ggtccagcgg      960

ctgttgccgg tgctgtgcca ggcccacggc ttgaccccgg agcaggtggt ggccatcgcc     1020

agccacgatg gcggcaagca ggcgctggag acggtccagc ggctgttgcc ggtgctgtgc     1080

caggcccacg gcttgacccc ggagcaggtg gtggccatcg ccagccacga tggcggcaag     1140

caggcgctgg agacggtcca gcggctgttg ccggtgctgt gccaggccca cggcttgacc     1200

ccggagcagg tggtggccat cgccagcaat attggtggca agcaggcgct ggagacggtg     1260

caggcgctgt tgccggtgct gtgccaggcc cacggcttga ccccccagca ggtggtggcc     1320

atcgccagca ataatggtgg caagcaggcg ctggagacgg tccagcggct gttgccggtg     1380

ctgtgccagg cccacggctt gaccccggag caggtggtgg ccatcgccag ccacgatggc     1440

ggcaagcagg cgctggagac ggtccagcgg ctgttgccgg tgctgtgcca ggcccacggc     1500

ttgaccccgg agcaggtggt ggccatcgcc agccacgatg gcggcaagca ggcgctggag     1560

acggtccagc ggctgttgcc ggtgctgtgc caggcccacg gcttgacccc ggagcaggtg     1620

gtggccatcg ccagccacga tggcggcaag caggcgctgg agacggtcca gcggctgttg     1680

ccggtgctgt gccaggccca cggcttgacc ccccagcagg tggtggccat cgccagcaat     1740

ggcggtggca agcaggcgct ggagacggtc cagcggctgt tgccggtgct gtgccaggcc     1800

cacggcttga ccccccagca ggtggtggcc atcgccagca ataatggtgg caagcaggcg     1860

ctggagacgg tccagcggct gttgccggtg ctgtgccagg cccacggctt gaccccggag     1920

caggtggtgg ccatcgccag ccacgatggc ggcaagcagg cgctggagac ggtccagcgg     1980

ctgttgccgg tgctgtgcca ggcccacggc ttgacccctc agcaggtggt ggccatcgcc     2040

agcaatggcg gcggcaggcc ggcgctggag agcattgttg cccagttatc tcgccctgat     2100

ccggcgttgg ccgcgttgac caacgaccac ctcgtcgcct tggcctgcct cggcgggcgt     2160

cctgcgctgg atgcagtgaa aaagggattg ggggatccta tcagccgttc ccagctggtg     2220

aagtccgagc tggaggagaa gaaatccgag ttgaggcaca agctgaagta cgtgccccac     2280

gagtacatcg agctgatcga gatcgcccgg aacagcaccc aggaccgtat cctggagatg     2340

aaggtgatgg agttcttcat gaaggtgtac ggctacaggg gcaagcacct gggcggctcc     2400

aggaagcccg acggcgccat ctacaccgtg ggctccccca tcgactacgg cgtgatcgtg     2460

gacaccaagg cctactccgg cggctacaac ctgcccatcg gccaggccga cgaaatgcag     2520

aggtacgtgg aggagaacca gaccaggaac aagcacatca accccaacga gtggtggaag     2580

gtgtacccct ccagcgtgac cgagttcaag ttcctgttcg tgtccggcca cttcaagggc     2640

aactacaagg cccagctgac caggctgaac cacatcacca actgcaacgg cgccgtgctg     2700

tccgtggagg agctcctgat cggcggcgag atgatcaagg ccggcaccct gaccctggag     2760

gaggtgagga ggaagttcaa caacggcgag atcaacttcg cggccgactg ataa           2814


<210>  134
<211>  2829
<212>  DNA
<213>  Artificial Sequence

<220>
<223>  2829

       DNA

       Artificial Sequence

synthetic construct PD-1-right TALEN 134

<400>  134
atgggcgatc ctaaaaagaa acgtaaggtc atcgataagg agaccgccgc tgccaagttc       60

gagagacagc acatggacag catcgatatc gccgatctac gcacgctcgg ctacagccag      120

cagcaacagg agaagatcaa accgaaggtt cgttcgacag tggcgcagca ccacgaggca      180

ctggtcggcc acgggtttac acacgcgcac atcgttgcgt taagccaaca cccggcagcg      240

ttagggaccg tcgctgtcaa gtatcaggac atgatcgcag cgttgccaga ggcgacacac      300

gaagcgatcg ttggcgtcgg caaacagtgg tccggcgcac gcgctctgga ggccttgctc      360

acggtggcgg gagagttgag aggtccaccg ttacagttgg acacaggcca acttctcaag      420

attgcaaaac gtggcggcgt gaccgcagtg gaggcagtgc atgcatggcg caatgcactg      480

acgggtgccc cgctcaactt gaccccccag caagtcgtcg caatcgccag caataacgga      540

gggaagcaag ccctcgaaac cgtgcagcgg ttgcttcctg tgctctgcca ggcccacggc      600

cttacccctg agcaggtggt ggccatcgca agtaacattg gaggaaagca agccttggag      660

acagtgcagg ccctgttgcc cgtgctgtgc caggcacacg gcctcacacc agagcaggtc      720

gtggccattg cctccaacat cggggggaaa caggctctgg agaccgtcca ggccctgctg      780

cccgtcctct gtcaagctca cggcctgact ccccaacaag tggtcgccat cgcctctaat      840

aacggcggga agcaggcact ggaaacagtg cagagactgc tccctgtgct ttgccaagct      900

catgggttga ccccccaaca ggtcgtcgct attgcctcaa acaacggggg caagcaggcc      960

cttgagactg tgcagaggct gttgccagtg ctgtgtcagg ctcacgggct cactccacaa     1020

caggtggtcg caattgccag caacggcggc ggaaagcaag ctcttgaaac cgtgcaacgc     1080

ctcctgcccg tgctctgtca ggctcatggc ctgacaccac aacaagtcgt ggccatcgcc     1140

agtaataatg gcgggaaaca ggctcttgag accgtccaga ggctgctccc agtgctctgc     1200

caggcacacg ggctgacccc ccagcaggtg gtggctatcg ccagcaataa tgggggcaag     1260

caggccctgg aaacagtcca gcgcctgctg ccagtgcttt gccaggctca cgggctcact     1320

cccgaacagg tcgtggcaat cgcctccaac ggagggaagc aggctctgga gaccgtgcag     1380

agactgctgc ccgtcttgtg ccaggcccac ggactcacac ctcagcaggt cgtcgccatt     1440

gcctctaaca acgggggcaa acaagccctg gagacagtgc agcggctgtt gcctgtgttg     1500

tgccaagccc acggcttgac tcctcaacaa gtggtcgcca tcgcctcaaa tggcggcgga     1560

aaacaagctc tggagacagt gcagaggttg ctgcccgtcc tctgccaagc ccacggcctg     1620

actccccaac aggtcgtcgc cattgccagc aacggcggag gaaagcaggc tctcgaaact     1680

gtgcagcggc tgcttcctgt gctgtgtcag gctcatgggc tgacccccca gcaagtggtg     1740

gctattgcct ctaacaatgg aggcaagcaa gcccttgaga cagtccagag gctgttgcca     1800

gtgctgtgcc aggcccacgg gctcacaccc cagcaggtgg tcgccatcgc cagtaacggc     1860

gggggcaaac aggcattgga aaccgtccag cgcctgcttc cagtgctctg ccaggcacac     1920

ggactgacac ccgaacaggt ggtggccatt gcatcccatg atgggggcaa gcaggccctg     1980

gagaccgtgc agagactcct gccagtgttg tgccaagctc acggcctcac ccctcagcaa     2040

gtcgtggcca tcgcctcaaa cggggggggc cggcctgcac tggagagcat tgttgcccag     2100

ttatctcgcc ctgatccggc gttggccgcg ttgaccaacg accacctcgt cgccttggcc     2160

tgcctcggcg ggcgtcctgc gctggatgca gtgaaaaagg gattggggga tcctatcagc     2220

cgttcccagc tggtgaagtc cgagctggag gagaagaaat ccgagttgag gcacaagctg     2280

aagtacgtgc cccacgagta catcgagctg atcgagatcg cccggaacag cacccaggac     2340

cgtatcctgg agatgaaggt gatggagttc ttcatgaagg tgtacggcta caggggcaag     2400

cacctgggcg gctccaggaa gcccgacggc gccatctaca ccgtgggctc ccccatcgac     2460

tacggcgtga tcgtggacac caaggcctac tccggcggct acaacctgcc catcggccag     2520

gccgacgaaa tgcagaggta cgtggaggag aaccagacca ggaacaagca catcaacccc     2580

aacgagtggt ggaaggtgta cccctccagc gtgaccgagt tcaagttcct gttcgtgtcc     2640

ggccacttca agggcaacta caaggcccag ctgaccaggc tgaaccacat caccaactgc     2700

aacggcgccg tgctgtccgt ggaggagctc ctgatcggcg gcgagatgat caaggccggc     2760

accctgaccc tggaggaggt gaggaggaag ttcaacaacg gcgagatcaa cttcgcggcc     2820

gactgataa                                                             2829


<210>  135
<211>  2814
<212>  DNA
<213>  Artificial Sequence

<220>
<223>  2814

       DNA

Artificial Sequence

synthetic construct PD-1-left TALEN 135

<400>  135
atgggcgatc ctaaaaagaa acgtaaggtc atcgattacc catacgatgt tccagattac       60

gctatcgata tcgccgatct acgcacgctc ggctacagcc agcagcaaca ggagaagatc      120

aaaccgaagg ttcgttcgac agtggcgcag caccacgagg cactggtcgg ccacgggttt      180

acacacgcgc acatcgttgc gttaagccaa cacccggcag cgttagggac cgtcgctgtc      240

aagtatcagg acatgatcgc agcgttgcca gaggcgacac acgaagcgat cgttggcgtc      300

ggcaaacagt ggtccggcgc acgcgctctg gaggccttgc tcacggtggc gggagagttg      360

agaggtccac cgttacagtt ggacacaggc caacttctca agattgcaaa acgtggcggc      420

gtgaccgcag tggaggcagt gcatgcatgg cgcaatgcac tgacgggtgc cccgctcaac      480

ttgaccccgg agcaggtggt ggccatcgcc agcaatattg gtggcaagca ggcgctggag      540

acggtgcagg cgctgttgcc ggtgctgtgc caggcccacg gcttgacccc ggagcaggtg      600

gtggccatcg ccagccacga tggcggcaag caggcgctgg agacggtcca gcggctgttg      660

ccggtgctgt gccaggccca cggcttgacc ccggagcagg tggtggccat cgccagccac      720

gatggcggca agcaggcgct ggagacggtc cagcggctgt tgccggtgct gtgccaggcc      780

cacggcttga ccccccagca ggtggtggcc atcgccagca atggcggtgg caagcaggcg      840

ctggagacgg tccagcggct gttgccggtg ctgtgccagg cccacggctt gaccccggag      900

caggtggtgg ccatcgccag ccacgatggc ggcaagcagg cgctggagac ggtccagcgg      960

ctgttgccgg tgctgtgcca ggcccacggc ttgacccccc agcaggtggt ggccatcgcc     1020

agcaatggcg gtggcaagca ggcgctggag acggtccagc ggctgttgcc ggtgctgtgc     1080

caggcccacg gcttgacccc ccagcaggtg gtggccatcg ccagcaataa tggtggcaag     1140

caggcgctgg agacggtcca gcggctgttg ccggtgctgt gccaggccca cggcttgacc     1200

ccccagcagg tggtggccat cgccagcaat ggcggtggca agcaggcgct ggagacggtc     1260

cagcggctgt tgccggtgct gtgccaggcc cacggcttga ccccccagca ggtggtggcc     1320

atcgccagca ataatggtgg caagcaggcg ctggagacgg tccagcggct gttgccggtg     1380

ctgtgccagg cccacggctt gaccccccag caggtggtgg ccatcgccag caataatggt     1440

ggcaagcagg cgctggagac ggtccagcgg ctgttgccgg tgctgtgcca ggcccacggc     1500

ttgacccccc agcaggtggt ggccatcgcc agcaataatg gtggcaagca ggcgctggag     1560

acggtccagc ggctgttgcc ggtgctgtgc caggcccacg gcttgacccc ccagcaggtg     1620

gtggccatcg ccagcaataa tggtggcaag caggcgctgg agacggtcca gcggctgttg     1680

ccggtgctgt gccaggccca cggcttgacc ccggagcagg tggtggccat cgccagccac     1740

gatggcggca agcaggcgct ggagacggtc cagcggctgt tgccggtgct gtgccaggcc     1800

cacggcttga ccccggagca ggtggtggcc atcgccagcc acgatggcgg caagcaggcg     1860

ctggagacgg tccagcggct gttgccggtg ctgtgccagg cccacggctt gaccccggag     1920

caggtggtgg ccatcgccag caatattggt ggcaagcagg cgctggagac ggtgcaggcg     1980

ctgttgccgg tgctgtgcca ggcccacggc ttgacccctc agcaggtggt ggccatcgcc     2040

agcaatggcg gcggcaggcc ggcgctggag agcattgttg cccagttatc tcgccctgat     2100

ccggcgttgg ccgcgttgac caacgaccac ctcgtcgcct tggcctgcct cggcgggcgt     2160

cctgcgctgg atgcagtgaa aaagggattg ggggatccta tcagccgttc ccagctggtg     2220

aagtccgagc tggaggagaa gaaatccgag ttgaggcaca agctgaagta cgtgccccac     2280

gagtacatcg agctgatcga gatcgcccgg aacagcaccc aggaccgtat cctggagatg     2340

aaggtgatgg agttcttcat gaaggtgtac ggctacaggg gcaagcacct gggcggctcc     2400

aggaagcccg acggcgccat ctacaccgtg ggctccccca tcgactacgg cgtgatcgtg     2460

gacaccaagg cctactccgg cggctacaac ctgcccatcg gccaggccga cgaaatgcag     2520

aggtacgtgg aggagaacca gaccaggaac aagcacatca accccaacga gtggtggaag     2580

gtgtacccct ccagcgtgac cgagttcaag ttcctgttcg tgtccggcca cttcaagggc     2640

aactacaagg cccagctgac caggctgaac cacatcacca actgcaacgg cgccgtgctg     2700

tccgtggagg agctcctgat cggcggcgag atgatcaagg ccggcaccct gaccctggag     2760

gaggtgagga ggaagttcaa caacggcgag atcaacttcg cggccgactg ataa           2814


<210>  136
<211>  2829
<212>  DNA
<213>  Artificial Sequence

<220>
<223>  2829

       DNA

       Artificial Sequence

synthetic construct PD-1-right TALEN 136

<400>  136
atgggcgatc ctaaaaagaa acgtaaggtc atcgataagg agaccgccgc tgccaagttc       60

gagagacagc acatggacag catcgatatc gccgatctac gcacgctcgg ctacagccag      120

cagcaacagg agaagatcaa accgaaggtt cgttcgacag tggcgcagca ccacgaggca      180

ctggtcggcc acgggtttac acacgcgcac atcgttgcgt taagccaaca cccggcagcg      240

ttagggaccg tcgctgtcaa gtatcaggac atgatcgcag cgttgccaga ggcgacacac      300

gaagcgatcg ttggcgtcgg caaacagtgg tccggcgcac gcgctctgga ggccttgctc      360

acggtggcgg gagagttgag aggtccaccg ttacagttgg acacaggcca acttctcaag      420

attgcaaaac gtggcggcgt gaccgcagtg gaggcagtgc atgcatggcg caatgcactg      480

acgggtgccc cgctcaactt gacccccgag caagtcgtcg caatcgccag ccatgatgga      540

gggaagcaag ccctcgaaac cgtgcagcgg ttgcttcctg tgctctgcca ggcccacggc      600

cttacccctc agcaggtggt ggccatcgca agtaacggag gaggaaagca agccttggag      660

acagtgcagc gcctgttgcc cgtgctgtgc caggcacacg gcctcacacc agagcaggtc      720

gtggccattg cctcccatga cggggggaaa caggctctgg agaccgtcca gaggctgctg      780

cccgtcctct gtcaagctca cggcctgact ccccaacaag tggtcgccat cgcctctaat      840

ggcggcggga agcaggcact ggaaacagtg cagagactgc tccctgtgct ttgccaagct      900

catgggttga ccccccaaca ggtcgtcgct attgcctcaa acgggggggg caagcaggcc      960

cttgagactg tgcagaggct gttgccagtg ctgtgtcagg ctcacgggct cactccacaa     1020

caggtggtcg caattgccag caacggcggc ggaaagcaag ctcttgaaac cgtgcaacgc     1080

ctcctgcccg tgctctgtca ggctcatggc ctgacaccac aacaagtcgt ggccatcgcc     1140

agtaataatg gcgggaaaca ggctcttgag accgtccaga ggctgctccc agtgctctgc     1200

caggcacacg ggctgacccc cgagcaggtg gtggctatcg ccagcaatat tgggggcaag     1260

caggccctgg aaacagtcca ggccctgctg ccagtgcttt gccaggctca cgggctcact     1320

ccccagcagg tcgtggcaat cgcctccaac ggcggaggga agcaggctct ggagaccgtg     1380

cagagactgc tgcccgtctt gtgccaggcc cacggactca cacctgaaca ggtcgtcgcc     1440

attgcctctc acgatggggg caaacaagcc ctggagacag tgcagcggct gttgcctgtg     1500

ttgtgccaag cccacggctt gactcctcaa caagtggtcg ccatcgcctc aaatggcggc     1560

ggaaaacaag ctctggagac agtgcagagg ttgctgcccg tcctctgcca agcccacggc     1620

ctgactcccc aacaggtcgt cgccattgcc agcaacaacg gaggaaagca ggctctcgaa     1680

actgtgcagc ggctgcttcc tgtgctgtgt caggctcatg ggctgacccc cgagcaagtg     1740

gtggctattg cctctaatgg aggcaagcaa gcccttgaga cagtccagag gctgttgcca     1800

gtgctgtgcc aggcccacgg gctcacaccc cagcaggtgg tcgccatcgc cagtaacaac     1860

gggggcaaac aggcattgga aaccgtccag cgcctgcttc cagtgctctg ccaggcacac     1920

ggactgacac ccgaacaggt ggtggccatt gcatcccatg atgggggcaa gcaggccctg     1980

gagaccgtgc agagactcct gccagtgttg tgccaagctc acggcctcac ccctcagcaa     2040

gtcgtggcca tcgcctcaaa cggggggggc cggcctgcac tggagagcat tgttgcccag     2100

ttatctcgcc ctgatccggc gttggccgcg ttgaccaacg accacctcgt cgccttggcc     2160

tgcctcggcg ggcgtcctgc gctggatgca gtgaaaaagg gattggggga tcctatcagc     2220

cgttcccagc tggtgaagtc cgagctggag gagaagaaat ccgagttgag gcacaagctg     2280

aagtacgtgc cccacgagta catcgagctg atcgagatcg cccggaacag cacccaggac     2340

cgtatcctgg agatgaaggt gatggagttc ttcatgaagg tgtacggcta caggggcaag     2400

cacctgggcg gctccaggaa gcccgacggc gccatctaca ccgtgggctc ccccatcgac     2460

tacggcgtga tcgtggacac caaggcctac tccggcggct acaacctgcc catcggccag     2520

gccgacgaaa tgcagaggta cgtggaggag aaccagacca ggaacaagca catcaacccc     2580

aacgagtggt ggaaggtgta cccctccagc gtgaccgagt tcaagttcct gttcgtgtcc     2640

ggccacttca agggcaacta caaggcccag ctgaccaggc tgaaccacat caccaactgc     2700

aacggcgccg tgctgtccgt ggaggagctc ctgatcggcg gcgagatgat caaggccggc     2760

accctgaccc tggaggaggt gaggaggaag ttcaacaacg gcgagatcaa cttcgcggcc     2820

gactgataa                                                             2829


<210>  137
<211>  153
<212>  PRT
<213>  Artificial Sequence

<220>
<223>  IL-2

<400>  137

Met Tyr Arg Met Gln Leu Leu Ser Cys Ile Ala Leu Ser Leu Ala Leu 
1               5                   10                  15      


Val Thr Asn Ser Ala Pro Thr Ser Ser Ser Thr Lys Lys Thr Gln Leu 
            20                  25                  30          


Gln Leu Glu His Leu Leu Leu Asp Leu Gln Met Ile Leu Asn Gly Ile 
        35                  40                  45              


Asn Asn Tyr Lys Asn Pro Lys Leu Thr Arg Met Leu Thr Phe Lys Phe 
    50                  55                  60                  


Tyr Met Pro Lys Lys Ala Thr Glu Leu Lys His Leu Gln Cys Leu Glu 
65                  70                  75                  80  


Glu Glu Leu Lys Pro Leu Glu Glu Val Leu Asn Leu Ala Gln Ser Lys 
                85                  90                  95      


Asn Phe His Leu Arg Pro Arg Asp Leu Ile Ser Asn Ile Asn Val Ile 
            100                 105                 110         


Val Leu Glu Leu Lys Gly Ser Glu Thr Thr Phe Met Cys Glu Tyr Ala 
        115                 120                 125             


Asp Glu Thr Ala Thr Ile Val Glu Phe Leu Asn Arg Trp Ile Thr Phe 
    130                 135                 140                 


Cys Gln Ser Ile Ile Ser Thr Leu Thr 
145                 150             


<210>  138
<211>  133
<212>  PRT
<213>  Artificial Sequence

<220>
<223>  IL-2 mutein

<400>  138

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


Leu Leu Leu Asp Leu Gln Met Ile Leu Asn Gly Ile Asn Asn Tyr Lys 
            20                  25                  30          


Asn Pro Lys Leu Thr Ala Met Leu Thr Phe Lys Phe Tyr Met Pro Lys 
        35                  40                  45              


Lys Ala Thr Glu Leu Lys His Leu Gln Cys Leu Glu Glu Glu Leu Lys 
    50                  55                  60                  


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


Arg Pro Arg Asp Leu Ile Ser Asn Ile Asn Val Ile Val Leu Glu Leu 
                85                  90                  95      


Lys Gly Ser Glu Thr Thr Phe Met Cys Glu Tyr Ala Asp Glu Thr Ala 
            100                 105                 110         


Thr Ile Val Glu Phe Leu Asn Arg Trp Ile Thr Phe Cys Gln Ser Ile 
        115                 120                 125             


Ile Ser Thr Leu Thr 
    130             


<210>  139
<211>  133
<212>  PRT
<213>  Artificial Sequence

<220>
<223>  IL-2 mutein

<400>  139

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


Leu Leu Leu Asp Leu Gln Met Ile Leu Asn Gly Ile Asn Asn Tyr Lys 
            20                  25                  30          


Asn Pro Lys Leu Thr Arg Met Leu Thr Ala Lys Phe Tyr Met Pro Lys 
        35                  40                  45              


Lys Ala Thr Glu Leu Lys His Leu Gln Cys Leu Glu Glu Glu Leu Lys 
    50                  55                  60                  


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


Arg Pro Arg Asp Leu Ile Ser Asn Ile Asn Val Ile Val Leu Glu Leu 
                85                  90                  95      


Lys Gly Ser Glu Thr Thr Phe Met Cys Glu Tyr Ala Asp Glu Thr Ala 
            100                 105                 110         


Thr Ile Val Glu Phe Leu Asn Arg Trp Ile Thr Phe Cys Gln Ser Ile 
        115                 120                 125             


Ile Ser Thr Leu Thr 
    130             


<210>  140
<211>  145
<212>  PRT
<213>  Artificial Sequence

<220>
<223>  HCDR1_IL-2

<400>  140

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


Gln Leu Glu His Leu Leu Leu Asp Leu Gln Met Ile Leu Asn Gly Ile 
            20                  25                  30          


Asn Asn Tyr Lys Asn Pro Lys Leu Thr Ala Met Leu Thr Phe Lys Phe 
        35                  40                  45              


Tyr Met Pro Lys Lys Ala Thr Glu Leu Lys His Leu Gln Cys Leu Glu 
    50                  55                  60                  


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


Asn Phe His Leu Arg Pro Arg Asp Leu Ile Ser Asn Ile Asn Val Ile 
                85                  90                  95      


Val Leu Glu Leu Lys Gly Ser Glu Thr Thr Phe Met Cys Glu Tyr Ala 
            100                 105                 110         


Asp Glu Thr Ala Thr Ile Val Glu Phe Leu Asn Arg Trp Ile Thr Phe 
        115                 120                 125             


Cys Gln Ser Ile Ile Ser Thr Leu Thr Ser Thr Ser Gly Met Ser Val 
    130                 135                 140                 


Gly 
145 


<210>  141
<211>  16
<212>  PRT
<213>  Artificial Sequence

<220>
<223>  HCDR2

<400>  141

Asp Ile Trp Trp Asp Asp Lys Lys Asp Tyr Asn Pro Ser Leu Lys Ser 
1               5                   10                  15      


<210>  142
<211>  10
<212>  PRT
<213>  Artificial Sequence

<220>
<223>  HCDR3

<400>  142

Ser Met Ile Thr Asn Trp Tyr Phe Asp Val 
1               5                   10  


<210>  143
<211>  91
<212>  PRT
<213>  Artificial Sequence

<220>
<223>  HCDR1_IL-2 kabat

<400>  143

Thr Glu Leu Lys His Leu Gln Cys Leu Glu Glu Glu Leu Lys Pro Leu 
1               5                   10                  15      


Glu Glu Val Leu Asn Leu Ala Gln Ser Lys Asn Phe His Leu Arg Pro 
            20                  25                  30          


Arg Asp Leu Ile Ser Asn Ile Asn Val Ile Val Leu Glu Leu Lys Gly 
        35                  40                  45              


Ser Glu Thr Thr Phe Met Cys Glu Tyr Ala Asp Glu Thr Ala Thr Ile 
    50                  55                  60                  


Val Glu Phe Leu Asn Arg Trp Ile Thr Phe Cys Gln Ser Ile Ile Ser 
65                  70                  75                  80  


Thr Leu Thr Ser Thr Ser Gly Met Ser Val Gly 
                85                  90      


<210>  144
<211>  16
<212>  PRT
<213>  Artificial Sequence

<220>
<223>  HCDR2 kabat

<400>  144

Asp Ile Trp Trp Asp Asp Lys Lys Asp Tyr Asn Pro Ser Leu Lys Ser 
1               5                   10                  15      


<210>  145
<211>  10
<212>  PRT
<213>  Artificial Sequence

<220>
<223>  HCDR3 kabat

<400>  145

Ser Met Ile Thr Asn Trp Tyr Phe Asp Val 
1               5                   10  


<210>  146
<211>  142
<212>  PRT
<213>  Artificial Sequence

<220>
<223>  HCDR1_IL-2 clothia

<400>  146

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


Gln Leu Glu His Leu Leu Leu Asp Leu Gln Met Ile Leu Asn Gly Ile 
            20                  25                  30          


Asn Asn Tyr Lys Asn Pro Lys Leu Thr Ala Met Leu Thr Phe Lys Phe 
        35                  40                  45              


Tyr Met Pro Lys Lys Ala Thr Glu Leu Lys His Leu Gln Cys Leu Glu 
    50                  55                  60                  


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


Asn Phe His Leu Arg Pro Arg Asp Leu Ile Ser Asn Ile Asn Val Ile 
                85                  90                  95      


Val Leu Glu Leu Lys Gly Ser Glu Thr Thr Phe Met Cys Glu Tyr Ala 
            100                 105                 110         


Asp Glu Thr Ala Thr Ile Val Glu Phe Leu Asn Arg Trp Ile Thr Phe 
        115                 120                 125             


Cys Gln Ser Ile Ile Ser Thr Leu Thr Ser Thr Ser Gly Met 
    130                 135                 140         


<210>  147
<211>  5
<212>  PRT
<213>  Artificial Sequence

<220>
<223>  HCDR2 clothia

<400>  147

Trp Trp Asp Asp Lys 
1               5   


<210>  148
<211>  10
<212>  PRT
<213>  Artificial Sequence

<220>
<223>  HCDR3 clothia

<400>  148

Ser Met Ile Thr Asn Trp Tyr Phe Asp Val 
1               5                   10  


<210>  149
<211>  143
<212>  PRT
<213>  Artificial Sequence

<220>
<223>  HCDR1_IL-2 IMGT

<400>  149

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


Gln Leu Glu His Leu Leu Leu Asp Leu Gln Met Ile Leu Asn Gly Ile 
            20                  25                  30          


Asn Asn Tyr Lys Asn Pro Lys Leu Thr Ala Met Leu Thr Phe Lys Phe 
        35                  40                  45              


Tyr Met Pro Lys Lys Ala Thr Glu Leu Lys His Leu Gln Cys Leu Glu 
    50                  55                  60                  


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


Asn Phe His Leu Arg Pro Arg Asp Leu Ile Ser Asn Ile Asn Val Ile 
                85                  90                  95      


Val Leu Glu Leu Lys Gly Ser Glu Thr Thr Phe Met Cys Glu Tyr Ala 
            100                 105                 110         


Asp Glu Thr Ala Thr Ile Val Glu Phe Leu Asn Arg Trp Ile Thr Phe 
        115                 120                 125             


Cys Gln Ser Ile Ile Ser Thr Leu Thr Ser Thr Ser Gly Met Ser 
    130                 135                 140             


<210>  150
<211>  7
<212>  PRT
<213>  Artificial Sequence

<220>
<223>  HCDR2 IMGT

<400>  150

Ile Trp Trp Asp Asp Lys Lys 
1               5           


<210>  151
<211>  12
<212>  PRT
<213>  Artificial Sequence

<220>
<223>  HCDR3 IMGT

<400>  151

Ala Arg Ser Met Ile Thr Asn Trp Tyr Phe Asp Val 
1               5                   10          


<210>  152
<211>  253
<212>  PRT
<213>  Artificial Sequence

<220>
<223>  VH

<400>  152

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


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


Ser Ser Ser Thr Lys Lys Thr Gln Leu Gln Leu Glu His Leu Leu Leu 
        35                  40                  45              


Asp Leu Gln Met Ile Leu Asn Gly Ile Asn Asn Tyr Lys Asn Pro Lys 
    50                  55                  60                  


Leu Thr Ala Met Leu Thr Phe Lys Phe Tyr Met Pro Lys Lys Ala Thr 
65                  70                  75                  80  


Glu Leu Lys His Leu Gln Cys Leu Glu Glu Glu Leu Lys Pro Leu Glu 
                85                  90                  95      


Glu Val Leu Asn Leu Ala Gln Ser Lys Asn Phe His Leu Arg Pro Arg 
            100                 105                 110         


Asp Leu Ile Ser Asn Ile Asn Val Ile Val Leu Glu Leu Lys Gly Ser 
        115                 120                 125             


Glu Thr Thr Phe Met Cys Glu Tyr Ala Asp Glu Thr Ala Thr Ile Val 
    130                 135                 140                 


Glu Phe Leu Asn Arg Trp Ile Thr Phe Cys Gln Ser Ile Ile Ser Thr 
145                 150                 155                 160 


Leu Thr Ser Thr Ser Gly Met Ser Val Gly Trp Ile Arg Gln Pro Pro 
                165                 170                 175     


Gly Lys Ala Leu Glu Trp Leu Ala Asp Ile Trp Trp Asp Asp Lys Lys 
            180                 185                 190         


Asp Tyr Asn Pro Ser Leu Lys Ser Arg Leu Thr Ile Ser Lys Asp Thr 
        195                 200                 205             


Ser Lys Asn Gln Val Val Leu Lys Val Thr Asn Met Asp Pro Ala Asp 
    210                 215                 220                 


Thr Ala Thr Tyr Tyr Cys Ala Arg Ser Met Ile Thr Asn Trp Tyr Phe 
225                 230                 235                 240 


Asp Val Trp Gly Ala Gly Thr Thr Val Thr Val Ser Ser 
                245                 250             


<210>  153
<211>  533
<212>  PRT
<213>  Artificial Sequence

<220>
<223>  Heavy chain

<400>  153

Gln Met Ile Leu Asn Gly Ile Asn Asn Tyr Lys Asn Pro Lys Leu Thr 
1               5                   10                  15      


Ala Met Leu Thr Phe Lys Phe Tyr Met Pro Lys Lys Ala Thr Glu Leu 
            20                  25                  30          


Lys His Leu Gln Cys Leu Glu Glu Glu Leu Lys Pro Leu Glu Glu Val 
        35                  40                  45              


Leu Asn Leu Ala Gln Ser Lys Asn Phe His Leu Arg Pro Arg Asp Leu 
    50                  55                  60                  


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


Thr Phe Met Cys Glu Tyr Ala Asp Glu Thr Ala Thr Ile Val Glu Phe 
                85                  90                  95      


Leu Asn Arg Trp Ile Thr Phe Cys Gln Ser Ile Ile Ser Thr Leu Thr 
            100                 105                 110         


Ser Thr Ser Gly Met Ser Val Gly Trp Ile Arg Gln Pro Pro Gly Lys 
        115                 120                 125             


Ala Leu Glu Trp Leu Ala Asp Ile Trp Trp Asp Asp Lys Lys Asp Tyr 
    130                 135                 140                 


Asn Pro Ser Leu Lys Ser Arg Leu Thr Ile Ser Lys Asp Thr Ser Lys 
145                 150                 155                 160 


Asn Gln Val Val Leu Lys Val Thr Asn Met Asp Pro Ala Asp Thr Ala 
                165                 170                 175     


Thr Tyr Tyr Cys Ala Arg Ser Met Ile Thr Asn Trp Tyr Phe Asp Val 
            180                 185                 190         


Trp Gly Ala Gly Thr Thr Val Thr Val Ser Ser Ala Ser Thr Lys Gly 
        195                 200                 205             


Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly 
    210                 215                 220                 


Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val 
225                 230                 235                 240 


Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe 
                245                 250                 255     


Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val 
            260                 265                 270         


Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val 
        275                 280                 285             


Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys Arg Val Glu Pro Lys 
    290                 295                 300                 


Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu 
305                 310                 315                 320 


Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr 
                325                 330                 335     


Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Ala Val 
            340                 345                 350         


Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val 
        355                 360                 365             


Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser 
    370                 375                 380                 


Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu 
385                 390                 395                 400 


Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Ala Ala 
                405                 410                 415     


Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro 
            420                 425                 430         


Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln 
        435                 440                 445             


Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala 
    450                 455                 460                 


Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr 
465                 470                 475                 480 


Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu 
                485                 490                 495     


Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser 
            500                 505                 510         


Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser 
        515                 520                 525             


Leu Ser Pro Gly Lys 
    530             


<210>  154
<211>  10
<212>  PRT
<213>  Artificial Sequence

<220>
<223>  LCDR1 kabat

<400>  154

Lys Ala Gln Leu Ser Val Gly Tyr Met His 
1               5                   10  


<210>  155
<211>  7
<212>  PRT
<213>  Artificial Sequence

<220>
<223>  LCDR2 kabat

<400>  155

Asp Thr Ser Lys Leu Ala Ser 
1               5           


<210>  156
<211>  9
<212>  PRT
<213>  Artificial Sequence

<220>
<223>  LCDR3 kabat

<400>  156

Phe Gln Gly Ser Gly Tyr Pro Phe Thr 
1               5                   


<210>  157
<211>  6
<212>  PRT
<213>  Artificial Sequence

<220>
<223>  LCDR1 chothia

<400>  157

Gln Leu Ser Val Gly Tyr 
1               5       


<210>  158
<211>  3
<212>  PRT
<213>  Artificial Sequence

<220>
<223>  LCDR2 chothia

<400>  158

Asp Thr Ser 
1           


<210>  159
<211>  6
<212>  PRT
<213>  Artificial Sequence

<220>
<223>  LCDR3 chothia

<400>  159

Gly Ser Gly Tyr Pro Phe 
1               5       


<210>  160
<211>  106
<212>  PRT
<213>  Artificial Sequence

<220>
<223>  VL

<400>  160

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


Asp Arg Val Thr Ile Thr Cys Lys Ala Gln Leu Ser Val Gly Tyr Met 
            20                  25                  30          


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


Asp Thr Ser Lys Leu Ala Ser Gly Val Pro Ser Arg Phe Ser Gly Ser 
    50                  55                  60                  


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


Asp Phe Ala Thr Tyr Tyr Cys Phe Gln Gly Ser Gly Tyr Pro Phe Thr 
                85                  90                  95      


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


<210>  161
<211>  213
<212>  PRT
<213>  Artificial Sequence

<220>
<223>  Light chain

<400>  161

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


Asp Arg Val Thr Ile Thr Cys Lys Ala Gln Leu Ser Val Gly Tyr Met 
            20                  25                  30          


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


Asp Thr Ser Lys Leu Ala Ser Gly Val Pro Ser Arg Phe Ser Gly Ser 
    50                  55                  60                  


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


Asp Phe Ala Thr Tyr Tyr Cys Phe Gln Gly Ser Gly Tyr Pro Phe Thr 
                85                  90                  95      


Phe Gly Gly 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>  162
<211>  583
<212>  PRT
<213>  Artificial Sequence

<220>
<223>  Light chain

<400>  162

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


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


Ser Ser Ser Thr Lys Lys Thr Gln Leu Gln Leu Glu His Leu Leu Leu 
        35                  40                  45              


Asp Leu Gln Met Ile Leu Asn Gly Ile Asn Asn Tyr Lys Asn Pro Lys 
    50                  55                  60                  


Leu Thr Arg Met Leu Thr Ala Lys Phe Tyr Met Pro Lys Lys Ala Thr 
65                  70                  75                  80  


Glu Leu Lys His Leu Gln Cys Leu Glu Glu Glu Leu Lys Pro Leu Glu 
                85                  90                  95      


Glu Val Leu Asn Leu Ala Gln Ser Lys Asn Phe His Leu Arg Pro Arg 
            100                 105                 110         


Asp Leu Ile Ser Asn Ile Asn Val Ile Val Leu Glu Leu Lys Gly Ser 
        115                 120                 125             


Glu Thr Thr Phe Met Cys Glu Tyr Ala Asp Glu Thr Ala Thr Ile Val 
    130                 135                 140                 


Glu Phe Leu Asn Arg Trp Ile Thr Phe Cys Gln Ser Ile Ile Ser Thr 
145                 150                 155                 160 


Leu Thr Ser Thr Ser Gly Met Ser Val Gly Trp Ile Arg Gln Pro Pro 
                165                 170                 175     


Gly Lys Ala Leu Glu Trp Leu Ala Asp Ile Trp Trp Asp Asp Lys Lys 
            180                 185                 190         


Asp Tyr Asn Pro Ser Leu Lys Ser Arg Leu Thr Ile Ser Lys Asp Thr 
        195                 200                 205             


Ser Lys Asn Gln Val Val Leu Lys Val Thr Asn Met Asp Pro Ala Asp 
    210                 215                 220                 


Thr Ala Thr Tyr Tyr Cys Ala Arg Ser Met Ile Thr Asn Trp Tyr Phe 
225                 230                 235                 240 


Asp Val Trp Gly Ala Gly Thr Thr Val Thr Val Ser Ser Ala Ser Thr 
                245                 250                 255     


Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser 
            260                 265                 270         


Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu 
        275                 280                 285             


Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His 
    290                 295                 300                 


Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser 
305                 310                 315                 320 


Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys 
                325                 330                 335     


Asn Val Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys Arg Val Glu 
            340                 345                 350         


Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro 
        355                 360                 365             


Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys 
    370                 375                 380                 


Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val 
385                 390                 395                 400 


Ala Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp 
                405                 410                 415     


Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr 
            420                 425                 430         


Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp 
        435                 440                 445             


Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu 
    450                 455                 460                 


Ala Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg 
465                 470                 475                 480 


Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys 
                485                 490                 495     


Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp 
            500                 505                 510         


Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys 
        515                 520                 525             


Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser 
    530                 535                 540                 


Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser 
545                 550                 555                 560 


Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser 
                565                 570                 575     


Leu Ser Leu Ser Pro Gly Lys 
            580             


<210>  163
<211>  213
<212>  PRT
<213>  Artificial Sequence

<220>
<223>  Light chain

<400>  163

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


Asp Arg Val Thr Ile Thr Cys Lys Ala Gln Leu Ser Val Gly Tyr Met 
            20                  25                  30          


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


Asp Thr Ser Lys Leu Ala Ser Gly Val Pro Ser Arg Phe Ser Gly Ser 
    50                  55                  60                  


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


Asp Phe Ala Thr Tyr Tyr Cys Phe Gln Gly Ser Gly Tyr Pro Phe Thr 
                85                  90                  95      


Phe Gly Gly 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>  164
<211>  2781
<212>  DNA
<213>  Artificial Sequence

<220>
<223>  Left CISH KO TALEN

pCLS34485 CISHe3_9-L1

Nucleotide sequence

<400>  164
atgggcgatc ctaaaaagaa acgtaaggtc atcgatatcg ccgatctacg cacgctcggc       60

tacagccagc agcaacagga gaagatcaaa ccgaaggttc gttcgacagt ggcgcagcac      120

cacgaggcac tggtcggcca cgggtttaca cacgcgcaca tcgttgcgtt aagccaacac      180

ccggcagcgt tagggaccgt cgctgtcaag tatcaggaca tgatcgcagc gttgccagag      240

gcgacacacg aagcgatcgt tggcgtcggc aaacagtggt ccggcgcacg cgctctggag      300

gccttgctca cggtggcggg agagttgaga ggtccaccgt tacagttgga cacaggccaa      360

cttctcaaga ttgcaaaacg tggcggcgtg accgcagtgg aggcagtgca tgcatggcgc      420

aatgcactga cgggtgcccc gctcaacttg accccccagc aggtggtggc catcgccagc      480

aataatggtg gcaagcaggc gctggagacg gtccagcggc tgttgccggt gctgtgccag      540

gcccacggct tgaccccgga gcaggtggtg gccatcgcca gccacgatgg cggcaagcag      600

gcgctggaga cggtccagcg gctgttgccg gtgctgtgcc aggcccacgg cttgaccccc      660

cagcaggtgg tggccatcgc cagcaataat ggtggcaagc aggcgctgga gacggtccag      720

cggctgttgc cggtgctgtg ccaggcccac ggcttgaccc cggagcaggt ggtggccatc      780

gccagccacg atggcggcaa gcaggcgctg gagacggtcc agcggctgtt gccggtgctg      840

tgccaggccc acggcttgac cccggagcag gtggtggcca tcgccagcca cgatggcggc      900

aagcaggcgc tggagacggt ccagcggctg ttgccggtgc tgtgccaggc ccacggcttg      960

accccccagc aggtggtggc catcgccagc aatggcggtg gcaagcaggc gctggagacg     1020

gtccagcggc tgttgccggt gctgtgccag gcccacggct tgaccccgga gcaggtggtg     1080

gccatcgcca gcaatattgg tggcaagcag gcgctggaga cggtgcaggc gctgttgccg     1140

gtgctgtgcc aggcccacgg cttgaccccc cagcaggtgg tggccatcgc cagcaataat     1200

ggtggcaagc aggcgctgga gacggtccag cggctgttgc cggtgctgtg ccaggcccac     1260

ggcttgaccc cccagcaggt ggtggccatc gccagcaatg gcggtggcaa gcaggcgctg     1320

gagacggtcc agcggctgtt gccggtgctg tgccaggccc acggcttgac cccccagcag     1380

gtggtggcca tcgccagcaa taatggtggc aagcaggcgc tggagacggt ccagcggctg     1440

ttgccggtgc tgtgccaggc ccacggcttg accccggagc aggtggtggc catcgccagc     1500

aatattggtg gcaagcaggc gctggagacg gtgcaggcgc tgttgccggt gctgtgccag     1560

gcccacggct tgaccccgga gcaggtggtg gccatcgcca gccacgatgg cggcaagcag     1620

gcgctggaga cggtccagcg gctgttgccg gtgctgtgcc aggcccacgg cttgaccccg     1680

gagcaggtgg tggccatcgc cagccacgat ggcggcaagc aggcgctgga gacggtccag     1740

cggctgttgc cggtgctgtg ccaggcccac ggcttgaccc cggagcaggt ggtggccatc     1800

gccagccacg atggcggcaa gcaggcgctg gagacggtcc agcggctgtt gccggtgctg     1860

tgccaggccc acggcttgac cccggagcag gtggtggcca tcgccagcaa tattggtggc     1920

aagcaggcgc tggagacggt gcaggcgctg ttgccggtgc tgtgccaggc ccacggcttg     1980

acccctcagc aggtggtggc catcgccagc aatggcggcg gcaggccggc gctggagagc     2040

attgttgccc agttatctcg ccctgatccg gcgttggccg cgttgaccaa cgaccacctc     2100

gtcgccttgg cctgcctcgg cgggcgtcct gcgctggatg cagtgaaaaa gggattgggg     2160

gatcctatca gccgttccca gctggtgaag tccgagctgg aggagaagaa atccgagttg     2220

aggcacaagc tgaagtacgt gccccacgag tacatcgagc tgatcgagat cgcccggaac     2280

agcacccagg accgtatcct ggagatgaag gtgatggagt tcttcatgaa ggtgtacggc     2340

tacaggggca agcacctggg cggctccagg aagcccgacg gcgccatcta caccgtgggc     2400

tcccccatcg actacggcgt gatcgtggac accaaggcct actccggcgg ctacaacctg     2460

cccatcggcc aggccgacga aatgcagagg tacgtggagg agaaccagac caggaacaag     2520

cacatcaacc ccaacgagtg gtggaaggtg tacccctcca gcgtgaccga gttcaagttc     2580

ctgttcgtgt ccggccactt caagggcaac tacaaggccc agctgaccag gctgaaccac     2640

atcaccaact gcaacggcgc cgtgctgtcc gtggaggagc tcctgatcgg cggcgagatg     2700

atcaaggccg gcaccctgac cctggaggag gtgaggagga agttcaacaa cggcgagatc     2760

aacttcgcgg ccgactgata a                                               2781


<210>  165
<211>  925
<212>  PRT
<213>  Artificial Sequence

<220>
<223>  Left CISH KO TALEN pCLS34485 CISHe3_9-L1 Amino acid sequence

<400>  165

Met Gly Asp Pro Lys Lys Lys Arg Lys Val Ile Asp Ile Ala Asp Leu 
1               5                   10                  15      


Arg Thr Leu Gly Tyr Ser Gln Gln Gln Gln Glu Lys Ile Lys Pro Lys 
            20                  25                  30          


Val Arg Ser Thr Val Ala Gln His His Glu Ala Leu Val Gly His Gly 
        35                  40                  45              


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


Gly Thr Val Ala Val Lys Tyr Gln Asp Met Ile Ala Ala Leu Pro Glu 
65                  70                  75                  80  


Ala Thr His Glu Ala Ile Val Gly Val Gly Lys Gln Trp Ser Gly Ala 
                85                  90                  95      


Arg Ala Leu Glu Ala Leu Leu Thr Val Ala Gly Glu Leu Arg Gly Pro 
            100                 105                 110         


Pro Leu Gln Leu Asp Thr Gly Gln Leu Leu Lys Ile Ala Lys Arg Gly 
        115                 120                 125             


Gly Val Thr Ala Val Glu Ala Val His Ala Trp Arg Asn Ala Leu Thr 
    130                 135                 140                 


Gly Ala Pro Leu Asn Leu Thr Pro Gln Gln Val Val Ala Ile Ala Ser 
145                 150                 155                 160 


Asn Asn Gly Gly Lys Gln Ala Leu Glu Thr Val Gln Arg Leu Leu Pro 
                165                 170                 175     


Val Leu Cys Gln Ala His Gly Leu Thr Pro Glu Gln Val Val Ala Ile 
            180                 185                 190         


Ala Ser His Asp Gly Gly Lys Gln Ala Leu Glu Thr Val Gln Arg Leu 
        195                 200                 205             


Leu Pro Val Leu Cys Gln Ala His Gly Leu Thr Pro Gln Gln Val Val 
    210                 215                 220                 


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


Arg Leu Leu Pro Val Leu Cys Gln Ala His Gly Leu Thr Pro Glu Gln 
                245                 250                 255     


Val Val Ala Ile Ala Ser His Asp Gly Gly Lys Gln Ala Leu Glu Thr 
            260                 265                 270         


Val Gln Arg Leu Leu Pro Val Leu Cys Gln Ala His Gly Leu Thr Pro 
        275                 280                 285             


Glu Gln Val Val Ala Ile Ala Ser His Asp Gly Gly Lys Gln Ala Leu 
    290                 295                 300                 


Glu Thr Val Gln Arg Leu Leu Pro Val Leu Cys Gln Ala His Gly Leu 
305                 310                 315                 320 


Thr Pro Gln Gln Val Val Ala Ile Ala Ser Asn Gly Gly Gly Lys Gln 
                325                 330                 335     


Ala Leu Glu Thr Val Gln Arg Leu Leu Pro Val Leu Cys Gln Ala His 
            340                 345                 350         


Gly Leu Thr Pro Glu Gln Val Val Ala Ile Ala Ser Asn Ile Gly Gly 
        355                 360                 365             


Lys Gln Ala Leu Glu Thr Val Gln Ala Leu Leu Pro Val Leu Cys Gln 
    370                 375                 380                 


Ala His Gly Leu Thr Pro Gln Gln Val Val Ala Ile Ala Ser Asn Asn 
385                 390                 395                 400 


Gly Gly Lys Gln Ala Leu Glu Thr Val Gln Arg Leu Leu Pro Val Leu 
                405                 410                 415     


Cys Gln Ala His Gly Leu Thr Pro Gln Gln Val Val Ala Ile Ala Ser 
            420                 425                 430         


Asn Gly Gly Gly Lys Gln Ala Leu Glu Thr Val Gln Arg Leu Leu Pro 
        435                 440                 445             


Val Leu Cys Gln Ala His Gly Leu Thr Pro Gln Gln Val Val Ala Ile 
    450                 455                 460                 


Ala Ser Asn Asn Gly Gly Lys Gln Ala Leu Glu Thr Val Gln Arg Leu 
465                 470                 475                 480 


Leu Pro Val Leu Cys Gln Ala His Gly Leu Thr Pro Glu Gln Val Val 
                485                 490                 495     


Ala Ile Ala Ser Asn Ile Gly Gly Lys Gln Ala Leu Glu Thr Val Gln 
            500                 505                 510         


Ala Leu Leu Pro Val Leu Cys Gln Ala His Gly Leu Thr Pro Glu Gln 
        515                 520                 525             


Val Val Ala Ile Ala Ser His Asp Gly Gly Lys Gln Ala Leu Glu Thr 
    530                 535                 540                 


Val Gln Arg Leu Leu Pro Val Leu Cys Gln Ala His Gly Leu Thr Pro 
545                 550                 555                 560 


Glu Gln Val Val Ala Ile Ala Ser His Asp Gly Gly Lys Gln Ala Leu 
                565                 570                 575     


Glu Thr Val Gln Arg Leu Leu Pro Val Leu Cys Gln Ala His Gly Leu 
            580                 585                 590         


Thr Pro Glu Gln Val Val Ala Ile Ala Ser His Asp Gly Gly Lys Gln 
        595                 600                 605             


Ala Leu Glu Thr Val Gln Arg Leu Leu Pro Val Leu Cys Gln Ala His 
    610                 615                 620                 


Gly Leu Thr Pro Glu Gln Val Val Ala Ile Ala Ser Asn Ile Gly Gly 
625                 630                 635                 640 


Lys Gln Ala Leu Glu Thr Val Gln Ala Leu Leu Pro Val Leu Cys Gln 
                645                 650                 655     


Ala His Gly Leu Thr Pro Gln Gln Val Val Ala Ile Ala Ser Asn Gly 
            660                 665                 670         


Gly Gly Arg Pro Ala Leu Glu Ser Ile Val Ala Gln Leu Ser Arg Pro 
        675                 680                 685             


Asp Pro Ala Leu Ala Ala Leu Thr Asn Asp His Leu Val Ala Leu Ala 
    690                 695                 700                 


Cys Leu Gly Gly Arg Pro Ala Leu Asp Ala Val Lys Lys Gly Leu Gly 
705                 710                 715                 720 


Asp Pro Ile Ser Arg Ser Gln Leu Val Lys Ser Glu Leu Glu Glu Lys 
                725                 730                 735     


Lys Ser Glu Leu Arg His Lys Leu Lys Tyr Val Pro His Glu Tyr Ile 
            740                 745                 750         


Glu Leu Ile Glu Ile Ala Arg Asn Ser Thr Gln Asp Arg Ile Leu Glu 
        755                 760                 765             


Met Lys Val Met Glu Phe Phe Met Lys Val Tyr Gly Tyr Arg Gly Lys 
    770                 775                 780                 


His Leu Gly Gly Ser Arg Lys Pro Asp Gly Ala Ile Tyr Thr Val Gly 
785                 790                 795                 800 


Ser Pro Ile Asp Tyr Gly Val Ile Val Asp Thr Lys Ala Tyr Ser Gly 
                805                 810                 815     


Gly Tyr Asn Leu Pro Ile Gly Gln Ala Asp Glu Met Gln Arg Tyr Val 
            820                 825                 830         


Glu Glu Asn Gln Thr Arg Asn Lys His Ile Asn Pro Asn Glu Trp Trp 
        835                 840                 845             


Lys Val Tyr Pro Ser Ser Val Thr Glu Phe Lys Phe Leu Phe Val Ser 
    850                 855                 860                 


Gly His Phe Lys Gly Asn Tyr Lys Ala Gln Leu Thr Arg Leu Asn His 
865                 870                 875                 880 


Ile Thr Asn Cys Asn Gly Ala Val Leu Ser Val Glu Glu Leu Leu Ile 
                885                 890                 895     


Gly Gly Glu Met Ile Lys Ala Gly Thr Leu Thr Leu Glu Glu Val Arg 
            900                 905                 910         


Arg Lys Phe Asn Asn Gly Glu Ile Asn Phe Ala Ala Asp 
        915                 920                 925 


<210>  166
<211>  2781
<212>  DNA
<213>  Artificial Sequence

<220>
<223>  Right CISH KO

TALEN

pCLS34486

CISHe3_9-R1 Nucleotide sequence

<400>  166
atgggcgatc ctaaaaagaa acgtaaggtc atcgatatcg ccgatctacg cacgctcggc       60

tacagccagc agcaacagga gaagatcaaa ccgaaggttc gttcgacagt ggcgcagcac      120

cacgaggcac tggtcggcca cgggtttaca cacgcgcaca tcgttgcgtt aagccaacac      180

ccggcagcgt tagggaccgt cgctgtcaag tatcaggaca tgatcgcagc gttgccagag      240

gcgacacacg aagcgatcgt tggcgtcggc aaacagtggt ccggcgcacg cgctctggag      300

gccttgctca cggtggcggg agagttgaga ggtccaccgt tacagttgga cacaggccaa      360

cttctcaaga ttgcaaaacg tggcggcgtg accgcagtgg aggcagtgca tgcatggcgc      420

aatgcactga cgggtgcccc gctcaacttg accccggagc aggtggtggc catcgccagc      480

aatattggtg gcaagcaggc gctggagacg gtgcaggcgc tgttgccggt gctgtgccag      540

gcccacggct tgaccccgga gcaggtggtg gccatcgcca gccacgatgg cggcaagcag      600

gcgctggaga cggtccagcg gctgttgccg gtgctgtgcc aggcccacgg cttgaccccg      660

gagcaggtgg tggccatcgc cagcaatatt ggtggcaagc aggcgctgga gacggtgcag      720

gcgctgttgc cggtgctgtg ccaggcccac ggcttgaccc cccagcaggt ggtggccatc      780

gccagcaata atggtggcaa gcaggcgctg gagacggtcc agcggctgtt gccggtgctg      840

tgccaggccc acggcttgac cccggagcag gtggtggcca tcgccagcca cgatggcggc      900

aagcaggcgc tggagacggt ccagcggctg ttgccggtgc tgtgccaggc ccacggcttg      960

accccggagc aggtggtggc catcgccagc aatattggtg gcaagcaggc gctggagacg     1020

gtgcaggcgc tgttgccggt gctgtgccag gcccacggct tgacccccca gcaggtggtg     1080

gccatcgcca gcaataatgg tggcaagcag gcgctggaga cggtccagcg gctgttgccg     1140

gtgctgtgcc aggcccacgg cttgaccccc cagcaggtgg tggccatcgc cagcaatggc     1200

ggtggcaagc aggcgctgga gacggtccag cggctgttgc cggtgctgtg ccaggcccac     1260

ggcttgaccc cccagcaggt ggtggccatc gccagcaata atggtggcaa gcaggcgctg     1320

gagacggtcc agcggctgtt gccggtgctg tgccaggccc acggcttgac cccccagcag     1380

gtggtggcca tcgccagcaa taatggtggc aagcaggcgc tggagacggt ccagcggctg     1440

ttgccggtgc tgtgccaggc ccacggcttg accccggagc aggtggtggc catcgccagc     1500

cacgatggcg gcaagcaggc gctggagacg gtccagcggc tgttgccggt gctgtgccag     1560

gcccacggct tgacccccca gcaggtggtg gccatcgcca gcaatggcgg tggcaagcag     1620

gcgctggaga cggtccagcg gctgttgccg gtgctgtgcc aggcccacgg cttgaccccc     1680

cagcaggtgg tggccatcgc cagcaataat ggtggcaagc aggcgctgga gacggtccag     1740

cggctgttgc cggtgctgtg ccaggcccac ggcttgaccc cccagcaggt ggtggccatc     1800

gccagcaata atggtggcaa gcaggcgctg gagacggtcc agcggctgtt gccggtgctg     1860

tgccaggccc acggcttgac cccccagcag gtggtggcca tcgccagcaa tggcggtggc     1920

aagcaggcgc tggagacggt ccagcggctg ttgccggtgc tgtgccaggc ccacggcttg     1980

acccctcagc aggtggtggc catcgccagc aatggcggcg gcaggccggc gctggagagc     2040

attgttgccc agttatctcg ccctgatccg gcgttggccg cgttgaccaa cgaccacctc     2100

gtcgccttgg cctgcctcgg cgggcgtcct gcgctggatg cagtgaaaaa gggattgggg     2160

gatcctatca gccgttccca gctggtgaag tccgagctgg aggagaagaa atccgagttg     2220

aggcacaagc tgaagtacgt gccccacgag tacatcgagc tgatcgagat cgcccggaac     2280

agcacccagg accgtatcct ggagatgaag gtgatggagt tcttcatgaa ggtgtacggc     2340

tacaggggca agcacctggg cggctccagg aagcccgacg gcgccatcta caccgtgggc     2400

tcccccatcg actacggcgt gatcgtggac accaaggcct actccggcgg ctacaacctg     2460

cccatcggcc aggccgacga aatgcagagg tacgtggagg agaaccagac caggaacaag     2520

cacatcaacc ccaacgagtg gtggaaggtg tacccctcca gcgtgaccga gttcaagttc     2580

ctgttcgtgt ccggccactt caagggcaac tacaaggccc agctgaccag gctgaaccac     2640

atcaccaact gcaacggcgc cgtgctgtcc gtggaggagc tcctgatcgg cggcgagatg     2700

atcaaggccg gcaccctgac cctggaggag gtgaggagga agttcaacaa cggcgagatc     2760

aacttcgcgg ccgactgata a                                               2781


<210>  167
<211>  925
<212>  PRT
<213>  Artificial Sequence

<220>
<223>  Right CISH KO TALEN

pCLS34486

CISHe3_9-R1

Amino acid sequence

<400>  167

Met Gly Asp Pro Lys Lys Lys Arg Lys Val Ile Asp Ile Ala Asp Leu 
1               5                   10                  15      


Arg Thr Leu Gly Tyr Ser Gln Gln Gln Gln Glu Lys Ile Lys Pro Lys 
            20                  25                  30          


Val Arg Ser Thr Val Ala Gln His His Glu Ala Leu Val Gly His Gly 
        35                  40                  45              


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


Gly Thr Val Ala Val Lys Tyr Gln Asp Met Ile Ala Ala Leu Pro Glu 
65                  70                  75                  80  


Ala Thr His Glu Ala Ile Val Gly Val Gly Lys Gln Trp Ser Gly Ala 
                85                  90                  95      


Arg Ala Leu Glu Ala Leu Leu Thr Val Ala Gly Glu Leu Arg Gly Pro 
            100                 105                 110         


Pro Leu Gln Leu Asp Thr Gly Gln Leu Leu Lys Ile Ala Lys Arg Gly 
        115                 120                 125             


Gly Val Thr Ala Val Glu Ala Val His Ala Trp Arg Asn Ala Leu Thr 
    130                 135                 140                 


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


Asn Ile Gly Gly Lys Gln Ala Leu Glu Thr Val Gln Ala Leu Leu Pro 
                165                 170                 175     


Val Leu Cys Gln Ala His Gly Leu Thr Pro Glu Gln Val Val Ala Ile 
            180                 185                 190         


Ala Ser His Asp Gly Gly Lys Gln Ala Leu Glu Thr Val Gln Arg Leu 
        195                 200                 205             


Leu Pro Val Leu Cys Gln Ala His Gly Leu Thr Pro Glu Gln Val Val 
    210                 215                 220                 


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


Ala Leu Leu Pro Val Leu Cys Gln Ala His Gly Leu Thr Pro Gln Gln 
                245                 250                 255     


Val Val Ala Ile Ala Ser Asn Asn Gly Gly Lys Gln Ala Leu Glu Thr 
            260                 265                 270         


Val Gln Arg Leu Leu Pro Val Leu Cys Gln Ala His Gly Leu Thr Pro 
        275                 280                 285             


Glu Gln Val Val Ala Ile Ala Ser His Asp Gly Gly Lys Gln Ala Leu 
    290                 295                 300                 


Glu Thr Val Gln Arg Leu Leu Pro Val Leu Cys Gln Ala His Gly Leu 
305                 310                 315                 320 


Thr Pro Glu Gln Val Val Ala Ile Ala Ser Asn Ile Gly Gly Lys Gln 
                325                 330                 335     


Ala Leu Glu Thr Val Gln Ala Leu Leu Pro Val Leu Cys Gln Ala His 
            340                 345                 350         


Gly Leu Thr Pro Gln Gln Val Val Ala Ile Ala Ser Asn Asn Gly Gly 
        355                 360                 365             


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


Ala His Gly Leu Thr Pro Gln Gln Val Val Ala Ile Ala Ser Asn Gly 
385                 390                 395                 400 


Gly Gly Lys Gln Ala Leu Glu Thr Val Gln Arg Leu Leu Pro Val Leu 
                405                 410                 415     


Cys Gln Ala His Gly Leu Thr Pro Gln Gln Val Val Ala Ile Ala Ser 
            420                 425                 430         


Asn Asn Gly Gly Lys Gln Ala Leu Glu Thr Val Gln Arg Leu Leu Pro 
        435                 440                 445             


Val Leu Cys Gln Ala His Gly Leu Thr Pro Gln Gln Val Val Ala Ile 
    450                 455                 460                 


Ala Ser Asn Asn Gly Gly Lys Gln Ala Leu Glu Thr Val Gln Arg Leu 
465                 470                 475                 480 


Leu Pro Val Leu Cys Gln Ala His Gly Leu Thr Pro Glu Gln Val Val 
                485                 490                 495     


Ala Ile Ala Ser His Asp Gly Gly Lys Gln Ala Leu Glu Thr Val Gln 
            500                 505                 510         


Arg Leu Leu Pro Val Leu Cys Gln Ala His Gly Leu Thr Pro Gln Gln 
        515                 520                 525             


Val Val Ala Ile Ala Ser Asn Gly Gly Gly Lys Gln Ala Leu Glu Thr 
    530                 535                 540                 


Val Gln Arg Leu Leu Pro Val Leu Cys Gln Ala His Gly Leu Thr Pro 
545                 550                 555                 560 


Gln Gln Val Val Ala Ile Ala Ser Asn Asn Gly Gly Lys Gln Ala Leu 
                565                 570                 575     


Glu Thr Val Gln Arg Leu Leu Pro Val Leu Cys Gln Ala His Gly Leu 
            580                 585                 590         


Thr Pro Gln Gln Val Val Ala Ile Ala Ser Asn Asn Gly Gly Lys Gln 
        595                 600                 605             


Ala Leu Glu Thr Val Gln Arg Leu Leu Pro Val Leu Cys Gln Ala His 
    610                 615                 620                 


Gly Leu Thr Pro Gln Gln Val Val Ala Ile Ala Ser Asn Gly Gly Gly 
625                 630                 635                 640 


Lys Gln Ala Leu Glu Thr Val Gln Arg Leu Leu Pro Val Leu Cys Gln 
                645                 650                 655     


Ala His Gly Leu Thr Pro Gln Gln Val Val Ala Ile Ala Ser Asn Gly 
            660                 665                 670         


Gly Gly Arg Pro Ala Leu Glu Ser Ile Val Ala Gln Leu Ser Arg Pro 
        675                 680                 685             


Asp Pro Ala Leu Ala Ala Leu Thr Asn Asp His Leu Val Ala Leu Ala 
    690                 695                 700                 


Cys Leu Gly Gly Arg Pro Ala Leu Asp Ala Val Lys Lys Gly Leu Gly 
705                 710                 715                 720 


Asp Pro Ile Ser Arg Ser Gln Leu Val Lys Ser Glu Leu Glu Glu Lys 
                725                 730                 735     


Lys Ser Glu Leu Arg His Lys Leu Lys Tyr Val Pro His Glu Tyr Ile 
            740                 745                 750         


Glu Leu Ile Glu Ile Ala Arg Asn Ser Thr Gln Asp Arg Ile Leu Glu 
        755                 760                 765             


Met Lys Val Met Glu Phe Phe Met Lys Val Tyr Gly Tyr Arg Gly Lys 
    770                 775                 780                 


His Leu Gly Gly Ser Arg Lys Pro Asp Gly Ala Ile Tyr Thr Val Gly 
785                 790                 795                 800 


Ser Pro Ile Asp Tyr Gly Val Ile Val Asp Thr Lys Ala Tyr Ser Gly 
                805                 810                 815     


Gly Tyr Asn Leu Pro Ile Gly Gln Ala Asp Glu Met Gln Arg Tyr Val 
            820                 825                 830         


Glu Glu Asn Gln Thr Arg Asn Lys His Ile Asn Pro Asn Glu Trp Trp 
        835                 840                 845             


Lys Val Tyr Pro Ser Ser Val Thr Glu Phe Lys Phe Leu Phe Val Ser 
    850                 855                 860                 


Gly His Phe Lys Gly Asn Tyr Lys Ala Gln Leu Thr Arg Leu Asn His 
865                 870                 875                 880 


Ile Thr Asn Cys Asn Gly Ala Val Leu Ser Val Glu Glu Leu Leu Ile 
                885                 890                 895     


Gly Gly Glu Met Ile Lys Ala Gly Thr Leu Thr Leu Glu Glu Val Arg 
            900                 905                 910         


Arg Lys Phe Asn Asn Gly Glu Ile Asn Phe Ala Ala Asp 
        915                 920                 925 


<210>  168
<211>  49
<212>  DNA
<213>  Artificial Sequence

<220>
<223>  CISH KO Cleavage Site sequence

CISHe3_9.1

Nucleotide sequence

<400>  168
tgcgcctagt gacccagcac tgcctgctcc tccaccagcc actgctgta                   49


<210>  169
<211>  2781
<212>  DNA
<213>  Artificial Sequence

<220>
<223>  Left PD-1 KO TALEN

mRNA sequence

(pCLS29259)

<400>  169
atgggcgatc ctaaaaagaa acgtaaggtc atcgatatcg ccgatctacg cacgctcggc       60

tacagccagc agcaacagga gaagatcaaa ccgaaggttc gttcgacagt ggcgcagcac      120

cacgaggcac tggtcggcca cgggtttaca cacgcgcaca tcgttgcgtt aagccaacac      180

ccggcagcgt tagggaccgt cgctgtcaag tatcaggaca tgatcgcagc gttgccagag      240

gcgacacacg aagcgatcgt tggcgtcggc aaacagtggt ccggcgcacg cgctctggag      300

gccttgctca cggtggcggg agagttgaga ggtccaccgt tacagttgga cacaggccaa      360

cttctcaaga ttgcaaaacg tggcggcgtg accgcagtgg aggcagtgca tgcatggcgc      420

aatgcactga cgggtgcccc gctcaacttg acccccgagc aagtggtggc tatcgcttcc      480

aagctggggg gaaagcaggc cctggagacc gtccaggccc ttctcccagt gctttgccag      540

gctcacggac tgacccctga acaggtggtg gcaattgcct cacacgacgg gggcaagcag      600

gcactggaga ctgtccagcg gctgctgcct gtcctctgcc aggcccacgg actcactcct      660

gagcaggtcg tggccattgc cagccacgat gggggcaaac aggctctgga gaccgtgcag      720

cgcctcctcc cagtgctgtg ccaggctcat gggctgaccc cacagcaggt cgtcgccatt      780

gccagtaacg gcggggggaa gcaggccctc gaaacagtgc agaggctgct gcccgtcttg      840

tgccaagcac acggcctgac acccgagcag gtggtggcca tcgcctctca tgacggcggc      900

aagcaggccc ttgagacagt gcagagactg ttgcccgtgt tgtgtcaggc ccacgggttg      960

acaccccagc aggtggtcgc catcgccagc aatggcgggg gaaagcaggc ccttgagacc     1020

gtgcagcggt tgcttccagt gttgtgccag gcacacggac tgacccctca acaggtggtc     1080

gcaatcgcca gctacaaggg cggaaagcag gctctggaga cagtgcagcg cctcctgccc     1140

gtgctgtgtc aggctcacgg actgacacca cagcaggtgg tcgccatcgc cagtaacggg     1200

ggcggcaagc aggctttgga gaccgtccag agactcctcc ccgtcctttg ccaggcccac     1260

gggttgacac ctcagcaggt cgtcgccatt gcctccaaca acgggggcaa gcaggccctc     1320

gaaactgtgc agaggctgct gcctgtgctg tgccaggctc atgggctgac accccagcag     1380

gtggtggcca ttgcctctaa caacggcggc aaacaggcac tggagaccgt gcaaaggctg     1440

ctgcccgtcc tctgccaagc ccacgggctc actccacagc aggtcgtggc catcgcctca     1500

aacaatggcg ggaagcaggc cctggagact gtgcaaaggc tgctccctgt gctctgccag     1560

gcacacggac tgacccctca gcaggtggtg gcaatcgctt ccaacaacgg gggaaagcag     1620

gccctcgaaa ccgtgcagcg cctcctccca gtgctgtgcc aggcacatgg cctcacaccc     1680

gagcaagtgg tggctatcgc cagccacgac ggagggaagc aggctctgga gaccgtgcag     1740

aggctgctgc ctgtcctgtg ccaggcccac gggcttactc cagagcaggt cgtcgccatc     1800

gccagtcatg atggggggaa gcaggccctt gagacagtcc agcggctgct gccagtcctt     1860

tgccaggctc acggcttgac tcccgagcag gtcgtggcca ttgcctcaaa cattgggggc     1920

aaacaggccc tggagacagt gcaggccctg ctgcccgtgt tgtgtcaggc ccacggcttg     1980

acaccccagc aggtggtcgc cattgcctct aatggcggcg ggagacccgc cttggagagc     2040

attgttgccc agttatctcg ccctgatccg gcgttggccg cgttgaccaa cgaccacctc     2100

gtcgccttgg cctgcctcgg cgggcgtcct gcgctggatg cagtgaaaaa gggattgggg     2160

gatcctatca gccgttccca gctggtgaag tccgagctgg aggagaagaa atccgagttg     2220

aggcacaagc tgaagtacgt gccccacgag tacatcgagc tgatcgagat cgcccggaac     2280

agcacccagg accgtatcct ggagatgaag gtgatggagt tcttcatgaa ggtgtacggc     2340

tacaggggca agcacctggg cggctccagg aagcccgacg gcgccatcta caccgtgggc     2400

tcccccatcg actacggcgt gatcgtggac accaaggcct actccggcgg ctacaacctg     2460

cccatcggcc aggccgacga aatgcagagg tacgtggagg agaaccagac caggaacaag     2520

cacatcaacc ccaacgagtg gtggaaggtg tacccctcca gcgtgaccga gttcaagttc     2580

ctgttcgtgt ccggccactt caagggcaac tacaaggccc agctgaccag gctgaaccac     2640

atcaccaact gcaacggcgc cgtgctgtcc gtggaggagc tcctgatcgg cggcgagatg     2700

atcaaggccg gcaccctgac cctggaggag gtgaggagga agttcaacaa cggcgagatc     2760

aacttcgcgg ccgactgata a                                               2781


<210>  170
<211>  925
<212>  PRT
<213>  Artificial Sequence

<220>
<223>  Left PD-1 KO TALEN

Amino acid sequence

<400>  170

Met Gly Asp Pro Lys Lys Lys Arg Lys Val Ile Asp Ile Ala Asp Leu 
1               5                   10                  15      


Arg Thr Leu Gly Tyr Ser Gln Gln Gln Gln Glu Lys Ile Lys Pro Lys 
            20                  25                  30          


Val Arg Ser Thr Val Ala Gln His His Glu Ala Leu Val Gly His Gly 
        35                  40                  45              


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


Gly Thr Val Ala Val Lys Tyr Gln Asp Met Ile Ala Ala Leu Pro Glu 
65                  70                  75                  80  


Ala Thr His Glu Ala Ile Val Gly Val Gly Lys Gln Trp Ser Gly Ala 
                85                  90                  95      


Arg Ala Leu Glu Ala Leu Leu Thr Val Ala Gly Glu Leu Arg Gly Pro 
            100                 105                 110         


Pro Leu Gln Leu Asp Thr Gly Gln Leu Leu Lys Ile Ala Lys Arg Gly 
        115                 120                 125             


Gly Val Thr Ala Val Glu Ala Val His Ala Trp Arg Asn Ala Leu Thr 
    130                 135                 140                 


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


Lys Leu Gly Gly Lys Gln Ala Leu Glu Thr Val Gln Ala Leu Leu Pro 
                165                 170                 175     


Val Leu Cys Gln Ala His Gly Leu Thr Pro Glu Gln Val Val Ala Ile 
            180                 185                 190         


Ala Ser His Asp Gly Gly Lys Gln Ala Leu Glu Thr Val Gln Arg Leu 
        195                 200                 205             


Leu Pro Val Leu Cys Gln Ala His Gly Leu Thr Pro Glu Gln Val Val 
    210                 215                 220                 


Ala Ile Ala Ser His Asp Gly Gly Lys Gln Ala Leu Glu Thr Val Gln 
225                 230                 235                 240 


Arg Leu Leu Pro Val Leu Cys Gln Ala His Gly Leu Thr Pro Gln Gln 
                245                 250                 255     


Val Val Ala Ile Ala Ser Asn Gly Gly Gly Lys Gln Ala Leu Glu Thr 
            260                 265                 270         


Val Gln Arg Leu Leu Pro Val Leu Cys Gln Ala His Gly Leu Thr Pro 
        275                 280                 285             


Glu Gln Val Val Ala Ile Ala Ser His Asp Gly Gly Lys Gln Ala Leu 
    290                 295                 300                 


Glu Thr Val Gln Arg Leu Leu Pro Val Leu Cys Gln Ala His Gly Leu 
305                 310                 315                 320 


Thr Pro Gln Gln Val Val Ala Ile Ala Ser Asn Gly Gly Gly Lys Gln 
                325                 330                 335     


Ala Leu Glu Thr Val Gln Arg Leu Leu Pro Val Leu Cys Gln Ala His 
            340                 345                 350         


Gly Leu Thr Pro Gln Gln Val Val Ala Ile Ala Ser Tyr Lys Gly Gly 
        355                 360                 365             


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


Ala His Gly Leu Thr Pro Gln Gln Val Val Ala Ile Ala Ser Asn Gly 
385                 390                 395                 400 


Gly Gly Lys Gln Ala Leu Glu Thr Val Gln Arg Leu Leu Pro Val Leu 
                405                 410                 415     


Cys Gln Ala His Gly Leu Thr Pro Gln Gln Val Val Ala Ile Ala Ser 
            420                 425                 430         


Asn Asn Gly Gly Lys Gln Ala Leu Glu Thr Val Gln Arg Leu Leu Pro 
        435                 440                 445             


Val Leu Cys Gln Ala His Gly Leu Thr Pro Gln Gln Val Val Ala Ile 
    450                 455                 460                 


Ala Ser Asn Asn Gly Gly Lys Gln Ala Leu Glu Thr Val Gln Arg Leu 
465                 470                 475                 480 


Leu Pro Val Leu Cys Gln Ala His Gly Leu Thr Pro Gln Gln Val Val 
                485                 490                 495     


Ala Ile Ala Ser Asn Asn Gly Gly Lys Gln Ala Leu Glu Thr Val Gln 
            500                 505                 510         


Arg Leu Leu Pro Val Leu Cys Gln Ala His Gly Leu Thr Pro Gln Gln 
        515                 520                 525             


Val Val Ala Ile Ala Ser Asn Asn Gly Gly Lys Gln Ala Leu Glu Thr 
    530                 535                 540                 


Val Gln Arg Leu Leu Pro Val Leu Cys Gln Ala His Gly Leu Thr Pro 
545                 550                 555                 560 


Glu Gln Val Val Ala Ile Ala Ser His Asp Gly Gly Lys Gln Ala Leu 
                565                 570                 575     


Glu Thr Val Gln Arg Leu Leu Pro Val Leu Cys Gln Ala His Gly Leu 
            580                 585                 590         


Thr Pro Glu Gln Val Val Ala Ile Ala Ser His Asp Gly Gly Lys Gln 
        595                 600                 605             


Ala Leu Glu Thr Val Gln Arg Leu Leu Pro Val Leu Cys Gln Ala His 
    610                 615                 620                 


Gly Leu Thr Pro Glu Gln Val Val Ala Ile Ala Ser Asn Ile Gly Gly 
625                 630                 635                 640 


Lys Gln Ala Leu Glu Thr Val Gln Ala Leu Leu Pro Val Leu Cys Gln 
                645                 650                 655     


Ala His Gly Leu Thr Pro Gln Gln Val Val Ala Ile Ala Ser Asn Gly 
            660                 665                 670         


Gly Gly Arg Pro Ala Leu Glu Ser Ile Val Ala Gln Leu Ser Arg Pro 
        675                 680                 685             


Asp Pro Ala Leu Ala Ala Leu Thr Asn Asp His Leu Val Ala Leu Ala 
    690                 695                 700                 


Cys Leu Gly Gly Arg Pro Ala Leu Asp Ala Val Lys Lys Gly Leu Gly 
705                 710                 715                 720 


Asp Pro Ile Ser Arg Ser Gln Leu Val Lys Ser Glu Leu Glu Glu Lys 
                725                 730                 735     


Lys Ser Glu Leu Arg His Lys Leu Lys Tyr Val Pro His Glu Tyr Ile 
            740                 745                 750         


Glu Leu Ile Glu Ile Ala Arg Asn Ser Thr Gln Asp Arg Ile Leu Glu 
        755                 760                 765             


Met Lys Val Met Glu Phe Phe Met Lys Val Tyr Gly Tyr Arg Gly Lys 
    770                 775                 780                 


His Leu Gly Gly Ser Arg Lys Pro Asp Gly Ala Ile Tyr Thr Val Gly 
785                 790                 795                 800 


Ser Pro Ile Asp Tyr Gly Val Ile Val Asp Thr Lys Ala Tyr Ser Gly 
                805                 810                 815     


Gly Tyr Asn Leu Pro Ile Gly Gln Ala Asp Glu Met Gln Arg Tyr Val 
            820                 825                 830         


Glu Glu Asn Gln Thr Arg Asn Lys His Ile Asn Pro Asn Glu Trp Trp 
        835                 840                 845             


Lys Val Tyr Pro Ser Ser Val Thr Glu Phe Lys Phe Leu Phe Val Ser 
    850                 855                 860                 


Gly His Phe Lys Gly Asn Tyr Lys Ala Gln Leu Thr Arg Leu Asn His 
865                 870                 875                 880 


Ile Thr Asn Cys Asn Gly Ala Val Leu Ser Val Glu Glu Leu Leu Ile 
                885                 890                 895     


Gly Gly Glu Met Ile Lys Ala Gly Thr Leu Thr Leu Glu Glu Val Arg 
            900                 905                 910         


Arg Lys Phe Asn Asn Gly Glu Ile Asn Phe Ala Ala Asp 
        915                 920                 925 


<210>  171
<211>  2778
<212>  DNA
<213>  Artificial Sequence

<220>
<223>  Right PD-1 KO TALEN

mRNA sequence

(pCLS25171)

<400>  171
atgggcgatc ctaaaaagaa acgtaaggtc atcgatatcg ccgatctacg cacgctcggc       60

tacagccagc agcaacagga gaagatcaaa ccgaaggttc gttcgacagt ggcgcagcac      120

cacgaggcac tggtcggcca cgggtttaca cacgcgcaca tcgttgcgtt aagccaacac      180

ccggcagcgt tagggaccgt cgctgtcaag tatcaggaca tgatcgcagc gttgccagag      240

gcgacacacg aagcgatcgt tggcgtcggc aaacagtggt ccggcgcacg cgctctggag      300

gccttgctca cggtggcggg agagttgaga ggtccaccgt tacagttgga cacaggccaa      360

cttctcaaga ttgcaaaacg tggcggcgtg accgcagtgg aggcagtgca tgcatggcgc      420

aatgcactga cgggtgcccc gctcaacttg acccccgagc aagtcgtcgc aatcgccagc      480

catgatggag ggaagcaagc cctcgaaacc gtgcagcggt tgcttcctgt gctctgccag      540

gcccacggcc ttacccctca gcaggtggtg gccatcgcaa gtaacggagg aggaaagcaa      600

gccttggaga cagtgcagcg cctgttgccc gtgctgtgcc aggcacacgg cctcacacca      660

gagcaggtcg tggccattgc ctcccatgac ggggggaaac aggctctgga gaccgtccag      720

aggctgctgc ccgtcctctg tcaagctcac ggcctgactc cccaacaagt ggtcgccatc      780

gcctctaatg gcggcgggaa gcaggcactg gaaacagtgc agagactgct ccctgtgctt      840

tgccaagctc atgggttgac cccccaacag gtcgtcgcta ttgcctcaaa cggggggggc      900

aagcaggccc ttgagactgt gcagaggctg ttgccagtgc tgtgtcaggc tcacgggctc      960

actccacaac aggtggtcgc aattgccagc aacggcggcg gaaagcaagc tcttgaaacc     1020

gtgcaacgcc tcctgcccgt gctctgtcag gctcatggcc tgacaccaca acaagtcgtg     1080

gccatcgcca gtaataatgg cgggaaacag gctcttgaga ccgtccagag gctgctccca     1140

gtgctctgcc aggcacacgg gctgaccccc gagcaggtgg tggctatcgc cagcaatatt     1200

gggggcaagc aggccctgga aacagtccag gccctgctgc cagtgctttg ccaggctcac     1260

gggctcactc cccagcaggt cgtggcaatc gcctccaacg gcggagggaa gcaggctctg     1320

gagaccgtgc agagactgct gcccgtcttg tgccaggccc acggactcac acctgaacag     1380

gtcgtcgcca ttgcctctca cgatgggggc aaacaagccc tggagacagt gcagcggctg     1440

ttgcctgtgt tgtgccaagc ccacggcttg actcctcaac aagtggtcgc catcgcctca     1500

aatggcggcg gaaaacaagc tctggagaca gtgcagaggt tgctgcccgt cctctgccaa     1560

gcccacggcc tgactcccca acaggtcgtc gccattgcca gcaacaacgg aggaaagcag     1620

gctctcgaaa ctgtgcagcg gctgcttcct gtgctgtgtc aggctcatgg gctgaccccc     1680

gagcaagtgg tggctattgc ctctaatgga ggcaagcaag cccttgagac agtccagagg     1740

ctgttgccag tgctgtgcca ggcccacggg ctcacacccc agcaggtggt cgccatcgcc     1800

agtaacaacg ggggcaaaca ggcattggaa accgtccagc gcctgcttcc agtgctctgc     1860

caggcacacg gactgacacc cgaacaggtg gtggccattg catcccatga tgggggcaag     1920

caggccctgg agaccgtgca gagactcctg ccagtgttgt gccaagctca cggcctcacc     1980

cctcagcaag tcgtggccat cgcctcaaac ggggggggcc ggcctgcact ggagagcatt     2040

gttgcccagt tatctcgccc tgatccggcg ttggccgcgt tgaccaacga ccacctcgtc     2100

gccttggcct gcctcggcgg gcgtcctgcg ctggatgcag tgaaaaaggg attgggggat     2160

cctatcagcc gttcccagct ggtgaagtcc gagctggagg agaagaaatc cgagttgagg     2220

cacaagctga agtacgtgcc ccacgagtac atcgagctga tcgagatcgc ccggaacagc     2280

acccaggacc gtatcctgga gatgaaggtg atggagttct tcatgaaggt gtacggctac     2340

aggggcaagc acctgggcgg ctccaggaag cccgacggcg ccatctacac cgtgggctcc     2400

cccatcgact acggcgtgat cgtggacacc aaggcctact ccggcggcta caacctgccc     2460

atcggccagg ccgacgaaat gcagaggtac gtggaggaga accagaccag gaacaagcac     2520

atcaacccca acgagtggtg gaaggtgtac ccctccagcg tgaccgagtt caagttcctg     2580

ttcgtgtccg gccacttcaa gggcaactac aaggcccagc tgaccaggct gaaccacatc     2640

accaactgca acggcgccgt gctgtccgtg gaggagctcc tgatcggcgg cgagatgatc     2700

aaggccggca ccctgaccct ggaggaggtg aggaggaagt tcaacaacgg cgagatcaac     2760

ttcgcggccg actgataa                                                   2778


<210>  172
<211>  924
<212>  PRT
<213>  Artificial Sequence

<220>
<223>  pCLS34486

CISHe3_9-

R1

Amino acid sequence

<400>  172

Met Gly Asp Pro Lys Lys Lys Arg Lys Val Ile Asp Ile Ala Asp Leu 
1               5                   10                  15      


Arg Thr Leu Gly Tyr Ser Gln Gln Gln Gln Glu Lys Ile Lys Pro Lys 
            20                  25                  30          


Val Arg Ser Thr Val Ala Gln His His Glu Ala Leu Val Gly His Gly 
        35                  40                  45              


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


Gly Thr Val Ala Val Lys Tyr Gln Asp Met Ile Ala Ala Leu Pro Glu 
65                  70                  75                  80  


Ala Thr His Glu Ala Ile Val Gly Val Gly Lys Gln Trp Ser Gly Ala 
                85                  90                  95      


Arg Ala Leu Glu Ala Leu Leu Thr Val Ala Gly Glu Leu Arg Gly Pro 
            100                 105                 110         


Pro Leu Gln Leu Asp Thr Gly Gln Leu Leu Lys Ile Ala Lys Arg Gly 
        115                 120                 125             


Gly Val Thr Ala Val Glu Ala Val His Ala Trp Arg Asn Ala Leu Thr 
    130                 135                 140                 


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


His Asp Gly Gly Lys Gln Ala Leu Glu Thr Val Gln Arg Leu Leu Pro 
                165                 170                 175     


Val Leu Cys Gln Ala His Gly Leu Thr Pro Gln Gln Val Val Ala Ile 
            180                 185                 190         


Ala Ser Asn Gly Gly Gly Lys Gln Ala Leu Glu Thr Val Gln Arg Leu 
        195                 200                 205             


Leu Pro Val Leu Cys Gln Ala His Gly Leu Thr Pro Glu Gln Val Val 
    210                 215                 220                 


Ala Ile Ala Ser His Asp Gly Gly Lys Gln Ala Leu Glu Thr Val Gln 
225                 230                 235                 240 


Arg Leu Leu Pro Val Leu Cys Gln Ala His Gly Leu Thr Pro Gln Gln 
                245                 250                 255     


Val Val Ala Ile Ala Ser Asn Gly Gly Gly Lys Gln Ala Leu Glu Thr 
            260                 265                 270         


Val Gln Arg Leu Leu Pro Val Leu Cys Gln Ala His Gly Leu Thr Pro 
        275                 280                 285             


Gln Gln Val Val Ala Ile Ala Ser Asn Gly Gly Gly Lys Gln Ala Leu 
    290                 295                 300                 


Glu Thr Val Gln Arg Leu Leu Pro Val Leu Cys Gln Ala His Gly Leu 
305                 310                 315                 320 


Thr Pro Gln Gln Val Val Ala Ile Ala Ser Asn Gly Gly Gly Lys Gln 
                325                 330                 335     


Ala Leu Glu Thr Val Gln Arg Leu Leu Pro Val Leu Cys Gln Ala His 
            340                 345                 350         


Gly Leu Thr Pro Gln Gln Val Val Ala Ile Ala Ser Asn Asn Gly Gly 
        355                 360                 365             


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


Ala His Gly Leu Thr Pro Glu Gln Val Val Ala Ile Ala Ser Asn Ile 
385                 390                 395                 400 


Gly Gly Lys Gln Ala Leu Glu Thr Val Gln Ala Leu Leu Pro Val Leu 
                405                 410                 415     


Cys Gln Ala His Gly Leu Thr Pro Gln Gln Val Val Ala Ile Ala Ser 
            420                 425                 430         


Asn Gly Gly Gly Lys Gln Ala Leu Glu Thr Val Gln Arg Leu Leu Pro 
        435                 440                 445             


Val Leu Cys Gln Ala His Gly Leu Thr Pro Glu Gln Val Val Ala Ile 
    450                 455                 460                 


Ala Ser His Asp Gly Gly Lys Gln Ala Leu Glu Thr Val Gln Arg Leu 
465                 470                 475                 480 


Leu Pro Val Leu Cys Gln Ala His Gly Leu Thr Pro Gln Gln Val Val 
                485                 490                 495     


Ala Ile Ala Ser Asn Gly Gly Gly Lys Gln Ala Leu Glu Thr Val Gln 
            500                 505                 510         


Arg Leu Leu Pro Val Leu Cys Gln Ala His Gly Leu Thr Pro Gln Gln 
        515                 520                 525             


Val Val Ala Ile Ala Ser Asn Asn Gly Gly Lys Gln Ala Leu Glu Thr 
    530                 535                 540                 


Val Gln Arg Leu Leu Pro Val Leu Cys Gln Ala His Gly Leu Thr Pro 
545                 550                 555                 560 


Glu Gln Val Val Ala Ile Ala Ser Asn Gly Gly Lys Gln Ala Leu Glu 
                565                 570                 575     


Thr Val Gln Arg Leu Leu Pro Val Leu Cys Gln Ala His Gly Leu Thr 
            580                 585                 590         


Pro Gln Gln Val Val Ala Ile Ala Ser Asn Asn Gly Gly Lys Gln Ala 
        595                 600                 605             


Leu Glu Thr Val Gln Arg Leu Leu Pro Val Leu Cys Gln Ala His Gly 
    610                 615                 620                 


Leu Thr Pro Glu Gln Val Val Ala Ile Ala Ser His Asp Gly Gly Lys 
625                 630                 635                 640 


Gln Ala Leu Glu Thr Val Gln Arg Leu Leu Pro Val Leu Cys Gln Ala 
                645                 650                 655     


His Gly Leu Thr Pro Gln Gln Val Val Ala Ile Ala Ser Asn Gly Gly 
            660                 665                 670         


Gly Arg Pro Ala Leu Glu Ser Ile Val Ala Gln Leu Ser Arg Pro Asp 
        675                 680                 685             


Pro Ala Leu Ala Ala Leu Thr Asn Asp His Leu Val Ala Leu Ala Cys 
    690                 695                 700                 


Leu Gly Gly Arg Pro Ala Leu Asp Ala Val Lys Lys Gly Leu Gly Asp 
705                 710                 715                 720 


Pro Ile Ser Arg Ser Gln Leu Val Lys Ser Glu Leu Glu Glu Lys Lys 
                725                 730                 735     


Ser Glu Leu Arg His Lys Leu Lys Tyr Val Pro His Glu Tyr Ile Glu 
            740                 745                 750         


Leu Ile Glu Ile Ala Arg Asn Ser Thr Gln Asp Arg Ile Leu Glu Met 
        755                 760                 765             


Lys Val Met Glu Phe Phe Met Lys Val Tyr Gly Tyr Arg Gly Lys His 
    770                 775                 780                 


Leu Gly Gly Ser Arg Lys Pro Asp Gly Ala Ile Tyr Thr Val Gly Ser 
785                 790                 795                 800 


Pro Ile Asp Tyr Gly Val Ile Val Asp Thr Lys Ala Tyr Ser Gly Gly 
                805                 810                 815     


Tyr Asn Leu Pro Ile Gly Gln Ala Asp Glu Met Gln Arg Tyr Val Glu 
            820                 825                 830         


Glu Asn Gln Thr Arg Asn Lys His Ile Asn Pro Asn Glu Trp Trp Lys 
        835                 840                 845             


Val Tyr Pro Ser Ser Val Thr Glu Phe Lys Phe Leu Phe Val Ser Gly 
    850                 855                 860                 


His Phe Lys Gly Asn Tyr Lys Ala Gln Leu Thr Arg Leu Asn His Ile 
865                 870                 875                 880 


Thr Asn Cys Asn Gly Ala Val Leu Ser Val Glu Glu Leu Leu Ile Gly 
                885                 890                 895     


Gly Glu Met Ile Lys Ala Gly Thr Leu Thr Leu Glu Glu Val Arg Arg 
            900                 905                 910         


Lys Phe Asn Asn Gly Glu Ile Asn Phe Ala Ala Asp 
        915                 920                 


<210>  173
<211>  20
<212>  DNA
<213>  Artificial Sequence

<220>
<223>  CISH forward primer

<400>  173
ctgcactgct gatacccgaa                                                   20


<210>  174
<211>  20
<212>  DNA
<213>  Artificial Sequence

<220>
<223>  CISH reverse primer

<400>  174
ggggtactgt cggaggtagt                                                   20


<210>  175
<211>  267
<212>  DNA
<213>  Artificial Sequence

<220>
<223>  CISH target site Sequence

<400>  175
ctgcactgct gatacccgaa gcgacagccc cgatcctgct cccaccccgg ccctgcctat       60

gcctaaggag gatgcgccta gtgacccagc actgcctgct cctccaccag ccactgctgt      120

acacctaaaa ctggtgcagc cctttgtacg cagaagcagt gcccgcagcc tgcaacacct      180

gtgccgcctt gtcatcaacc gtctggtggc cgacgtggac tgcctgccac tgccccggcg      240

catggccgac tacctccgac agtaccc                                          267


