                           Sequence Listing

<110>  Larson, Steven
       Cheung, Nai-Kong V.
       Cheal, Sarah
 
<120>  BISPECIFIC BINDING AGENTS AND USES THEREOF

<130>  13542-061-228

<140>  
<141>  

<150>  62/813,592
<151>  2019-03-04

<150>  62/641,645
<151>  2018-03-12

<160>  56    

<170>  PatentIn version 3.5

<210>  1
<211>  4664
<212>  DNA
<213>  Homo sapiens

<220>
<223>  Human HER2, NM_004448.3

<400>  1
gcttgctccc aatcacagga gaaggaggag gtggaggagg agggctgctt gaggaagtat       60

aagaatgaag ttgtgaagct gagattcccc tccattggga ccggagaaac caggggagcc      120

ccccgggcag ccgcgcgccc cttcccacgg ggccctttac tgcgccgcgc gcccggcccc      180

cacccctcgc agcaccccgc gccccgcgcc ctcccagccg ggtccagccg gagccatggg      240

gccggagccg cagtgagcac catggagctg gcggccttgt gccgctgggg gctcctcctc      300

gccctcttgc cccccggagc cgcgagcacc caagtgtgca ccggcacaga catgaagctg      360

cggctccctg ccagtcccga gacccacctg gacatgctcc gccacctcta ccagggctgc      420

caggtggtgc agggaaacct ggaactcacc tacctgccca ccaatgccag cctgtccttc      480

ctgcaggata tccaggaggt gcagggctac gtgctcatcg ctcacaacca agtgaggcag      540

gtcccactgc agaggctgcg gattgtgcga ggcacccagc tctttgagga caactatgcc      600

ctggccgtgc tagacaatgg agacccgctg aacaatacca cccctgtcac aggggcctcc      660

ccaggaggcc tgcgggagct gcagcttcga agcctcacag agatcttgaa aggaggggtc      720

ttgatccagc ggaaccccca gctctgctac caggacacga ttttgtggaa ggacatcttc      780

cacaagaaca accagctggc tctcacactg atagacacca accgctctcg ggcctgccac      840

ccctgttctc cgatgtgtaa gggctcccgc tgctggggag agagttctga ggattgtcag      900

agcctgacgc gcactgtctg tgccggtggc tgtgcccgct gcaaggggcc actgcccact      960

gactgctgcc atgagcagtg tgctgccggc tgcacgggcc ccaagcactc tgactgcctg     1020

gcctgcctcc acttcaacca cagtggcatc tgtgagctgc actgcccagc cctggtcacc     1080

tacaacacag acacgtttga gtccatgccc aatcccgagg gccggtatac attcggcgcc     1140

agctgtgtga ctgcctgtcc ctacaactac ctttctacgg acgtgggatc ctgcaccctc     1200

gtctgccccc tgcacaacca agaggtgaca gcagaggatg gaacacagcg gtgtgagaag     1260

tgcagcaagc cctgtgcccg agtgtgctat ggtctgggca tggagcactt gcgagaggtg     1320

agggcagtta ccagtgccaa tatccaggag tttgctggct gcaagaagat ctttgggagc     1380

ctggcatttc tgccggagag ctttgatggg gacccagcct ccaacactgc cccgctccag     1440

ccagagcagc tccaagtgtt tgagactctg gaagagatca caggttacct atacatctca     1500

gcatggccgg acagcctgcc tgacctcagc gtcttccaga acctgcaagt aatccgggga     1560

cgaattctgc acaatggcgc ctactcgctg accctgcaag ggctgggcat cagctggctg     1620

gggctgcgct cactgaggga actgggcagt ggactggccc tcatccacca taacacccac     1680

ctctgcttcg tgcacacggt gccctgggac cagctctttc ggaacccgca ccaagctctg     1740

ctccacactg ccaaccggcc agaggacgag tgtgtgggcg agggcctggc ctgccaccag     1800

ctgtgcgccc gagggcactg ctggggtcca gggcccaccc agtgtgtcaa ctgcagccag     1860

ttccttcggg gccaggagtg cgtggaggaa tgccgagtac tgcaggggct ccccagggag     1920

tatgtgaatg ccaggcactg tttgccgtgc caccctgagt gtcagcccca gaatggctca     1980

gtgacctgtt ttggaccgga ggctgaccag tgtgtggcct gtgcccacta taaggaccct     2040

cccttctgcg tggcccgctg ccccagcggt gtgaaacctg acctctccta catgcccatc     2100

tggaagtttc cagatgagga gggcgcatgc cagccttgcc ccatcaactg cacccactcc     2160

tgtgtggacc tggatgacaa gggctgcccc gccgagcaga gagccagccc tctgacgtcc     2220

atcatctctg cggtggttgg cattctgctg gtcgtggtct tgggggtggt ctttgggatc     2280

ctcatcaagc gacggcagca gaagatccgg aagtacacga tgcggagact gctgcaggaa     2340

acggagctgg tggagccgct gacacctagc ggagcgatgc ccaaccaggc gcagatgcgg     2400

atcctgaaag agacggagct gaggaaggtg aaggtgcttg gatctggcgc ttttggcaca     2460

gtctacaagg gcatctggat ccctgatggg gagaatgtga aaattccagt ggccatcaaa     2520

gtgttgaggg aaaacacatc ccccaaagcc aacaaagaaa tcttagacga agcatacgtg     2580

atggctggtg tgggctcccc atatgtctcc cgccttctgg gcatctgcct gacatccacg     2640

gtgcagctgg tgacacagct tatgccctat ggctgcctct tagaccatgt ccgggaaaac     2700

cgcggacgcc tgggctccca ggacctgctg aactggtgta tgcagattgc caaggggatg     2760

agctacctgg aggatgtgcg gctcgtacac agggacttgg ccgctcggaa cgtgctggtc     2820

aagagtccca accatgtcaa aattacagac ttcgggctgg ctcggctgct ggacattgac     2880

gagacagagt accatgcaga tgggggcaag gtgcccatca agtggatggc gctggagtcc     2940

attctccgcc ggcggttcac ccaccagagt gatgtgtgga gttatggtgt gactgtgtgg     3000

gagctgatga cttttggggc caaaccttac gatgggatcc cagcccggga gatccctgac     3060

ctgctggaaa agggggagcg gctgccccag ccccccatct gcaccattga tgtctacatg     3120

atcatggtca aatgttggat gattgactct gaatgtcggc caagattccg ggagttggtg     3180

tctgaattct cccgcatggc cagggacccc cagcgctttg tggtcatcca gaatgaggac     3240

ttgggcccag ccagtccctt ggacagcacc ttctaccgct cactgctgga ggacgatgac     3300

atgggggacc tggtggatgc tgaggagtat ctggtacccc agcagggctt cttctgtcca     3360

gaccctgccc cgggcgctgg gggcatggtc caccacaggc accgcagctc atctaccagg     3420

agtggcggtg gggacctgac actagggctg gagccctctg aagaggaggc ccccaggtct     3480

ccactggcac cctccgaagg ggctggctcc gatgtatttg atggtgacct gggaatgggg     3540

gcagccaagg ggctgcaaag cctccccaca catgacccca gccctctaca gcggtacagt     3600

gaggacccca cagtacccct gccctctgag actgatggct acgttgcccc cctgacctgc     3660

agcccccagc ctgaatatgt gaaccagcca gatgttcggc cccagccccc ttcgccccga     3720

gagggccctc tgcctgctgc ccgacctgct ggtgccactc tggaaaggcc caagactctc     3780

tccccaggga agaatggggt cgtcaaagac gtttttgcct ttgggggtgc cgtggagaac     3840

cccgagtact tgacacccca gggaggagct gcccctcagc cccaccctcc tcctgccttc     3900

agcccagcct tcgacaacct ctattactgg gaccaggacc caccagagcg gggggctcca     3960

cccagcacct tcaaagggac acctacggca gagaacccag agtacctggg tctggacgtg     4020

ccagtgtgaa ccagaaggcc aagtccgcag aagccctgat gtgtcctcag ggagcaggga     4080

aggcctgact tctgctggca tcaagaggtg ggagggccct ccgaccactt ccaggggaac     4140

ctgccatgcc aggaacctgt cctaaggaac cttccttcct gcttgagttc ccagatggct     4200

ggaaggggtc cagcctcgtt ggaagaggaa cagcactggg gagtctttgt ggattctgag     4260

gccctgccca atgagactct agggtccagt ggatgccaca gcccagcttg gccctttcct     4320

tccagatcct gggtactgaa agccttaggg aagctggcct gagaggggaa gcggccctaa     4380

gggagtgtct aagaacaaaa gcgacccatt cagagactgt ccctgaaacc tagtactgcc     4440

ccccatgagg aaggaacagc aatggtgtca gtatccaggc tttgtacaga gtgcttttct     4500

gtttagtttt tacttttttt gttttgtttt tttaaagatg aaataaagac ccagggggag     4560

aatgggtgtt gtatggggag gcaagtgtgg ggggtccttc tccacaccca ctttgtccat     4620

ttgcaaatat attttggaaa acagctaaaa aaaaaaaaaa aaaa                      4664


<210>  2
<211>  1255
<212>  PRT
<213>  Homo sapiens

<220>
<223>  Human HER2, NP_004439.2

<400>  2

Met Glu Leu Ala Ala Leu Cys Arg Trp Gly Leu Leu Leu Ala Leu Leu 
1               5                   10                  15      


Pro Pro Gly Ala Ala Ser Thr Gln Val Cys Thr Gly Thr Asp Met Lys 
            20                  25                  30          


Leu Arg Leu Pro Ala Ser Pro Glu Thr His Leu Asp Met Leu Arg His 
        35                  40                  45              


Leu Tyr Gln Gly Cys Gln Val Val Gln Gly Asn Leu Glu Leu Thr Tyr 
    50                  55                  60                  


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


Gln Gly Tyr Val Leu Ile Ala His Asn Gln Val Arg Gln Val Pro Leu 
                85                  90                  95      


Gln Arg Leu Arg Ile Val Arg Gly Thr Gln Leu Phe Glu Asp Asn Tyr 
            100                 105                 110         


Ala Leu Ala Val Leu Asp Asn Gly Asp Pro Leu Asn Asn Thr Thr Pro 
        115                 120                 125             


Val Thr Gly Ala Ser Pro Gly Gly Leu Arg Glu Leu Gln Leu Arg Ser 
    130                 135                 140                 


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


Leu Cys Tyr Gln Asp Thr Ile Leu Trp Lys Asp Ile Phe His Lys Asn 
                165                 170                 175     


Asn Gln Leu Ala Leu Thr Leu Ile Asp Thr Asn Arg Ser Arg Ala Cys 
            180                 185                 190         


His Pro Cys Ser Pro Met Cys Lys Gly Ser Arg Cys Trp Gly Glu Ser 
        195                 200                 205             


Ser Glu Asp Cys Gln Ser Leu Thr Arg Thr Val Cys Ala Gly Gly Cys 
    210                 215                 220                 


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


Ala Ala Gly Cys Thr Gly Pro Lys His Ser Asp Cys Leu Ala Cys Leu 
                245                 250                 255     


His Phe Asn His Ser Gly Ile Cys Glu Leu His Cys Pro Ala Leu Val 
            260                 265                 270         


Thr Tyr Asn Thr Asp Thr Phe Glu Ser Met Pro Asn Pro Glu Gly Arg 
        275                 280                 285             


Tyr Thr Phe Gly Ala Ser Cys Val Thr Ala Cys Pro Tyr Asn Tyr Leu 
    290                 295                 300                 


Ser Thr Asp Val Gly Ser Cys Thr Leu Val Cys Pro Leu His Asn Gln 
305                 310                 315                 320 


Glu Val Thr Ala Glu Asp Gly Thr Gln Arg Cys Glu Lys Cys Ser Lys 
                325                 330                 335     


Pro Cys Ala Arg Val Cys Tyr Gly Leu Gly Met Glu His Leu Arg Glu 
            340                 345                 350         


Val Arg Ala Val Thr Ser Ala Asn Ile Gln Glu Phe Ala Gly Cys Lys 
        355                 360                 365             


Lys Ile Phe Gly Ser Leu Ala Phe Leu Pro Glu Ser Phe Asp Gly Asp 
    370                 375                 380                 


Pro Ala Ser Asn Thr Ala Pro Leu Gln Pro Glu Gln Leu Gln Val Phe 
385                 390                 395                 400 


Glu Thr Leu Glu Glu Ile Thr Gly Tyr Leu Tyr Ile Ser Ala Trp Pro 
                405                 410                 415     


Asp Ser Leu Pro Asp Leu Ser Val Phe Gln Asn Leu Gln Val Ile Arg 
            420                 425                 430         


Gly Arg Ile Leu His Asn Gly Ala Tyr Ser Leu Thr Leu Gln Gly Leu 
        435                 440                 445             


Gly Ile Ser Trp Leu Gly Leu Arg Ser Leu Arg Glu Leu Gly Ser Gly 
    450                 455                 460                 


Leu Ala Leu Ile His His Asn Thr His Leu Cys Phe Val His Thr Val 
465                 470                 475                 480 


Pro Trp Asp Gln Leu Phe Arg Asn Pro His Gln Ala Leu Leu His Thr 
                485                 490                 495     


Ala Asn Arg Pro Glu Asp Glu Cys Val Gly Glu Gly Leu Ala Cys His 
            500                 505                 510         


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


Val Asn Cys Ser Gln Phe Leu Arg Gly Gln Glu Cys Val Glu Glu Cys 
    530                 535                 540                 


Arg Val Leu Gln Gly Leu Pro Arg Glu Tyr Val Asn Ala Arg His Cys 
545                 550                 555                 560 


Leu Pro Cys His Pro Glu Cys Gln Pro Gln Asn Gly Ser Val Thr Cys 
                565                 570                 575     


Phe Gly Pro Glu Ala Asp Gln Cys Val Ala Cys Ala His Tyr Lys Asp 
            580                 585                 590         


Pro Pro Phe Cys Val Ala Arg Cys Pro Ser Gly Val Lys Pro Asp Leu 
        595                 600                 605             


Ser Tyr Met Pro Ile Trp Lys Phe Pro Asp Glu Glu Gly Ala Cys Gln 
    610                 615                 620                 


Pro Cys Pro Ile Asn Cys Thr His Ser Cys Val Asp Leu Asp Asp Lys 
625                 630                 635                 640 


Gly Cys Pro Ala Glu Gln Arg Ala Ser Pro Leu Thr Ser Ile Ile Ser 
                645                 650                 655     


Ala Val Val Gly Ile Leu Leu Val Val Val Leu Gly Val Val Phe Gly 
            660                 665                 670         


Ile Leu Ile Lys Arg Arg Gln Gln Lys Ile Arg Lys Tyr Thr Met Arg 
        675                 680                 685             


Arg Leu Leu Gln Glu Thr Glu Leu Val Glu Pro Leu Thr Pro Ser Gly 
    690                 695                 700                 


Ala Met Pro Asn Gln Ala Gln Met Arg Ile Leu Lys Glu Thr Glu Leu 
705                 710                 715                 720 


Arg Lys Val Lys Val Leu Gly Ser Gly Ala Phe Gly Thr Val Tyr Lys 
                725                 730                 735     


Gly Ile Trp Ile Pro Asp Gly Glu Asn Val Lys Ile Pro Val Ala Ile 
            740                 745                 750         


Lys Val Leu Arg Glu Asn Thr Ser Pro Lys Ala Asn Lys Glu Ile Leu 
        755                 760                 765             


Asp Glu Ala Tyr Val Met Ala Gly Val Gly Ser Pro Tyr Val Ser Arg 
    770                 775                 780                 


Leu Leu Gly Ile Cys Leu Thr Ser Thr Val Gln Leu Val Thr Gln Leu 
785                 790                 795                 800 


Met Pro Tyr Gly Cys Leu Leu Asp His Val Arg Glu Asn Arg Gly Arg 
                805                 810                 815     


Leu Gly Ser Gln Asp Leu Leu Asn Trp Cys Met Gln Ile Ala Lys Gly 
            820                 825                 830         


Met Ser Tyr Leu Glu Asp Val Arg Leu Val His Arg Asp Leu Ala Ala 
        835                 840                 845             


Arg Asn Val Leu Val Lys Ser Pro Asn His Val Lys Ile Thr Asp Phe 
    850                 855                 860                 


Gly Leu Ala Arg Leu Leu Asp Ile Asp Glu Thr Glu Tyr His Ala Asp 
865                 870                 875                 880 


Gly Gly Lys Val Pro Ile Lys Trp Met Ala Leu Glu Ser Ile Leu Arg 
                885                 890                 895     


Arg Arg Phe Thr His Gln Ser Asp Val Trp Ser Tyr Gly Val Thr Val 
            900                 905                 910         


Trp Glu Leu Met Thr Phe Gly Ala Lys Pro Tyr Asp Gly Ile Pro Ala 
        915                 920                 925             


Arg Glu Ile Pro Asp Leu Leu Glu Lys Gly Glu Arg Leu Pro Gln Pro 
    930                 935                 940                 


Pro Ile Cys Thr Ile Asp Val Tyr Met Ile Met Val Lys Cys Trp Met 
945                 950                 955                 960 


Ile Asp Ser Glu Cys Arg Pro Arg Phe Arg Glu Leu Val Ser Glu Phe 
                965                 970                 975     


Ser Arg Met Ala Arg Asp Pro Gln Arg Phe Val Val Ile Gln Asn Glu 
            980                 985                 990         


Asp Leu Gly Pro Ala Ser Pro Leu  Asp Ser Thr Phe Tyr  Arg Ser Leu 
        995                 1000                 1005             


Leu Glu  Asp Asp Asp Met Gly  Asp Leu Val Asp Ala  Glu Glu Tyr 
    1010                 1015                 1020             


Leu Val  Pro Gln Gln Gly Phe  Phe Cys Pro Asp Pro  Ala Pro Gly 
    1025                 1030                 1035             


Ala Gly  Gly Met Val His His  Arg His Arg Ser Ser  Ser Thr Arg 
    1040                 1045                 1050             


Ser Gly  Gly Gly Asp Leu Thr  Leu Gly Leu Glu Pro  Ser Glu Glu 
    1055                 1060                 1065             


Glu Ala  Pro Arg Ser Pro Leu  Ala Pro Ser Glu Gly  Ala Gly Ser 
    1070                 1075                 1080             


Asp Val  Phe Asp Gly Asp Leu  Gly Met Gly Ala Ala  Lys Gly Leu 
    1085                 1090                 1095             


Gln Ser  Leu Pro Thr His Asp  Pro Ser Pro Leu Gln  Arg Tyr Ser 
    1100                 1105                 1110             


Glu Asp  Pro Thr Val Pro Leu  Pro Ser Glu Thr Asp  Gly Tyr Val 
    1115                 1120                 1125             


Ala Pro  Leu Thr Cys Ser Pro  Gln Pro Glu Tyr Val  Asn Gln Pro 
    1130                 1135                 1140             


Asp Val  Arg Pro Gln Pro Pro  Ser Pro Arg Glu Gly  Pro Leu Pro 
    1145                 1150                 1155             


Ala Ala  Arg Pro Ala Gly Ala  Thr Leu Glu Arg Pro  Lys Thr Leu 
    1160                 1165                 1170             


Ser Pro  Gly Lys Asn Gly Val  Val Lys Asp Val Phe  Ala Phe Gly 
    1175                 1180                 1185             


Gly Ala  Val Glu Asn Pro Glu  Tyr Leu Thr Pro Gln  Gly Gly Ala 
    1190                 1195                 1200             


Ala Pro  Gln Pro His Pro Pro  Pro Ala Phe Ser Pro  Ala Phe Asp 
    1205                 1210                 1215             


Asn Leu  Tyr Tyr Trp Asp Gln  Asp Pro Pro Glu Arg  Gly Ala Pro 
    1220                 1225                 1230             


Pro Ser  Thr Phe Lys Gly Thr  Pro Thr Ala Glu Asn  Pro Glu Tyr 
    1235                 1240                 1245             


Leu Gly  Leu Asp Val Pro Val  
    1250                 1255 


<210>  3
<211>  3780
<212>  DNA
<213>  Canis familiaris

<220>
<223>  Canine HER2, NM_001003217.1

<400>  3
atggagctgg cggcctggtg ccgctggggg ctccttctcg ccctcctgcc ctccggagcc       60

gcgggcaccc aagtgtgcac cggcacagac atgaagctcc ggctcccggc cagtcccgag      120

acccacctgg atatgctccg ccacctgtac cagggctgtc aagtggtaca ggggaacctg      180

gagctcactt acctgcctgc caatgccagc ctgtccttcc tgcaggatat ccaggaggtg      240

cagggctatg tgctcattgc tcacagccaa gtgaggcaga tcccactgca gaggctacga      300

attgtgcgag gcacccagct ctttgaggac aactacgccc tggccgtgct ggacaatgga      360

gacccgctgg agggtggcat ccctgcacca ggggcggccc aaggagggct gcgggagctg      420

cagcttcgaa gcctcacaga gatcctgaag ggaggggtct tgattcagcg gagcccgcag      480

ctctgccacc aggacacgat tttatggaag gacgtcttcc ataagaacaa ccagctggcc      540

ctcacgctga tagacaccaa ccgcttttcg gcctgcccgc cctgttctcc agcttgtaaa      600

gacgcccact gctggggggc cagctccggg gactgtcaga gcttgacgcg gactgtctgt      660

gccgggggct gtgcccgctg caagggccca caacccaccg actgctgcca cgagcagtgt      720

gctgctggct gcacgggccc caagcactct gactgcctgg cctgccttca cttcaaccac      780

agtggcatct gtgagctgca ctgcccagcc ctggtcacct acaacacgga caccttcgaa      840

tccatgccca accctgaggg ccgatatacc ttcggggcca gctgtgtgac ctcctgtccc      900

tacaactacc tgtctacgga tgtgggatcc tgcaccctgg tctgtcccct gaacaaccaa      960

gaggtgacgg ctgaggatgg gacacagcgg tgcgagaaat gcagcaagcc ctgtgcccga     1020

gtgtgctacg gtctgggcat ggagcacctg cgagaggtga gagcggtcac cagtgcgaac     1080

atccaggagt ttgccggctg caagaagatc tttggaagcc tggcattttt gccagagagc     1140

tttgatgggg acccagcctc caacactgcc cccctacagc ctgagcagct cagagtgttt     1200

gaggctctgg aggagatcac aggttacctg tacatctcag cgtggccaga cagcctgcct     1260

aacctcagtg tcttccagaa cctgcgagta atccggggac gagttctgca tgatggtgcc     1320

tactcgctga ccctgcaagg gctgggcatc agctggctgg ggctgcgctc gctgcgggaa     1380

ctgggcagtg ggctggccct catccaccgc aacgcccgcc tttgcttcgt gcacacggtg     1440

ccctgggacc agctcttccg gaacccccac caggccctgc tccatagtgc caaccggcca     1500

gaggaggagt gcgtgggcga gggcctggcc tgctacccct gtgcccatgg gcactgctgg     1560

ggtccagggc ccacccagtg cgtcaactgc agccaattcc tccggggcca ggagtgcgtg     1620

gaggaatgcc gagtactgca ggggctgccc cgagagtatg tgaaggacag gtactgtcta     1680

ccgtgccact cagagtgtca gccccagaat ggctcagtga cctgtttcgg atcggaggct     1740

gaccagtgtg tggcctgcgc ccactacaag gaccctccct tctgtgtggc tcgctgcccc     1800

agtggtgtga aacctgacct gtccttcatg cccatctgga agttcgcaga tgaggagggc     1860

acttgccagc cgtgccccat caactgcacc cactcctgtg cggacctgga cgagaagggc     1920

tgtcccgccg agcagagagc cagccctgtg acatccatca ttgccgctgt ggtgggcatt     1980

ctgctggctg tggtcgtggg gctggtcctc ggcatcctga tcaagcgaag gcggcagaag     2040

atccggaagt acactatgcg gaggctgctg caggaaaccg agctggtgga gccgctgacg     2100

cctagtggag cgatgcccaa ccaggctcag atgcggatcc tgaaagagac agagctgagg     2160

aaggtgaagg tgcttggatc cggagctttt ggcacagtct acaagggcat ctggatccct     2220

gatggggaaa atgtgaaaat cccagtggcc atcaaagtgt tgagggaaaa cacatctccc     2280

aaagccaaca aagaaatctt ggacgaagca tatgtgatgg ctggagtggg ctccccgtat     2340

gtgtcccgcc tcctgggcat ctgcctgaca tccacggtgc agctggtgac acagcttatg     2400

ccctacggct gcctcttaga ccatgtccga gaacaccgtg ggcgcctggg ctcccaggac     2460

ttgctgaact ggtgtgtgca gattgccaag gggatgagct acttggagga tgtccggctg     2520

gtgcacaggg acctggctgc ccggaatgtg ctggtcaaga gtcccaacca tgtcaagatt     2580

acagatttcg ggctggctcg gttgctggac atcgacgaga cagagtacca tgcggatggg     2640

ggcaaggtgc ccatcaagtg gatggcgctg gagtccattc ctccgcggcg gttcacccac     2700

cagagtgatg tgtggagcta tggtgtgact gtgtgggaac tgatgacttt tggggccaaa     2760

ccttatgatg ggatcccagc ccgggagatc cctgacctgc tggagaaggg ggaacggctg     2820

ccccagcccc ccatctgcac cattgatgtc tacatgatca tggtcaagtg ctggatgata     2880

gactctgaat gccgaccccg gttccgggag ttggtggccg aattctcacg tatggccagg     2940

gacccccagc gctttgtggt cattcagaat gaagacttgg gccccgccag ccccttggac     3000

agcaccttct accgttcact actggaagat gatgacatgg gggacctggt ggatgctgag     3060

gagtacctgg taccccagca gggtttcttc tgcccagaac ctaccccagg ggctgggggc     3120

actgcccacc gacggcaccg cagctcatcc accaggaatg gcggtggtga gctgactcta     3180

ggactggagc cctccgagga ggagcccccc aagtctccac tggcaccctc agagggcgct     3240

ggctctgacg tgtttgatgg tgacttggga atgggggcag ccaaggggct gcagagcctt     3300

ccctcacagg accccagccc tctccagcgg tacagtgagg accctacggt acccttgccc     3360

cctgagactg atggtaaggt tgcccccctg acctgcagcc cccagcctga atatgtgaac     3420

cagccagaag tttggccgca gccccccctt gccctagaag gccctttgcc tccttcccga     3480

ccggctggtg ccactctgga aaggcccaag actctgtccc ccaagactct ctcccctggc     3540

aagaatgggg ttgtcaaaga cgtttttgcc tttgggagtg ctgtggagaa tccggagtac     3600

ctggcacccc ggggcagagc tgcccctcag ccccaccctc ctccagcctt cagcccagcc     3660

tttgacaacc tgtattactg ggaccaggat ccatcagagc ggggctctcc acccagcacc     3720

tttgaaggga cccctacagc agagaacccg gagtacctgg ggctggacgt gccagtgtga     3780


<210>  4
<211>  1259
<212>  PRT
<213>  Canis familiaris

<220>
<223>  Canine HER2, NP_001003217.1

<400>  4

Met Glu Leu Ala Ala Trp Cys Arg Trp Gly Leu Leu Leu Ala Leu Leu 
1               5                   10                  15      


Pro Ser Gly Ala Ala Gly Thr Gln Val Cys Thr Gly Thr Asp Met Lys 
            20                  25                  30          


Leu Arg Leu Pro Ala Ser Pro Glu Thr His Leu Asp Met Leu Arg His 
        35                  40                  45              


Leu Tyr Gln Gly Cys Gln Val Val Gln Gly Asn Leu Glu Leu Thr Tyr 
    50                  55                  60                  


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


Gln Gly Tyr Val Leu Ile Ala His Ser Gln Val Arg Gln Ile Pro Leu 
                85                  90                  95      


Gln Arg Leu Arg Ile Val Arg Gly Thr Gln Leu Phe Glu Asp Asn Tyr 
            100                 105                 110         


Ala Leu Ala Val Leu Asp Asn Gly Asp Pro Leu Glu Gly Gly Ile Pro 
        115                 120                 125             


Ala Pro Gly Ala Ala Gln Gly Gly Leu Arg Glu Leu Gln Leu Arg Ser 
    130                 135                 140                 


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


Leu Cys His Gln Asp Thr Ile Leu Trp Lys Asp Val Phe His Lys Asn 
                165                 170                 175     


Asn Gln Leu Ala Leu Thr Leu Ile Asp Thr Asn Arg Phe Ser Ala Cys 
            180                 185                 190         


Pro Pro Cys Ser Pro Ala Cys Lys Asp Ala His Cys Trp Gly Ala Ser 
        195                 200                 205             


Ser Gly Asp Cys Gln Ser Leu Thr Arg Thr Val Cys Ala Gly Gly Cys 
    210                 215                 220                 


Ala Arg Cys Lys Gly Pro Gln Pro Thr Asp Cys Cys His Glu Gln Cys 
225                 230                 235                 240 


Ala Ala Gly Cys Thr Gly Pro Lys His Ser Asp Cys Leu Ala Cys Leu 
                245                 250                 255     


His Phe Asn His Ser Gly Ile Cys Glu Leu His Cys Pro Ala Leu Val 
            260                 265                 270         


Thr Tyr Asn Thr Asp Thr Phe Glu Ser Met Pro Asn Pro Glu Gly Arg 
        275                 280                 285             


Tyr Thr Phe Gly Ala Ser Cys Val Thr Ser Cys Pro Tyr Asn Tyr Leu 
    290                 295                 300                 


Ser Thr Asp Val Gly Ser Cys Thr Leu Val Cys Pro Leu Asn Asn Gln 
305                 310                 315                 320 


Glu Val Thr Ala Glu Asp Gly Thr Gln Arg Cys Glu Lys Cys Ser Lys 
                325                 330                 335     


Pro Cys Ala Arg Val Cys Tyr Gly Leu Gly Met Glu His Leu Arg Glu 
            340                 345                 350         


Val Arg Ala Val Thr Ser Ala Asn Ile Gln Glu Phe Ala Gly Cys Lys 
        355                 360                 365             


Lys Ile Phe Gly Ser Leu Ala Phe Leu Pro Glu Ser Phe Asp Gly Asp 
    370                 375                 380                 


Pro Ala Ser Asn Thr Ala Pro Leu Gln Pro Glu Gln Leu Arg Val Phe 
385                 390                 395                 400 


Glu Ala Leu Glu Glu Ile Thr Gly Tyr Leu Tyr Ile Ser Ala Trp Pro 
                405                 410                 415     


Asp Ser Leu Pro Asn Leu Ser Val Phe Gln Asn Leu Arg Val Ile Arg 
            420                 425                 430         


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


Gly Ile Ser Trp Leu Gly Leu Arg Ser Leu Arg Glu Leu Gly Ser Gly 
    450                 455                 460                 


Leu Ala Leu Ile His Arg Asn Ala Arg Leu Cys Phe Val His Thr Val 
465                 470                 475                 480 


Pro Trp Asp Gln Leu Phe Arg Asn Pro His Gln Ala Leu Leu His Ser 
                485                 490                 495     


Ala Asn Arg Pro Glu Glu Glu Cys Val Gly Glu Gly Leu Ala Cys Tyr 
            500                 505                 510         


Pro Cys Ala His Gly His Cys Trp Gly Pro Gly Pro Thr Gln Cys Val 
        515                 520                 525             


Asn Cys Ser Gln Phe Leu Arg Gly Gln Glu Cys Val Glu Glu Cys Arg 
    530                 535                 540                 


Val Leu Gln Gly Leu Pro Arg Glu Tyr Val Lys Asp Arg Tyr Cys Leu 
545                 550                 555                 560 


Pro Cys His Ser Glu Cys Gln Pro Gln Asn Gly Ser Val Thr Cys Phe 
                565                 570                 575     


Gly Ser Glu Ala Asp Gln Cys Val Ala Cys Ala His Tyr Lys Asp Pro 
            580                 585                 590         


Pro Phe Cys Val Ala Arg Cys Pro Ser Gly Val Lys Pro Asp Leu Ser 
        595                 600                 605             


Phe Met Pro Ile Trp Lys Phe Ala Asp Glu Glu Gly Thr Cys Gln Pro 
    610                 615                 620                 


Cys Pro Ile Asn Cys Thr His Ser Cys Ala Asp Leu Asp Glu Lys Gly 
625                 630                 635                 640 


Cys Pro Ala Glu Gln Arg Ala Ser Pro Val Thr Ser Ile Ile Ala Ala 
                645                 650                 655     


Val Val Gly Ile Leu Leu Ala Val Val Val Gly Leu Val Leu Gly Ile 
            660                 665                 670         


Leu Ile Lys Arg Arg Arg Gln Lys Ile Arg Lys Tyr Thr Met Arg Arg 
        675                 680                 685             


Leu Leu Gln Glu Thr Glu Leu Val Glu Pro Leu Thr Pro Ser Gly Ala 
    690                 695                 700                 


Met Pro Asn Gln Ala Gln Met Arg Ile Leu Lys Glu Thr Glu Leu Arg 
705                 710                 715                 720 


Lys Val Lys Val Leu Gly Ser Gly Ala Phe Gly Thr Val Tyr Lys Gly 
                725                 730                 735     


Ile Trp Ile Pro Asp Gly Glu Asn Val Lys Ile Pro Val Ala Ile Lys 
            740                 745                 750         


Val Leu Arg Glu Asn Thr Ser Pro Lys Ala Asn Lys Glu Ile Leu Asp 
        755                 760                 765             


Glu Ala Tyr Val Met Ala Gly Val Gly Ser Pro Tyr Val Ser Arg Leu 
    770                 775                 780                 


Leu Gly Ile Cys Leu Thr Ser Thr Val Gln Leu Val Thr Gln Leu Met 
785                 790                 795                 800 


Pro Tyr Gly Cys Leu Leu Asp His Val Arg Glu His Arg Gly Arg Leu 
                805                 810                 815     


Gly Ser Gln Asp Leu Leu Asn Trp Cys Val Gln Ile Ala Lys Gly Met 
            820                 825                 830         


Ser Tyr Leu Glu Asp Val Arg Leu Val His Arg Asp Leu Ala Ala Arg 
        835                 840                 845             


Asn Val Leu Val Lys Ser Pro Asn His Val Lys Ile Thr Asp Phe Gly 
    850                 855                 860                 


Leu Ala Arg Leu Leu Asp Ile Asp Glu Thr Glu Tyr His Ala Asp Gly 
865                 870                 875                 880 


Gly Lys Val Pro Ile Lys Trp Met Ala Leu Glu Ser Ile Pro Pro Arg 
                885                 890                 895     


Arg Phe Thr His Gln Ser Asp Val Trp Ser Tyr Gly Val Thr Val Trp 
            900                 905                 910         


Glu Leu Met Thr Phe Gly Ala Lys Pro Tyr Asp Gly Ile Pro Ala Arg 
        915                 920                 925             


Glu Ile Pro Asp Leu Leu Glu Lys Gly Glu Arg Leu Pro Gln Pro Pro 
    930                 935                 940                 


Ile Cys Thr Ile Asp Val Tyr Met Ile Met Val Lys Cys Trp Met Ile 
945                 950                 955                 960 


Asp Ser Glu Cys Arg Pro Arg Phe Arg Glu Leu Val Ala Glu Phe Ser 
                965                 970                 975     


Arg Met Ala Arg Asp Pro Gln Arg Phe Val Val Ile Gln Asn Glu Asp 
            980                 985                 990         


Leu Gly Pro Ala Ser Pro Leu Asp  Ser Thr Phe Tyr Arg  Ser Leu Leu 
        995                 1000                 1005             


Glu Asp  Asp Asp Met Gly Asp  Leu Val Asp Ala Glu  Glu Tyr Leu 
    1010                 1015                 1020             


Val Pro  Gln Gln Gly Phe Phe  Cys Pro Glu Pro Thr  Pro Gly Ala 
    1025                 1030                 1035             


Gly Gly  Thr Ala His Arg Arg  His Arg Ser Ser Ser  Thr Arg Asn 
    1040                 1045                 1050             


Gly Gly  Gly Glu Leu Thr Leu  Gly Leu Glu Pro Ser  Glu Glu Glu 
    1055                 1060                 1065             


Pro Pro  Lys Ser Pro Leu Ala  Pro Ser Glu Gly Ala  Gly Ser Asp 
    1070                 1075                 1080             


Val Phe  Asp Gly Asp Leu Gly  Met Gly Ala Ala Lys  Gly Leu Gln 
    1085                 1090                 1095             


Ser Leu  Pro Ser Gln Asp Pro  Ser Pro Leu Gln Arg  Tyr Ser Glu 
    1100                 1105                 1110             


Asp Pro  Thr Val Pro Leu Pro  Pro Glu Thr Asp Gly  Lys Val Ala 
    1115                 1120                 1125             


Pro Leu  Thr Cys Ser Pro Gln  Pro Glu Tyr Val Asn  Gln Pro Glu 
    1130                 1135                 1140             


Val Trp  Pro Gln Pro Pro Leu  Ala Leu Glu Gly Pro  Leu Pro Pro 
    1145                 1150                 1155             


Ser Arg  Pro Ala Gly Ala Thr  Leu Glu Arg Pro Lys  Thr Leu Ser 
    1160                 1165                 1170             


Pro Lys  Thr Leu Ser Pro Gly  Lys Asn Gly Val Val  Lys Asp Val 
    1175                 1180                 1185             


Phe Ala  Phe Gly Ser Ala Val  Glu Asn Pro Glu Tyr  Leu Ala Pro 
    1190                 1195                 1200             


Arg Gly  Arg Ala Ala Pro Gln  Pro His Pro Pro Pro  Ala Phe Ser 
    1205                 1210                 1215             


Pro Ala  Phe Asp Asn Leu Tyr  Tyr Trp Asp Gln Asp  Pro Ser Glu 
    1220                 1225                 1230             


Arg Gly  Ser Pro Pro Ser Thr  Phe Glu Gly Thr Pro  Thr Ala Glu 
    1235                 1240                 1245             


Asn Pro  Glu Tyr Leu Gly Leu  Asp Val Pro Val 
    1250                 1255                 


<210>  5
<211>  460
<212>  PRT
<213>  Artificial Sequence

<220>
<223>  Trastuzumab LC-(G4S)2AS linker- C825 VH-G4S linker-C825 VL

<400>  5

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


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


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


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


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


Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln His Tyr Thr Thr Pro Pro 
                85                  90                  95      


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


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


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


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


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


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


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


Phe Asn Arg Gly Glu Cys Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser 
    210                 215                 220                 


Ala Ser His Val Lys Leu Gln Glu Ser Gly Pro Gly Leu Val Gln Pro 
225                 230                 235                 240 


Ser Gln Ser Leu Ser Leu Thr Cys Thr Val Ser Gly Phe Ser Leu Thr 
                245                 250                 255     


Asp Tyr Gly Val His Trp Val Arg Gln Ser Pro Gly Lys Gly Leu Glu 
            260                 265                 270         


Trp Leu Gly Val Ile Trp Ser Gly Gly Gly Thr Ala Tyr Asn Thr Ala 
        275                 280                 285             


Leu Ile Ser Arg Leu Asn Ile Tyr Arg Asp Asn Ser Lys Asn Gln Val 
    290                 295                 300                 


Phe Leu Glu Met Asn Ser Leu Gln Ala Glu Asp Thr Ala Met Tyr Tyr 
305                 310                 315                 320 


Cys Ala Arg Arg Gly Ser Tyr Pro Tyr Asn Tyr Phe Asp Ala Trp Gly 
                325                 330                 335     


Cys Gly Thr Thr Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gln Ala 
            340                 345                 350         


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


Thr Leu Thr Cys Gly Ser Ser Thr Gly Ala Val Thr Ala Ser Asn Tyr 
    370                 375                 380                 


Ala Asn Trp Val Gln Glu Lys Pro Asp His Cys Phe Thr Gly Leu Ile 
385                 390                 395                 400 


Gly Gly His Asn Asn Arg Pro Pro Gly Val Pro Ala Arg Phe Ser Gly 
                405                 410                 415     


Ser Leu Ile Gly Asp Lys Ala Ala Leu Thr Ile Ala Gly Thr Gln Thr 
            420                 425                 430         


Glu Asp Glu Ala Ile Tyr Phe Cys Ala Leu Trp Tyr Ser Asp His Trp 
        435                 440                 445             


Val Ile Gly Gly Gly Thr Arg Leu Thr Val Leu Gly 
    450                 455                 460 


<210>  6
<211>  465
<212>  PRT
<213>  Artificial Sequence

<220>
<223>  Trastuzumab LC-(G4S)2AS linker- C825 VH-(G4S)2 linker-C825 VL

<400>  6

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


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


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


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


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


Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln His Tyr Thr Thr Pro Pro 
                85                  90                  95      


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


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


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


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


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


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


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


Phe Asn Arg Gly Glu Cys Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser 
    210                 215                 220                 


Ala Ser His Val Lys Leu Gln Glu Ser Gly Pro Gly Leu Val Gln Pro 
225                 230                 235                 240 


Ser Gln Ser Leu Ser Leu Thr Cys Thr Val Ser Gly Phe Ser Leu Thr 
                245                 250                 255     


Asp Tyr Gly Val His Trp Val Arg Gln Ser Pro Gly Lys Gly Leu Glu 
            260                 265                 270         


Trp Leu Gly Val Ile Trp Ser Gly Gly Gly Thr Ala Tyr Asn Thr Ala 
        275                 280                 285             


Leu Ile Ser Arg Leu Asn Ile Tyr Arg Asp Asn Ser Lys Asn Gln Val 
    290                 295                 300                 


Phe Leu Glu Met Asn Ser Leu Gln Ala Glu Asp Thr Ala Met Tyr Tyr 
305                 310                 315                 320 


Cys Ala Arg Arg Gly Ser Tyr Pro Tyr Asn Tyr Phe Asp Ala Trp Gly 
                325                 330                 335     


Cys Gly Thr Thr Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly 
            340                 345                 350         


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


Pro Gly Glu Thr Val Thr Leu Thr Cys Gly Ser Ser Thr Gly Ala Val 
    370                 375                 380                 


Thr Ala Ser Asn Tyr Ala Asn Trp Val Gln Glu Lys Pro Asp His Cys 
385                 390                 395                 400 


Phe Thr Gly Leu Ile Gly Gly His Asn Asn Arg Pro Pro Gly Val Pro 
                405                 410                 415     


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


Ala Gly Thr Gln Thr Glu Asp Glu Ala Ile Tyr Phe Cys Ala Leu Trp 
        435                 440                 445             


Tyr Ser Asp His Trp Val Ile Gly Gly Gly Thr Arg Leu Thr Val Leu 
    450                 455                 460                 


Gly 
465 


<210>  7
<211>  470
<212>  PRT
<213>  Artificial Sequence

<220>
<223>  Trastuzumab LC-(G4S)2AS linker- C825 VH-(G4S)3 linker-C825 VL

<400>  7

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


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


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


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


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


Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln His Tyr Thr Thr Pro Pro 
                85                  90                  95      


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


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


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


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


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


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


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


Phe Asn Arg Gly Glu Cys Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser 
    210                 215                 220                 


Ala Ser His Val Lys Leu Gln Glu Ser Gly Pro Gly Leu Val Gln Pro 
225                 230                 235                 240 


Ser Gln Ser Leu Ser Leu Thr Cys Thr Val Ser Gly Phe Ser Leu Thr 
                245                 250                 255     


Asp Tyr Gly Val His Trp Val Arg Gln Ser Pro Gly Lys Gly Leu Glu 
            260                 265                 270         


Trp Leu Gly Val Ile Trp Ser Gly Gly Gly Thr Ala Tyr Asn Thr Ala 
        275                 280                 285             


Leu Ile Ser Arg Leu Asn Ile Tyr Arg Asp Asn Ser Lys Asn Gln Val 
    290                 295                 300                 


Phe Leu Glu Met Asn Ser Leu Gln Ala Glu Asp Thr Ala Met Tyr Tyr 
305                 310                 315                 320 


Cys Ala Arg Arg Gly Ser Tyr Pro Tyr Asn Tyr Phe Asp Ala Trp Gly 
                325                 330                 335     


Cys Gly Thr Thr Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly 
            340                 345                 350         


Gly Gly Ser Gly Gly Gly Gly Ser Gln Ala Val Val Ile Gln Glu Ser 
        355                 360                 365             


Ala Leu Thr Thr Pro Pro Gly Glu Thr Val Thr Leu Thr Cys Gly Ser 
    370                 375                 380                 


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


Lys Pro Asp His Cys Phe Thr Gly Leu Ile Gly Gly His Asn Asn Arg 
                405                 410                 415     


Pro Pro Gly Val Pro Ala Arg Phe Ser Gly Ser Leu Ile Gly Asp Lys 
            420                 425                 430         


Ala Ala Leu Thr Ile Ala Gly Thr Gln Thr Glu Asp Glu Ala Ile Tyr 
        435                 440                 445             


Phe Cys Ala Leu Trp Tyr Ser Asp His Trp Val Ile Gly Gly Gly Thr 
    450                 455                 460                 


Arg Leu Thr Val Leu Gly 
465                 470 


<210>  8
<211>  475
<212>  PRT
<213>  Artificial Sequence

<220>
<223>  Trastuzumab LC-(G4S)2AS linker- C825 VH-(G4S)4 linker-C825 VL

<400>  8

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


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


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


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


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


Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln His Tyr Thr Thr Pro Pro 
                85                  90                  95      


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


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


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


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


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


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


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


Phe Asn Arg Gly Glu Cys Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser 
    210                 215                 220                 


Ala Ser His Val Lys Leu Gln Glu Ser Gly Pro Gly Leu Val Gln Pro 
225                 230                 235                 240 


Ser Gln Ser Leu Ser Leu Thr Cys Thr Val Ser Gly Phe Ser Leu Thr 
                245                 250                 255     


Asp Tyr Gly Val His Trp Val Arg Gln Ser Pro Gly Lys Gly Leu Glu 
            260                 265                 270         


Trp Leu Gly Val Ile Trp Ser Gly Gly Gly Thr Ala Tyr Asn Thr Ala 
        275                 280                 285             


Leu Ile Ser Arg Leu Asn Ile Tyr Arg Asp Asn Ser Lys Asn Gln Val 
    290                 295                 300                 


Phe Leu Glu Met Asn Ser Leu Gln Ala Glu Asp Thr Ala Met Tyr Tyr 
305                 310                 315                 320 


Cys Ala Arg Arg Gly Ser Tyr Pro Tyr Asn Tyr Phe Asp Ala Trp Gly 
                325                 330                 335     


Cys Gly Thr Thr Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly 
            340                 345                 350         


Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gln Ala Val 
        355                 360                 365             


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


Leu Thr Cys Gly Ser Ser Thr Gly Ala Val Thr Ala Ser Asn Tyr Ala 
385                 390                 395                 400 


Asn Trp Val Gln Glu Lys Pro Asp His Cys Phe Thr Gly Leu Ile Gly 
                405                 410                 415     


Gly His Asn Asn Arg Pro Pro Gly Val Pro Ala Arg Phe Ser Gly Ser 
            420                 425                 430         


Leu Ile Gly Asp Lys Ala Ala Leu Thr Ile Ala Gly Thr Gln Thr Glu 
        435                 440                 445             


Asp Glu Ala Ile Tyr Phe Cys Ala Leu Trp Tyr Ser Asp His Trp Val 
    450                 455                 460                 


Ile Gly Gly Gly Thr Arg Leu Thr Val Leu Gly 
465                 470                 475 


<210>  9
<211>  480
<212>  PRT
<213>  Artificial Sequence

<220>
<223>  Trastuzumab LC-(G4S)2AS linker- C825 VH-(G4S)5 linker-C825 VL

<400>  9

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


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


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


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


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


Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln His Tyr Thr Thr Pro Pro 
                85                  90                  95      


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


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


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


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


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


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


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


Phe Asn Arg Gly Glu Cys Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser 
    210                 215                 220                 


Ala Ser His Val Lys Leu Gln Glu Ser Gly Pro Gly Leu Val Gln Pro 
225                 230                 235                 240 


Ser Gln Ser Leu Ser Leu Thr Cys Thr Val Ser Gly Phe Ser Leu Thr 
                245                 250                 255     


Asp Tyr Gly Val His Trp Val Arg Gln Ser Pro Gly Lys Gly Leu Glu 
            260                 265                 270         


Trp Leu Gly Val Ile Trp Ser Gly Gly Gly Thr Ala Tyr Asn Thr Ala 
        275                 280                 285             


Leu Ile Ser Arg Leu Asn Ile Tyr Arg Asp Asn Ser Lys Asn Gln Val 
    290                 295                 300                 


Phe Leu Glu Met Asn Ser Leu Gln Ala Glu Asp Thr Ala Met Tyr Tyr 
305                 310                 315                 320 


Cys Ala Arg Arg Gly Ser Tyr Pro Tyr Asn Tyr Phe Asp Ala Trp Gly 
                325                 330                 335     


Cys Gly Thr Thr Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly 
            340                 345                 350         


Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly 
        355                 360                 365             


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


Gly Glu Thr Val Thr Leu Thr Cys Gly Ser Ser Thr Gly Ala Val Thr 
385                 390                 395                 400 


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


Thr Gly Leu Ile Gly Gly His Asn Asn Arg Pro Pro Gly Val Pro Ala 
            420                 425                 430         


Arg Phe Ser Gly Ser Leu Ile Gly Asp Lys Ala Ala Leu Thr Ile Ala 
        435                 440                 445             


Gly Thr Gln Thr Glu Asp Glu Ala Ile Tyr Phe Cys Ala Leu Trp Tyr 
    450                 455                 460                 


Ser Asp His Trp Val Ile Gly Gly Gly Thr Arg Leu Thr Val Leu Gly 
465                 470                 475                 480 


<210>  10
<211>  485
<212>  PRT
<213>  Artificial Sequence

<220>
<223>  Trastuzumab LC-(G4S)2AS linker- C825 VH-(G4S)6 linker-C825 VL

<400>  10

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


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


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


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


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


Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln His Tyr Thr Thr Pro Pro 
                85                  90                  95      


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


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


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


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


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


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


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


Phe Asn Arg Gly Glu Cys Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser 
    210                 215                 220                 


Ala Ser His Val Lys Leu Gln Glu Ser Gly Pro Gly Leu Val Gln Pro 
225                 230                 235                 240 


Ser Gln Ser Leu Ser Leu Thr Cys Thr Val Ser Gly Phe Ser Leu Thr 
                245                 250                 255     


Asp Tyr Gly Val His Trp Val Arg Gln Ser Pro Gly Lys Gly Leu Glu 
            260                 265                 270         


Trp Leu Gly Val Ile Trp Ser Gly Gly Gly Thr Ala Tyr Asn Thr Ala 
        275                 280                 285             


Leu Ile Ser Arg Leu Asn Ile Tyr Arg Asp Asn Ser Lys Asn Gln Val 
    290                 295                 300                 


Phe Leu Glu Met Asn Ser Leu Gln Ala Glu Asp Thr Ala Met Tyr Tyr 
305                 310                 315                 320 


Cys Ala Arg Arg Gly Ser Tyr Pro Tyr Asn Tyr Phe Asp Ala Trp Gly 
                325                 330                 335     


Cys Gly Thr Thr Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly 
            340                 345                 350         


Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly 
        355                 360                 365             


Gly Ser Gly Gly Gly Gly Ser Gln Ala Val Val Ile Gln Glu Ser Ala 
    370                 375                 380                 


Leu Thr Thr Pro Pro Gly Glu Thr Val Thr Leu Thr Cys Gly Ser Ser 
385                 390                 395                 400 


Thr Gly Ala Val Thr Ala Ser Asn Tyr Ala Asn Trp Val Gln Glu Lys 
                405                 410                 415     


Pro Asp His Cys Phe Thr Gly Leu Ile Gly Gly His Asn Asn Arg Pro 
            420                 425                 430         


Pro Gly Val Pro Ala Arg Phe Ser Gly Ser Leu Ile Gly Asp Lys Ala 
        435                 440                 445             


Ala Leu Thr Ile Ala Gly Thr Gln Thr Glu Asp Glu Ala Ile Tyr Phe 
    450                 455                 460                 


Cys Ala Leu Trp Tyr Ser Asp His Trp Val Ile Gly Gly Gly Thr Arg 
465                 470                 475                 480 


Leu Thr Val Leu Gly 
                485 


<210>  11
<211>  214
<212>  PRT
<213>  Artificial Sequence

<220>
<223>  Trastuzumab light chain

<400>  11

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


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


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


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


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


Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln His Tyr Thr Thr Pro Pro 
                85                  90                  95      


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


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


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


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


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


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


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


Phe Asn Arg Gly Glu Cys 
    210                 


<210>  12
<211>  1350
<212>  DNA
<213>  Artificial Sequence

<220>
<223>  Nucleic acid encoding Trastuzumab VH with human IgG1 constant 
       region and N297A

<400>  12
gaagtgcagc tggtcgagag cggaggaggt ctggtgcagc ccggaggttc cctgagactg       60

tcctgtgccg catctgggtt taatatcaag gacacataca tccactgggt gagacaggca      120

cccggcaaag gactggagtg ggtcgccagg atctacccta ccaacgggta cacaagatat      180

gctgactctg tgaagggccg gttcaccatc tccgccgata ctagcaaaaa caccgcttac      240

ctgcagatga attccctgag ggcagaagat accgctgtct actactgttc aagatggggg      300

ggggatggtt tttacgctat ggattattgg ggccagggca ccctggtgac cgtgtcctcc      360

gcctccacca agggcccatc ggtcttcccc ctggcaccct cctccaagag cacctctggg      420

ggcacagcgg ccctgggctg cctggtcaag gactacttcc ccgaaccggt gacggtgtcg      480

tggaactcag gcgccctgac cagcggcgtg cacaccttcc cggccgtcct acagtcctca      540

ggactctact ccctcagcag cgtggtgacc gtgccctcca gcagcttggg cacccagacc      600

tacatctgca acgtgaatca caagcccagc aacaccaagg tggacaagag agttgagccc      660

aaatcttgtg acaaaactca cacatgccca ccgtgcccag cacctgaact cctgggggga      720

ccgtcagtct tcctcttccc cccaaaaccc aaggacaccc tcatgatctc ccggacccct      780

gaggtcacat gcgtggtggt ggacgtgagc cacgaagacc ctgaggtcaa gttcaactgg      840

tacgtggacg gcgtggaggt gcataatgcc aagacaaagc cgcgggagga gcagtacgcc      900

agcacgtacc gtgtggtcag cgtcctcacc gtcctgcacc aggactggct gaatggcaag      960

gagtacaagt gcaaggtctc caacaaagcc ctcccagccc ccatcgagaa aaccatctcc     1020

aaagccaaag ggcagccccg agaaccacag gtgtacaccc tgcccccatc ccgggatgag     1080

ctgaccaaga accaggtcag cctgacctgc ctggtcaaag gcttctatcc cagcgacatc     1140

gccgtggagt gggagagcaa tgggcagccg gagaacaact acaagaccac gcctcccgtg     1200

ctggactccg acggctcctt cttcctctac agcaagctca ccgtggacaa gagcaggtgg     1260

cagcagggga acgtcttctc atgctccgtg atgcatgagg ctctgcacaa ccactacacg     1320

cagaagagcc tctccctgtc tccgggtaaa                                      1350


<210>  13
<211>  642
<212>  DNA
<213>  Artificial Sequence

<220>
<223>  Nucleic acid encoding Trastuzumab light chain

<400>  13
gatattcaga tgactcagtc tccctcttcc ctgtccgctt cagtcggcga tcgggtcact       60

attacttgtc gggcttcaca ggatgtcaac acagccgtgg cttggtacca gcagaagccc      120

gggaaagcac ctaagctgct gatctactct gccagtttcc tgtattctgg cgtcccaagt      180

aggttttcag gctcccggag cggaactgac ttcaccctga caatttccag cctgcagccc      240

gaggattttg ctacctacta ttgccagcag cattatacta cccccccaac attcggccag      300

ggcacaaaag tcgaaatcaa gcggaccgtg gccgccccct ccgtgttcat cttccccccc      360

tccgacgagc agctgaagtc cggcaccgcc tccgtggtgt gcctgctgaa caacttctac      420

ccccgggagg ccaaggtgca gtggaaggtg gacaacgccc tgcagtccgg caactcccag      480

gagtccgtga ccgagcagga ctccaaggac tccacctact ccctgtcctc caccctgacc      540

ctgtccaagg ccgactacga gaagcacaag gtgtacgcct gcgaggtgac ccaccagggc      600

ctgtcctccc ccgtgaccaa gtccttcaac cggggcgagt gc                         642


<210>  14
<211>  450
<212>  PRT
<213>  Artificial Sequence

<220>
<223>  Trastuzumab VH domain with human IgG1 constant region

<400>  14

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


Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Asn Ile Lys Asp Thr 
            20                  25                  30          


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


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


Lys Gly Arg Phe Thr Ile Ser Ala Asp Thr Ser Lys Asn Thr Ala Tyr 
65                  70                  75                  80  


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


Ser Arg Trp Gly Gly Asp Gly Phe Tyr Ala Met Asp Tyr Trp Gly Gln 
            100                 105                 110         


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


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


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


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


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


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


Pro Ser Asn Thr Lys Val Asp Lys Arg Val Glu 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>  15
<211>  450
<212>  PRT
<213>  Artificial Sequence

<220>
<223>  Trastuzumab VH with human IgG1 constant region and N297A

<400>  15

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


Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Asn Ile Lys Asp Thr 
            20                  25                  30          


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


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


Lys Gly Arg Phe Thr Ile Ser Ala Asp Thr Ser Lys Asn Thr Ala Tyr 
65                  70                  75                  80  


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


Ser Arg Trp Gly Gly Asp Gly Phe Tyr Ala Met Asp Tyr Trp Gly Gln 
            100                 105                 110         


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


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


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


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


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


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


Pro Ser Asn Thr Lys Val Asp Lys Arg Val Glu 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 Ala 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>  16
<211>  450
<212>  PRT
<213>  Artificial Sequence

<220>
<223>  Trastuzumab VH with human IgG1 constant region, N297A, and K322A

<400>  16

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


Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Asn Ile Lys Asp Thr 
            20                  25                  30          


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


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


Lys Gly Arg Phe Thr Ile Ser Ala Asp Thr Ser Lys Asn Thr Ala Tyr 
65                  70                  75                  80  


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


Ser Arg Trp Gly Gly Asp Gly Phe Tyr Ala Met Asp Tyr Trp Gly Gln 
            100                 105                 110         


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


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


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


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


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


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


Pro Ser Asn Thr Lys Val Asp Lys Arg Val Glu 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 Ala 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 Ala 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>  17
<211>  450
<212>  PRT
<213>  Artificial Sequence

<220>
<223>  Trastuzumab VH domain with human IgG1 constant region; K322A

<400>  17

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


Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Asn Ile Lys Asp Thr 
            20                  25                  30          


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


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


Lys Gly Arg Phe Thr Ile Ser Ala Asp Thr Ser Lys Asn Thr Ala Tyr 
65                  70                  75                  80  


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


Ser Arg Trp Gly Gly Asp Gly Phe Tyr Ala Met Asp Tyr Trp Gly Gln 
            100                 105                 110         


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


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


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


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


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


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


Pro Ser Asn Thr Lys Val Asp Lys Arg Val Glu 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 Ala 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>  18
<211>  1410
<212>  DNA
<213>  Artificial Sequence

<220>
<223>  Nucleic acid encoding Trastuzumab LC-(G4S)2AS linker- C825 
       VH-(G4S)3 linker-C825 VL

<400>  18
gatattcaga tgactcagtc tccctcttcc ctgtccgctt cagtcggcga tcgggtcact       60

attacttgtc gggcttcaca ggatgtcaac acagccgtgg cttggtacca gcagaagccc      120

gggaaagcac ctaagctgct gatctactct gccagtttcc tgtattctgg cgtcccaagt      180

aggttttcag gctcccggag cggaactgac ttcaccctga caatttccag cctgcagccc      240

gaggattttg ctacctacta ttgccagcag cattatacta cccccccaac attcggccag      300

ggcacaaaag tcgaaatcaa gcggaccgtg gccgccccct ccgtgttcat cttccccccc      360

tccgacgagc agctgaagtc cggcaccgcc tccgtggtgt gcctgctgaa caacttctac      420

ccccgggagg ccaaggtgca gtggaaggtg gacaacgccc tgcagtccgg caactcccag      480

gagtccgtga ccgagcagga ctccaaggac tccacctact ccctgtcctc caccctgacc      540

ctgtccaagg ccgactacga gaagcacaag gtgtacgcct gcgaggtgac ccaccagggc      600

ctgtcctccc ccgtgaccaa gtccttcaac cggggcgagt gcggtggtgg tggtagcggc      660

ggcggtggaa gcgcatccca tgtgaaactg caggaaagcg gcccaggtct ggtccagcca      720

tcccagtctc tgagcctgac atgcactgtg agcggattct ctctgacaga ctatggggtg      780

cactgggtca gacagagtcc aggaaagggg ctggagtggc tgggcgtcat ctggtcaggc      840

ggagggactg cttataacac cgcactgatc agcagactga atatctaccg cgacaactct      900

aaaaatcagg tgttcctgga gatgaacagt ctgcaggccg aagataccgc tatgtactat      960

tgcgccaggc ggggcagcta cccttataat tactttgacg cttggggttg tggcaccaca     1020

gtgacagtct ccagcggtgg aggagggagt ggtggaggag ggtcaggtgg aggagggtcc     1080

caggcagtgg tcattcagga gtctgccctg actacccccc ctggagaaac cgtgacactg     1140

acttgcggat ctagtacagg ggcagtgact gcctccaact atgcaaattg ggtccaggaa     1200

aagcctgatc actgtttcac tggcctgatc ggtggccata acaatcgacc acccggagtg     1260

ccagctaggt tttcaggttc cctgatcggc gacaaagccg ctctgaccat tgctggcacc     1320

cagacagagg atgaagcaat ctacttttgt gccctgtggt attccgatca ctgggtcatt     1380

ggggggggga cacgtctgac tgtgctgggg                                      1410


<210>  19
<211>  108
<212>  PRT
<213>  Artificial Sequence

<220>
<223>  Trastuzumab VL

<400>  19

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


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


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


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


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


Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln His Tyr Thr Thr Pro Pro 
                85                  90                  95      


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


<210>  20
<211>  120
<212>  PRT
<213>  Artificial Sequence

<220>
<223>  Trastuzumab VH

<400>  20

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


Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Asn Ile Lys Asp Thr 
            20                  25                  30          


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


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


Lys Gly Arg Phe Thr Ile Ser Ala Asp Thr Ser Lys Asn Thr Ala Tyr 
65                  70                  75                  80  


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


Ser Arg Trp Gly Gly Asp Gly Phe Tyr Ala Met Asp Tyr Trp Gly Gln 
            100                 105                 110         


Gly Thr Leu Val Thr Val Ser Ser 
        115                 120 


<210>  21
<211>  119
<212>  PRT
<213>  Artificial Sequence

<220>
<223>  C825 VH

<400>  21

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


Ser Leu Ser Leu Thr Cys Thr Val Ser Gly Phe Ser Leu Thr Asp Tyr 
            20                  25                  30          


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


Gly Val Ile Trp Ser Gly Gly Gly Thr Ala Tyr Asn Thr Ala Leu Ile 
    50                  55                  60                  


Ser Arg Leu Asn Ile Tyr Arg Asp Asn Ser Lys Asn Gln Val Phe Leu 
65                  70                  75                  80  


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


Arg Arg Gly Ser Tyr Pro Tyr Asn Tyr Phe Asp Ala Trp Gly Cys Gly 
            100                 105                 110         


Thr Thr Val Thr Val Ser Ser 
        115                 


<210>  22
<211>  110
<212>  PRT
<213>  Artificial Sequence

<220>
<223>  C825 VL

<400>  22

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


Thr Val Thr Leu Thr Cys Gly Ser Ser Thr Gly Ala Val Thr Ala Ser 
            20                  25                  30          


Asn Tyr Ala Asn Trp Val Gln Glu Lys Pro Asp His Cys Phe Thr Gly 
        35                  40                  45              


Leu Ile Gly Gly His Asn Asn Arg Pro Pro Gly Val Pro Ala Arg Phe 
    50                  55                  60                  


Ser Gly Ser Leu Ile Gly Asp Lys Ala Ala Leu Thr Ile Ala Gly Thr 
65                  70                  75                  80  


Gln Thr Glu Asp Glu Ala Ile Tyr Phe Cys Ala Leu Trp Tyr Ser Asp 
                85                  90                  95      


His Trp Val Ile Gly Gly Gly Thr Arg Leu Thr Val Leu Gly 
            100                 105                 110 


<210>  23
<211>  12
<212>  PRT
<213>  Artificial Sequence

<220>
<223>  (G4S)2AS Linker

<400>  23

Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Ala Ser 
1               5                   10          


<210>  24
<211>  732
<212>  DNA
<213>  Artificial Sequence

<220>
<223>  Nucleic acid encoding C825 VH-(G4S)3 intra-scFv linker-C825 VL

<400>  24
catgtgaaac tgcaggaaag cggcccaggt ctggtccagc catcccagtc tctgagcctg       60

acatgcactg tgagcggatt ctctctgaca gactatgggg tgcactgggt cagacagagt      120

ccaggaaagg ggctggagtg gctgggcgtc atctggtcag gcggagggac tgcttataac      180

accgcactga tcagcagact gaatatctac cgcgacaact ctaaaaatca ggtgttcctg      240

gagatgaaca gtctgcaggc cgaagatacc gctatgtact attgcgccag gcggggcagc      300

tacccttata attactttga cgcttggggt tgtggcacca cagtgacagt ctccagcggt      360

ggaggaggga gtggtggagg agggtcaggt ggaggagggt cccaggcagt ggtcattcag      420

gagtctgccc tgactacccc ccctggagaa accgtgacac tgacttgcgg atctagtaca      480

ggggcagtga ctgcctccaa ctatgcaaat tgggtccagg aaaagcctga tcactgtttc      540

actggcctga tcggtggcca taacaatcga ccacccggag tgccagctag gttttcaggt      600

tccctgatcg gcgacaaagc cgctctgacc attgctggca cccagacaga ggatgaagca      660

atctactttt gtgccctgtg gtattccgat cactgggtca ttgggggggg gacacgtctg      720

actgtgctgg gg                                                          732


<210>  25
<211>  5
<212>  PRT
<213>  Artificial Sequence

<220>
<223>  G4S Linker

<400>  25

Gly Gly Gly Gly Ser 
1               5   


<210>  26
<211>  10
<212>  PRT
<213>  Artificial Sequence

<220>
<223>  (G4S)2 Linker

<400>  26

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


<210>  27
<211>  15
<212>  PRT
<213>  Artificial Sequence

<220>
<223>  (G4S)3 Linker

<400>  27

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


<210>  28
<211>  20
<212>  PRT
<213>  Artificial Sequence

<220>
<223>  (G4S)4 Linker

<400>  28

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


Gly Gly Gly Ser 
            20  


<210>  29
<211>  25
<212>  PRT
<213>  Artificial Sequence

<220>
<223>  (G4S)5 Linker

<400>  29

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


Gly Gly Gly Ser Gly Gly Gly Gly Ser 
            20                  25  


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

<220>
<223>  (G4S)6 Linker

<400>  30

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


Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser 
            20                  25                  30  


<210>  31
<211>  234
<212>  PRT
<213>  Artificial Sequence

<220>
<223>  C825 VH-(G4S) intra-scFv linker-C825 VL

<400>  31

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


Ser Leu Ser Leu Thr Cys Thr Val Ser Gly Phe Ser Leu Thr Asp Tyr 
            20                  25                  30          


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


Gly Val Ile Trp Ser Gly Gly Gly Thr Ala Tyr Asn Thr Ala Leu Ile 
    50                  55                  60                  


Ser Arg Leu Asn Ile Tyr Arg Asp Asn Ser Lys Asn Gln Val Phe Leu 
65                  70                  75                  80  


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


Arg Arg Gly Ser Tyr Pro Tyr Asn Tyr Phe Asp Ala Trp Gly Cys Gly 
            100                 105                 110         


Thr Thr Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gln Ala Val Val 
        115                 120                 125             


Ile Gln Glu Ser Ala Leu Thr Thr Pro Pro Gly Glu Thr Val Thr Leu 
    130                 135                 140                 


Thr Cys Gly Ser Ser Thr Gly Ala Val Thr Ala Ser Asn Tyr Ala Asn 
145                 150                 155                 160 


Trp Val Gln Glu Lys Pro Asp His Cys Phe Thr Gly Leu Ile Gly Gly 
                165                 170                 175     


His Asn Asn Arg Pro Pro Gly Val Pro Ala Arg Phe Ser Gly Ser Leu 
            180                 185                 190         


Ile Gly Asp Lys Ala Ala Leu Thr Ile Ala Gly Thr Gln Thr Glu Asp 
        195                 200                 205             


Glu Ala Ile Tyr Phe Cys Ala Leu Trp Tyr Ser Asp His Trp Val Ile 
    210                 215                 220                 


Gly Gly Gly Thr Arg Leu Thr Val Leu Gly 
225                 230                 


<210>  32
<211>  239
<212>  PRT
<213>  Artificial Sequence

<220>
<223>  C825 VH-(G4S)2 intra-scFv linker-C825 VL

<400>  32

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


Ser Leu Ser Leu Thr Cys Thr Val Ser Gly Phe Ser Leu Thr Asp Tyr 
            20                  25                  30          


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


Gly Val Ile Trp Ser Gly Gly Gly Thr Ala Tyr Asn Thr Ala Leu Ile 
    50                  55                  60                  


Ser Arg Leu Asn Ile Tyr Arg Asp Asn Ser Lys Asn Gln Val Phe Leu 
65                  70                  75                  80  


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


Arg Arg Gly Ser Tyr Pro Tyr Asn Tyr Phe Asp Ala Trp Gly Cys Gly 
            100                 105                 110         


Thr Thr Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly 
        115                 120                 125             


Ser Gln Ala Val Val Ile Gln Glu Ser Ala Leu Thr Thr Pro Pro Gly 
    130                 135                 140                 


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


Ser Asn Tyr Ala Asn Trp Val Gln Glu Lys Pro Asp His Cys Phe Thr 
                165                 170                 175     


Gly Leu Ile Gly Gly His Asn Asn Arg Pro Pro Gly Val Pro Ala Arg 
            180                 185                 190         


Phe Ser Gly Ser Leu Ile Gly Asp Lys Ala Ala Leu Thr Ile Ala Gly 
        195                 200                 205             


Thr Gln Thr Glu Asp Glu Ala Ile Tyr Phe Cys Ala Leu Trp Tyr Ser 
    210                 215                 220                 


Asp His Trp Val Ile Gly Gly Gly Thr Arg Leu Thr Val Leu Gly 
225                 230                 235                 


<210>  33
<211>  244
<212>  PRT
<213>  Artificial Sequence

<220>
<223>  C825 VH-(G4S)3 intra-scFv linker-C825 VL

<400>  33

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


Ser Leu Ser Leu Thr Cys Thr Val Ser Gly Phe Ser Leu Thr Asp Tyr 
            20                  25                  30          


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


Gly Val Ile Trp Ser Gly Gly Gly Thr Ala Tyr Asn Thr Ala Leu Ile 
    50                  55                  60                  


Ser Arg Leu Asn Ile Tyr Arg Asp Asn Ser Lys Asn Gln Val Phe Leu 
65                  70                  75                  80  


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


Arg Arg Gly Ser Tyr Pro Tyr Asn Tyr Phe Asp Ala Trp Gly Cys Gly 
            100                 105                 110         


Thr Thr Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly 
        115                 120                 125             


Ser Gly Gly Gly Gly Ser Gln Ala Val Val Ile Gln Glu Ser Ala Leu 
    130                 135                 140                 


Thr Thr Pro Pro Gly Glu Thr Val Thr Leu Thr Cys Gly Ser Ser Thr 
145                 150                 155                 160 


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


Asp His Cys Phe Thr Gly Leu Ile Gly Gly His Asn Asn Arg Pro Pro 
            180                 185                 190         


Gly Val Pro Ala Arg Phe Ser Gly Ser Leu Ile Gly Asp Lys Ala Ala 
        195                 200                 205             


Leu Thr Ile Ala Gly Thr Gln Thr Glu Asp Glu Ala Ile Tyr Phe Cys 
    210                 215                 220                 


Ala Leu Trp Tyr Ser Asp His Trp Val Ile Gly Gly Gly Thr Arg Leu 
225                 230                 235                 240 


Thr Val Leu Gly 
                


<210>  34
<211>  249
<212>  PRT
<213>  Artificial Sequence

<220>
<223>  C825 VH-(G4S)4 intra-scFv linker-C825 VL

<400>  34

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


Ser Leu Ser Leu Thr Cys Thr Val Ser Gly Phe Ser Leu Thr Asp Tyr 
            20                  25                  30          


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


Gly Val Ile Trp Ser Gly Gly Gly Thr Ala Tyr Asn Thr Ala Leu Ile 
    50                  55                  60                  


Ser Arg Leu Asn Ile Tyr Arg Asp Asn Ser Lys Asn Gln Val Phe Leu 
65                  70                  75                  80  


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


Arg Arg Gly Ser Tyr Pro Tyr Asn Tyr Phe Asp Ala Trp Gly Cys Gly 
            100                 105                 110         


Thr Thr Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly 
        115                 120                 125             


Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gln Ala Val Val Ile 
    130                 135                 140                 


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


Cys Gly Ser Ser Thr Gly Ala Val Thr Ala Ser Asn Tyr Ala Asn Trp 
                165                 170                 175     


Val Gln Glu Lys Pro Asp His Cys Phe Thr Gly Leu Ile Gly Gly His 
            180                 185                 190         


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


Gly Asp Lys Ala Ala Leu Thr Ile Ala Gly Thr Gln Thr Glu Asp Glu 
    210                 215                 220                 


Ala Ile Tyr Phe Cys Ala Leu Trp Tyr Ser Asp His Trp Val Ile Gly 
225                 230                 235                 240 


Gly Gly Thr Arg Leu Thr Val Leu Gly 
                245                 


<210>  35
<211>  254
<212>  PRT
<213>  Artificial Sequence

<220>
<223>  C825 VH-(G4S)5 intra-scFv linker-C825 VL

<400>  35

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


Ser Leu Ser Leu Thr Cys Thr Val Ser Gly Phe Ser Leu Thr Asp Tyr 
            20                  25                  30          


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


Gly Val Ile Trp Ser Gly Gly Gly Thr Ala Tyr Asn Thr Ala Leu Ile 
    50                  55                  60                  


Ser Arg Leu Asn Ile Tyr Arg Asp Asn Ser Lys Asn Gln Val Phe Leu 
65                  70                  75                  80  


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


Arg Arg Gly Ser Tyr Pro Tyr Asn Tyr Phe Asp Ala Trp Gly Cys Gly 
            100                 105                 110         


Thr Thr Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly 
        115                 120                 125             


Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser 
    130                 135                 140                 


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


Thr Val Thr Leu Thr Cys Gly Ser Ser Thr Gly Ala Val Thr Ala Ser 
                165                 170                 175     


Asn Tyr Ala Asn Trp Val Gln Glu Lys Pro Asp His Cys Phe Thr Gly 
            180                 185                 190         


Leu Ile Gly Gly His Asn Asn Arg Pro Pro Gly Val Pro Ala Arg Phe 
        195                 200                 205             


Ser Gly Ser Leu Ile Gly Asp Lys Ala Ala Leu Thr Ile Ala Gly Thr 
    210                 215                 220                 


Gln Thr Glu Asp Glu Ala Ile Tyr Phe Cys Ala Leu Trp Tyr Ser Asp 
225                 230                 235                 240 


His Trp Val Ile Gly Gly Gly Thr Arg Leu Thr Val Leu Gly 
                245                 250                 


<210>  36
<211>  259
<212>  PRT
<213>  Artificial Sequence

<220>
<223>  C825 VH-(G4S)6 intra-scFv linker-C825 VL

<400>  36

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


Ser Leu Ser Leu Thr Cys Thr Val Ser Gly Phe Ser Leu Thr Asp Tyr 
            20                  25                  30          


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


Gly Val Ile Trp Ser Gly Gly Gly Thr Ala Tyr Asn Thr Ala Leu Ile 
    50                  55                  60                  


Ser Arg Leu Asn Ile Tyr Arg Asp Asn Ser Lys Asn Gln Val Phe Leu 
65                  70                  75                  80  


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


Arg Arg Gly Ser Tyr Pro Tyr Asn Tyr Phe Asp Ala Trp Gly Cys Gly 
            100                 105                 110         


Thr Thr Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly 
        115                 120                 125             


Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser 
    130                 135                 140                 


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


Thr Pro Pro Gly Glu Thr Val Thr Leu Thr Cys Gly Ser Ser Thr Gly 
                165                 170                 175     


Ala Val Thr Ala Ser Asn Tyr Ala Asn Trp Val Gln Glu Lys Pro Asp 
            180                 185                 190         


His Cys Phe Thr Gly Leu Ile Gly Gly His Asn Asn Arg Pro Pro Gly 
        195                 200                 205             


Val Pro Ala Arg Phe Ser Gly Ser Leu Ile Gly Asp Lys Ala Ala Leu 
    210                 215                 220                 


Thr Ile Ala Gly Thr Gln Thr Glu Asp Glu Ala Ile Tyr Phe Cys Ala 
225                 230                 235                 240 


Leu Trp Tyr Ser Asp His Trp Val Ile Gly Gly Gly Thr Arg Leu Thr 
                245                 250                 255     


Val Leu Gly 
            

<210>  37
<211>  119
<212>  PRT
<213>  Artificial Sequence

<220>
<223>  Humanized C825 VH domain

<400>  37

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


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


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


Gly Val Ile Trp Ser Gly Gly Gly Thr Ala Tyr Asn Thr Ala Leu Ile 
    50                  55                  60                  


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


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


Arg Arg Gly Ser Tyr Pro Tyr Asn Tyr Phe Asp Ala Trp Gly Cys Gly 
            100                 105                 110         


Thr Leu Val Thr Val Ser Ser 
        115                 


<210>  38
<211>  110
<212>  PRT
<213>  Artificial Sequence

<220>
<223>  Humanized C825 VL domain

<400>  38

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


Thr Val Thr Leu Thr Cys Gly Ser Ser Thr Gly Ala Val Thr Ala Ser 
            20                  25                  30          


Asn Tyr Ala Asn Trp Val Gln Gln Lys Pro Gly Gln Cys Pro Arg Gly 
        35                  40                  45              


Leu Ile Gly Gly His Asn Asn Arg Pro Pro Gly Val Pro Ala Arg Phe 
    50                  55                  60                  


Ser Gly Ser Leu Leu Gly Gly Lys Ala Ala Leu Thr Leu Leu Gly Ala 
65                  70                  75                  80  


Gln Pro Glu Asp Glu Ala Glu Tyr Tyr Cys Ala Leu Trp Tyr Ser Asp 
                85                  90                  95      


His Trp Val Ile Gly Gly Gly Thr Lys Leu Thr Val Leu Gly 
            100                 105                 110 


<210>  39
<211>  234
<212>  PRT
<213>  Artificial Sequence

<220>
<223>  Humanized C825 VH-(G4S) intra-scFv linker-humanized C825 VL

<400>  39

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


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


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


Gly Val Ile Trp Ser Gly Gly Gly Thr Ala Tyr Asn Thr Ala Leu Ile 
    50                  55                  60                  


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


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


Arg Arg Gly Ser Tyr Pro Tyr Asn Tyr Phe Asp Ala Trp Gly Cys Gly 
            100                 105                 110         


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


Thr Gln Glu Pro Ser Leu Thr Val Ser Pro Gly Gly Thr Val Thr Leu 
    130                 135                 140                 


Thr Cys Gly Ser Ser Thr Gly Ala Val Thr Ala Ser Asn Tyr Ala Asn 
145                 150                 155                 160 


Trp Val Gln Gln Lys Pro Gly Gln Cys Pro Arg Gly Leu Ile Gly Gly 
                165                 170                 175     


His Asn Asn Arg Pro Pro Gly Val Pro Ala Arg Phe Ser Gly Ser Leu 
            180                 185                 190         


Leu Gly Gly Lys Ala Ala Leu Thr Leu Leu Gly Ala Gln Pro Glu Asp 
        195                 200                 205             


Glu Ala Glu Tyr Tyr Cys Ala Leu Trp Tyr Ser Asp His Trp Val Ile 
    210                 215                 220                 


Gly Gly Gly Thr Lys Leu Thr Val Leu Gly 
225                 230                 


<210>  40
<211>  239
<212>  PRT
<213>  Artificial Sequence

<220>
<223>  Humanized C825 VH-(G4S)2 intra-scFv linker-humanized C825 VL

<400>  40

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


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


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


Gly Val Ile Trp Ser Gly Gly Gly Thr Ala Tyr Asn Thr Ala Leu Ile 
    50                  55                  60                  


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


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


Arg Arg Gly Ser Tyr Pro Tyr Asn Tyr Phe Asp Ala Trp Gly Cys Gly 
            100                 105                 110         


Thr Leu Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly 
        115                 120                 125             


Ser Gln Ala Val Val Thr Gln Glu Pro Ser Leu Thr Val Ser Pro Gly 
    130                 135                 140                 


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


Ser Asn Tyr Ala Asn Trp Val Gln Gln Lys Pro Gly Gln Cys Pro Arg 
                165                 170                 175     


Gly Leu Ile Gly Gly His Asn Asn Arg Pro Pro Gly Val Pro Ala Arg 
            180                 185                 190         


Phe Ser Gly Ser Leu Leu Gly Gly Lys Ala Ala Leu Thr Leu Leu Gly 
        195                 200                 205             


Ala Gln Pro Glu Asp Glu Ala Glu Tyr Tyr Cys Ala Leu Trp Tyr Ser 
    210                 215                 220                 


Asp His Trp Val Ile Gly Gly Gly Thr Lys Leu Thr Val Leu Gly 
225                 230                 235                 


<210>  41
<211>  244
<212>  PRT
<213>  Artificial Sequence

<220>
<223>  Humanized C825 VH-(G4S)3 intra-scFv linker-humanized C825 VL

<400>  41

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


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


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


Gly Val Ile Trp Ser Gly Gly Gly Thr Ala Tyr Asn Thr Ala Leu Ile 
    50                  55                  60                  


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


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


Arg Arg Gly Ser Tyr Pro Tyr Asn Tyr Phe Asp Ala Trp Gly Cys Gly 
            100                 105                 110         


Thr Leu Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly 
        115                 120                 125             


Ser Gly Gly Gly Gly Ser Gln Ala Val Val Thr Gln Glu Pro Ser Leu 
    130                 135                 140                 


Thr Val Ser Pro Gly Gly Thr Val Thr Leu Thr Cys Gly Ser Ser Thr 
145                 150                 155                 160 


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


Gly Gln Cys Pro Arg Gly Leu Ile Gly Gly His Asn Asn Arg Pro Pro 
            180                 185                 190         


Gly Val Pro Ala Arg Phe Ser Gly Ser Leu Leu Gly Gly Lys Ala Ala 
        195                 200                 205             


Leu Thr Leu Leu Gly Ala Gln Pro Glu Asp Glu Ala Glu Tyr Tyr Cys 
    210                 215                 220                 


Ala Leu Trp Tyr Ser Asp His Trp Val Ile Gly Gly Gly Thr Lys Leu 
225                 230                 235                 240 


Thr Val Leu Gly 
                


<210>  42
<211>  249
<212>  PRT
<213>  Artificial Sequence

<220>
<223>  Humanized C825 VH-(G4S)4 intra-scFv linker-humanized C825 VL

<400>  42

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


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


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


Gly Val Ile Trp Ser Gly Gly Gly Thr Ala Tyr Asn Thr Ala Leu Ile 
    50                  55                  60                  


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


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


Arg Arg Gly Ser Tyr Pro Tyr Asn Tyr Phe Asp Ala Trp Gly Cys Gly 
            100                 105                 110         


Thr Leu Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly 
        115                 120                 125             


Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gln Ala Val Val Thr 
    130                 135                 140                 


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


Cys Gly Ser Ser Thr Gly Ala Val Thr Ala Ser Asn Tyr Ala Asn Trp 
                165                 170                 175     


Val Gln Gln Lys Pro Gly Gln Cys Pro Arg Gly Leu Ile Gly Gly His 
            180                 185                 190         


Asn Asn Arg Pro Pro Gly Val Pro Ala Arg Phe Ser Gly Ser Leu Leu 
        195                 200                 205             


Gly Gly Lys Ala Ala Leu Thr Leu Leu Gly Ala Gln Pro Glu Asp Glu 
    210                 215                 220                 


Ala Glu Tyr Tyr Cys Ala Leu Trp Tyr Ser Asp His Trp Val Ile Gly 
225                 230                 235                 240 


Gly Gly Thr Lys Leu Thr Val Leu Gly 
                245                 


<210>  43
<211>  254
<212>  PRT
<213>  Artificial Sequence

<220>
<223>  Humanized C825 VH-(G4S)5 intra-scFv linker-humanized C825 VL

<400>  43

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


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


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


Gly Val Ile Trp Ser Gly Gly Gly Thr Ala Tyr Asn Thr Ala Leu Ile 
    50                  55                  60                  


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


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


Arg Arg Gly Ser Tyr Pro Tyr Asn Tyr Phe Asp Ala Trp Gly Cys Gly 
            100                 105                 110         


Thr Leu Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly 
        115                 120                 125             


Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser 
    130                 135                 140                 


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


Thr Val Thr Leu Thr Cys Gly Ser Ser Thr Gly Ala Val Thr Ala Ser 
                165                 170                 175     


Asn Tyr Ala Asn Trp Val Gln Gln Lys Pro Gly Gln Cys Pro Arg Gly 
            180                 185                 190         


Leu Ile Gly Gly His Asn Asn Arg Pro Pro Gly Val Pro Ala Arg Phe 
        195                 200                 205             


Ser Gly Ser Leu Leu Gly Gly Lys Ala Ala Leu Thr Leu Leu Gly Ala 
    210                 215                 220                 


Gln Pro Glu Asp Glu Ala Glu Tyr Tyr Cys Ala Leu Trp Tyr Ser Asp 
225                 230                 235                 240 


His Trp Val Ile Gly Gly Gly Thr Lys Leu Thr Val Leu Gly 
                245                 250                 


<210>  44
<211>  259
<212>  PRT
<213>  Artificial Sequence

<220>
<223>  Humanized C825 VH-(G4S)6 intra-scFv linker-humanized C825 VL

<400>  44

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


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


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


Gly Val Ile Trp Ser Gly Gly Gly Thr Ala Tyr Asn Thr Ala Leu Ile 
    50                  55                  60                  


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


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


Arg Arg Gly Ser Tyr Pro Tyr Asn Tyr Phe Asp Ala Trp Gly Cys Gly 
            100                 105                 110         


Thr Leu Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly 
        115                 120                 125             


Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser 
    130                 135                 140                 


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


Val Ser Pro Gly Gly Thr Val Thr Leu Thr Cys Gly Ser Ser Thr Gly 
                165                 170                 175     


Ala Val Thr Ala Ser Asn Tyr Ala Asn Trp Val Gln Gln Lys Pro Gly 
            180                 185                 190         


Gln Cys Pro Arg Gly Leu Ile Gly Gly His Asn Asn Arg Pro Pro Gly 
        195                 200                 205             


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


Thr Leu Leu Gly Ala Gln Pro Glu Asp Glu Ala Glu Tyr Tyr Cys Ala 
225                 230                 235                 240 


Leu Trp Tyr Ser Asp His Trp Val Ile Gly Gly Gly Thr Lys Leu Thr 
                245                 250                 255     


Val Leu Gly 
            


<210>  45
<211>  465
<212>  PRT
<213>  Artificial Sequence

<220>
<223>  Trastuzumab LC-TS(G4S)3 linker- humanized C825 VH-G4S 
linker- humanized C825 VL

<400>  45

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


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


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


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


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


Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln His Tyr Thr Thr Pro Pro 
                85                  90                  95      


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


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


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


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


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


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


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


Phe Asn Arg Gly Glu Cys Thr Ser Gly Gly Gly Gly Ser Gly Gly Gly 
    210                 215                 220                 


Gly Ser Gly Gly Gly Gly Ser His Val Gln Leu Val Glu Ser Gly Gly 
225                 230                 235                 240 


Gly Leu Val Gln Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser 
                245                 250                 255     


Gly Phe Ser Leu Thr Asp Tyr Gly Val His Trp Val Arg Gln Ala Pro 
            260                 265                 270         


Gly Lys Gly Leu Glu Trp Leu Gly Val Ile Trp Ser Gly Gly Gly Thr 
        275                 280                 285             


Ala Tyr Asn Thr Ala Leu Ile Ser Arg Phe Thr Ile Ser Arg Asp Asn 
    290                 295                 300                 


Ser Lys Asn Thr Leu Tyr Leu Gln Met Asn Ser Leu Arg Ala Glu Asp 
305                 310                 315                 320 


Thr Ala Val Tyr Tyr Cys Ala Arg Arg Gly Ser Tyr Pro Tyr Asn Tyr 
                325                 330                 335     


Phe Asp Ala Trp Gly Cys Gly Thr Leu Val Thr Val Ser Ser Gly Gly 
            340                 345                 350         


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


Pro Gly Gly Thr Val Thr Leu Thr Cys Gly Ser Ser Thr Gly Ala Val 
    370                 375                 380                 


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


Pro Arg Gly Leu Ile Gly Gly His Asn Asn Arg Pro Pro Gly Val Pro 
                405                 410                 415     


Ala Arg Phe Ser Gly Ser Leu Leu Gly Gly Lys Ala Ala Leu Thr Leu 
            420                 425                 430         


Leu Gly Ala Gln Pro Glu Asp Glu Ala Glu Tyr Tyr Cys Ala Leu Trp 
        435                 440                 445             


Tyr Ser Asp His Trp Val Ile Gly Gly Gly Thr Lys Leu Thr Val Leu 
    450                 455                 460                 


Gly 
465 


<210>  46
<211>  470
<212>  PRT
<213>  Artificial Sequence

<220>
<223>  Trastuzumab LC-TS(G4S)3 linker- humanized C825 VH-(G4S)2 
linker- humanized C825 VL

<400>  46

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


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


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


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


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


Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln His Tyr Thr Thr Pro Pro 
                85                  90                  95      


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


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


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


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


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


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


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


Phe Asn Arg Gly Glu Cys Thr Ser Gly Gly Gly Gly Ser Gly Gly Gly 
    210                 215                 220                 


Gly Ser Gly Gly Gly Gly Ser His Val Gln Leu Val Glu Ser Gly Gly 
225                 230                 235                 240 


Gly Leu Val Gln Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser 
                245                 250                 255     


Gly Phe Ser Leu Thr Asp Tyr Gly Val His Trp Val Arg Gln Ala Pro 
            260                 265                 270         


Gly Lys Gly Leu Glu Trp Leu Gly Val Ile Trp Ser Gly Gly Gly Thr 
        275                 280                 285             


Ala Tyr Asn Thr Ala Leu Ile Ser Arg Phe Thr Ile Ser Arg Asp Asn 
    290                 295                 300                 


Ser Lys Asn Thr Leu Tyr Leu Gln Met Asn Ser Leu Arg Ala Glu Asp 
305                 310                 315                 320 


Thr Ala Val Tyr Tyr Cys Ala Arg Arg Gly Ser Tyr Pro Tyr Asn Tyr 
                325                 330                 335     


Phe Asp Ala Trp Gly Cys Gly Thr Leu Val Thr Val Ser Ser Gly Gly 
            340                 345                 350         


Gly Gly Ser Gly Gly Gly Gly Ser Gln Ala Val Val Thr Gln Glu Pro 
        355                 360                 365             


Ser Leu Thr Val Ser Pro Gly Gly Thr Val Thr Leu Thr Cys Gly Ser 
    370                 375                 380                 


Ser Thr Gly Ala Val Thr Ala Ser Asn Tyr Ala Asn Trp Val Gln Gln 
385                 390                 395                 400 


Lys Pro Gly Gln Cys Pro Arg Gly Leu Ile Gly Gly His Asn Asn Arg 
                405                 410                 415     


Pro Pro Gly Val Pro Ala Arg Phe Ser Gly Ser Leu Leu Gly Gly Lys 
            420                 425                 430         


Ala Ala Leu Thr Leu Leu Gly Ala Gln Pro Glu Asp Glu Ala Glu Tyr 
        435                 440                 445             


Tyr Cys Ala Leu Trp Tyr Ser Asp His Trp Val Ile Gly Gly Gly Thr 
    450                 455                 460                 


Lys Leu Thr Val Leu Gly 
465                 470 


<210>  47
<211>  475
<212>  PRT
<213>  Artificial Sequence

<220>
<223>  Trastuzumab LC-TS(G4S)3 linker- humanized C825 VH-(G4S)3
 linker-humanized C825 VL

<400>  47

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


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


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


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


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


Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln His Tyr Thr Thr Pro Pro 
                85                  90                  95      


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


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


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


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


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


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


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


Phe Asn Arg Gly Glu Cys Thr Ser Gly Gly Gly Gly Ser Gly Gly Gly 
    210                 215                 220                 


Gly Ser Gly Gly Gly Gly Ser His Val Gln Leu Val Glu Ser Gly Gly 
225                 230                 235                 240 


Gly Leu Val Gln Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser 
                245                 250                 255     


Gly Phe Ser Leu Thr Asp Tyr Gly Val His Trp Val Arg Gln Ala Pro 
            260                 265                 270         


Gly Lys Gly Leu Glu Trp Leu Gly Val Ile Trp Ser Gly Gly Gly Thr 
        275                 280                 285             


Ala Tyr Asn Thr Ala Leu Ile Ser Arg Phe Thr Ile Ser Arg Asp Asn 
    290                 295                 300                 


Ser Lys Asn Thr Leu Tyr Leu Gln Met Asn Ser Leu Arg Ala Glu Asp 
305                 310                 315                 320 


Thr Ala Val Tyr Tyr Cys Ala Arg Arg Gly Ser Tyr Pro Tyr Asn Tyr 
                325                 330                 335     


Phe Asp Ala Trp Gly Cys Gly Thr Leu Val Thr Val Ser Ser Gly Gly 
            340                 345                 350         


Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gln Ala Val 
        355                 360                 365             


Val Thr Gln Glu Pro Ser Leu Thr Val Ser Pro Gly Gly Thr Val Thr 
    370                 375                 380                 


Leu Thr Cys Gly Ser Ser Thr Gly Ala Val Thr Ala Ser Asn Tyr Ala 
385                 390                 395                 400 


Asn Trp Val Gln Gln Lys Pro Gly Gln Cys Pro Arg Gly Leu Ile Gly 
                405                 410                 415     


Gly His Asn Asn Arg Pro Pro Gly Val Pro Ala Arg Phe Ser Gly Ser 
            420                 425                 430         


Leu Leu Gly Gly Lys Ala Ala Leu Thr Leu Leu Gly Ala Gln Pro Glu 
        435                 440                 445             


Asp Glu Ala Glu Tyr Tyr Cys Ala Leu Trp Tyr Ser Asp His Trp Val 
    450                 455                 460                 


Ile Gly Gly Gly Thr Lys Leu Thr Val Leu Gly 
465                 470                 475 


<210>  48
<211>  480
<212>  PRT
<213>  Artificial Sequence

<220>
<223>  Trastuzumab LC-TS(G4S)3 linker- humanized C825 VH-(G4S)4 
linker- humanized C825 VL

<400>  48

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


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


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


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


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


Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln His Tyr Thr Thr Pro Pro 
                85                  90                  95      


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


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


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


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


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


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


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


Phe Asn Arg Gly Glu Cys Thr Ser Gly Gly Gly Gly Ser Gly Gly Gly 
    210                 215                 220                 


Gly Ser Gly Gly Gly Gly Ser His Val Gln Leu Val Glu Ser Gly Gly 
225                 230                 235                 240 


Gly Leu Val Gln Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser 
                245                 250                 255     


Gly Phe Ser Leu Thr Asp Tyr Gly Val His Trp Val Arg Gln Ala Pro 
            260                 265                 270         


Gly Lys Gly Leu Glu Trp Leu Gly Val Ile Trp Ser Gly Gly Gly Thr 
        275                 280                 285             


Ala Tyr Asn Thr Ala Leu Ile Ser Arg Phe Thr Ile Ser Arg Asp Asn 
    290                 295                 300                 


Ser Lys Asn Thr Leu Tyr Leu Gln Met Asn Ser Leu Arg Ala Glu Asp 
305                 310                 315                 320 


Thr Ala Val Tyr Tyr Cys Ala Arg Arg Gly Ser Tyr Pro Tyr Asn Tyr 
                325                 330                 335     


Phe Asp Ala Trp Gly Cys Gly Thr Leu Val Thr Val Ser Ser Gly Gly 
            340                 345                 350         


Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly 
        355                 360                 365             


Gly Ser Gln Ala Val Val Thr Gln Glu Pro Ser Leu Thr Val Ser Pro 
    370                 375                 380                 


Gly Gly Thr Val Thr Leu Thr Cys Gly Ser Ser Thr Gly Ala Val Thr 
385                 390                 395                 400 


Ala Ser Asn Tyr Ala Asn Trp Val Gln Gln Lys Pro Gly Gln Cys Pro 
                405                 410                 415     


Arg Gly Leu Ile Gly Gly His Asn Asn Arg Pro Pro Gly Val Pro Ala 
            420                 425                 430         


Arg Phe Ser Gly Ser Leu Leu Gly Gly Lys Ala Ala Leu Thr Leu Leu 
        435                 440                 445             


Gly Ala Gln Pro Glu Asp Glu Ala Glu Tyr Tyr Cys Ala Leu Trp Tyr 
    450                 455                 460                 


Ser Asp His Trp Val Ile Gly Gly Gly Thr Lys Leu Thr Val Leu Gly 
465                 470                 475                 480 


<210>  49
<211>  485
<212>  PRT
<213>  Artificial Sequence

<220>
<223>  Trastuzumab LC-TS(G4S)3 linker- humanized C825 VH-(G4S)5 
linker- humanized C825 VL

<400>  49

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


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


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


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


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


Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln His Tyr Thr Thr Pro Pro 
                85                  90                  95      


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


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


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


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


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


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


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


Phe Asn Arg Gly Glu Cys Thr Ser Gly Gly Gly Gly Ser Gly Gly Gly 
    210                 215                 220                 


Gly Ser Gly Gly Gly Gly Ser His Val Gln Leu Val Glu Ser Gly Gly 
225                 230                 235                 240 


Gly Leu Val Gln Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser 
                245                 250                 255     


Gly Phe Ser Leu Thr Asp Tyr Gly Val His Trp Val Arg Gln Ala Pro 
            260                 265                 270         


Gly Lys Gly Leu Glu Trp Leu Gly Val Ile Trp Ser Gly Gly Gly Thr 
        275                 280                 285             


Ala Tyr Asn Thr Ala Leu Ile Ser Arg Phe Thr Ile Ser Arg Asp Asn 
    290                 295                 300                 


Ser Lys Asn Thr Leu Tyr Leu Gln Met Asn Ser Leu Arg Ala Glu Asp 
305                 310                 315                 320 


Thr Ala Val Tyr Tyr Cys Ala Arg Arg Gly Ser Tyr Pro Tyr Asn Tyr 
                325                 330                 335     


Phe Asp Ala Trp Gly Cys Gly Thr Leu Val Thr Val Ser Ser Gly Gly 
            340                 345                 350         


Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly 
        355                 360                 365             


Gly Ser Gly Gly Gly Gly Ser Gln Ala Val Val Thr Gln Glu Pro Ser 
    370                 375                 380                 


Leu Thr Val Ser Pro Gly Gly Thr Val Thr Leu Thr Cys Gly Ser Ser 
385                 390                 395                 400 


Thr Gly Ala Val Thr Ala Ser Asn Tyr Ala Asn Trp Val Gln Gln Lys 
                405                 410                 415     


Pro Gly Gln Cys Pro Arg Gly Leu Ile Gly Gly His Asn Asn Arg Pro 
            420                 425                 430         


Pro Gly Val Pro Ala Arg Phe Ser Gly Ser Leu Leu Gly Gly Lys Ala 
        435                 440                 445             


Ala Leu Thr Leu Leu Gly Ala Gln Pro Glu Asp Glu Ala Glu Tyr Tyr 
    450                 455                 460                 


Cys Ala Leu Trp Tyr Ser Asp His Trp Val Ile Gly Gly Gly Thr Lys 
465                 470                 475                 480 


Leu Thr Val Leu Gly 
                485 


<210>  50
<211>  490
<212>  PRT
<213>  Artificial Sequence

<220>
<223>  Trastuzumab LC-TS(G4S)3 linker- humanized C825 VH-(G4S)6 
linker- humanized C825 VL

<400>  50

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


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


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


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


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


Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln His Tyr Thr Thr Pro Pro 
                85                  90                  95      


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


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


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


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


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


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


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


Phe Asn Arg Gly Glu Cys Thr Ser Gly Gly Gly Gly Ser Gly Gly Gly 
    210                 215                 220                 


Gly Ser Gly Gly Gly Gly Ser His Val Gln Leu Val Glu Ser Gly Gly 
225                 230                 235                 240 


Gly Leu Val Gln Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser 
                245                 250                 255     


Gly Phe Ser Leu Thr Asp Tyr Gly Val His Trp Val Arg Gln Ala Pro 
            260                 265                 270         


Gly Lys Gly Leu Glu Trp Leu Gly Val Ile Trp Ser Gly Gly Gly Thr 
        275                 280                 285             


Ala Tyr Asn Thr Ala Leu Ile Ser Arg Phe Thr Ile Ser Arg Asp Asn 
    290                 295                 300                 


Ser Lys Asn Thr Leu Tyr Leu Gln Met Asn Ser Leu Arg Ala Glu Asp 
305                 310                 315                 320 


Thr Ala Val Tyr Tyr Cys Ala Arg Arg Gly Ser Tyr Pro Tyr Asn Tyr 
                325                 330                 335     


Phe Asp Ala Trp Gly Cys Gly Thr Leu Val Thr Val Ser Ser Gly Gly 
            340                 345                 350         


Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly 
        355                 360                 365             


Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gln Ala Val Val 
    370                 375                 380                 


Thr Gln Glu Pro Ser Leu Thr Val Ser Pro Gly Gly Thr Val Thr Leu 
385                 390                 395                 400 


Thr Cys Gly Ser Ser Thr Gly Ala Val Thr Ala Ser Asn Tyr Ala Asn 
                405                 410                 415     


Trp Val Gln Gln Lys Pro Gly Gln Cys Pro Arg Gly Leu Ile Gly Gly 
            420                 425                 430         


His Asn Asn Arg Pro Pro Gly Val Pro Ala Arg Phe Ser Gly Ser Leu 
        435                 440                 445             


Leu Gly Gly Lys Ala Ala Leu Thr Leu Leu Gly Ala Gln Pro Glu Asp 
    450                 455                 460                 


Glu Ala Glu Tyr Tyr Cys Ala Leu Trp Tyr Ser Asp His Trp Val Ile 
465                 470                 475                 480 


Gly Gly Gly Thr Lys Leu Thr Val Leu Gly 
                485                 490 


<210>  51
<211>  7
<212>  PRT
<213>  Artificial Sequence

<220>
<223>  TSG4S Linker

<400>  51

Thr Ser Gly Gly Gly Gly Ser 
1               5           


<210>  52
<211>  12
<212>  PRT
<213>  Artificial Sequence

<220>
<223>  TS(G4S)2 Linker

<400>  52

Thr Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser 
1               5                   10          


<210>  53
<211>  17
<212>  PRT
<213>  Artificial Sequence

<220>
<223>  TS(G4S)3 Linker

<400>  53

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


Ser 
    


<210>  54
<211>  22
<212>  PRT
<213>  Artificial Sequence

<220>
<223>  TS(G4S)4 Linker

<400>  54

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


Ser Gly Gly Gly Gly Ser 
            20          


<210>  55
<211>  27
<212>  PRT
<213>  Artificial Sequence

<220>
<223>  TS(G4S)5 Linker

<400>  55

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


Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser 
            20                  25          


<210>  56
<211>  32
<212>  PRT
<213>  Artificial Sequence

<220>
<223>  TS(G4S)6 Linker

<400>  56

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


Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser 
            20                  25                  30          
