                         SEQUENCE LISTING

<110>  Valerion Therapeutics, LLC
 
<120>  METHODS AND COMPOSITIONS FOR TREATMENT OF PROTEIN 
       AGGREGATION-BASED DISORDERS

<130>  VLRN-041-WO1

<140>  PCT/US2019/055982
<141>  2019-10-11

<150>  62/744,613
<151>  2018-10-11

<150>  62/760,911
<151>  2018-11-13

<150>  62/760,914
<151>  2018-11-13

<160>  35    

<170>  PatentIn version 3.5

<210>  1
<211>  750
<212>  PRT
<213>  Homo sapiens

<400>  1

Met Gly Lys Ser Glu Ser Gln Met Asp Ile Thr Asp Ile Asn Thr Pro 
1               5                   10                  15      


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


Val Leu Val Leu Leu Leu Thr Ile Ile Ala Val Thr Met Ile Ala Leu 
        35                  40                  45              


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


Ser Ala Ala Arg Leu Ile Gln Asn Met Asp Ala Thr Thr Glu Pro Cys 
65                  70                  75                  80  


Thr Asp Phe Phe Lys Tyr Ala Cys Gly Gly Trp Leu Lys Arg Asn Val 
                85                  90                  95      


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


Glu Leu Glu Val Val Leu Lys Asp Val Leu Gln Glu Pro Lys Thr Glu 
        115                 120                 125             


Asp Ile Val Ala Val Gln Lys Ala Lys Ala Leu Tyr Arg Ser Cys Ile 
    130                 135                 140                 


Asn Glu Ser Ala Ile Asp Ser Arg Gly Gly Glu Pro Leu Leu Lys Leu 
145                 150                 155                 160 


Leu Pro Asp Ile Tyr Gly Trp Pro Val Ala Thr Glu Asn Trp Glu Gln 
                165                 170                 175     


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


Ser Lys Tyr Gly Lys Lys Val Leu Ile Asn Leu Phe Val Gly Thr Asp 
        195                 200                 205             


Asp Lys Asn Ser Val Asn His Val Ile His Ile Asp Gln Pro Arg Leu 
    210                 215                 220                 


Gly Leu Pro Ser Arg Asp Tyr Tyr Glu Cys Thr Gly Ile Tyr Lys Glu 
225                 230                 235                 240 


Ala Cys Thr Ala Tyr Val Asp Phe Met Ile Ser Val Ala Arg Leu Ile 
                245                 250                 255     


Arg Gln Glu Glu Arg Leu Pro Ile Asp Glu Asn Gln Leu Ala Leu Glu 
            260                 265                 270         


Met Asn Lys Val Met Glu Leu Glu Lys Glu Ile Ala Asn Ala Thr Ala 
        275                 280                 285             


Lys Pro Glu Asp Arg Asn Asp Pro Met Leu Leu Tyr Asn Lys Met Thr 
    290                 295                 300                 


Leu Ala Gln Ile Gln Asn Asn Phe Ser Leu Glu Ile Asn Gly Lys Pro 
305                 310                 315                 320 


Phe Ser Trp Leu Asn Phe Thr Asn Glu Ile Met Ser Thr Val Asn Ile 
                325                 330                 335     


Ser Ile Thr Asn Glu Glu Asp Val Val Val Tyr Ala Pro Glu Tyr Leu 
            340                 345                 350         


Thr Lys Leu Lys Pro Ile Leu Thr Lys Tyr Ser Ala Arg Asp Leu Gln 
        355                 360                 365             


Asn Leu Met Ser Trp Arg Phe Ile Met Asp Leu Val Ser Ser Leu Ser 
    370                 375                 380                 


Arg Thr Tyr Lys Glu Ser Arg Asn Ala Phe Arg Lys Ala Leu Tyr Gly 
385                 390                 395                 400 


Thr Thr Ser Glu Thr Ala Thr Trp Arg Arg Cys Ala Asn Tyr Val Asn 
                405                 410                 415     


Gly Asn Met Glu Asn Ala Val Gly Arg Leu Tyr Val Glu Ala Ala Phe 
            420                 425                 430         


Ala Gly Glu Ser Lys His Val Val Glu Asp Leu Ile Ala Gln Ile Arg 
        435                 440                 445             


Glu Val Phe Ile Gln Thr Leu Asp Asp Leu Thr Trp Met Asp Ala Glu 
    450                 455                 460                 


Thr Lys Lys Arg Ala Glu Glu Lys Ala Leu Ala Ile Lys Glu Arg Ile 
465                 470                 475                 480 


Gly Tyr Pro Asp Asp Ile Val Ser Asn Asp Asn Lys Leu Asn Asn Glu 
                485                 490                 495     


Tyr Leu Glu Leu Asn Tyr Lys Glu Asp Glu Tyr Phe Glu Asn Ile Ile 
            500                 505                 510         


Gln Asn Leu Lys Phe Ser Gln Ser Lys Gln Leu Lys Lys Leu Arg Glu 
        515                 520                 525             


Lys Val Asp Lys Asp Glu Trp Ile Ser Gly Ala Ala Val Val Asn Ala 
    530                 535                 540                 


Phe Tyr Ser Ser Gly Arg Asn Gln Ile Val Phe Pro Ala Gly Ile Leu 
545                 550                 555                 560 


Gln Pro Pro Phe Phe Ser Ala Gln Gln Ser Asn Ser Leu Asn Tyr Gly 
                565                 570                 575     


Gly Ile Gly Met Val Ile Gly His Glu Ile Thr His Gly Phe Asp Asp 
            580                 585                 590         


Asn Gly Arg Asn Phe Asn Lys Asp Gly Asp Leu Val Asp Trp Trp Thr 
        595                 600                 605             


Gln Gln Ser Ala Ser Asn Phe Lys Glu Gln Ser Gln Cys Met Val Tyr 
    610                 615                 620                 


Gln Tyr Gly Asn Phe Ser Trp Asp Leu Ala Gly Gly Gln His Leu Asn 
625                 630                 635                 640 


Gly Ile Asn Thr Leu Gly Glu Asn Ile Ala Asp Asn Gly Gly Leu Gly 
                645                 650                 655     


Gln Ala Tyr Arg Ala Tyr Gln Asn Tyr Ile Lys Lys Asn Gly Glu Glu 
            660                 665                 670         


Lys Leu Leu Pro Gly Leu Asp Leu Asn His Lys Gln Leu Phe Phe Leu 
        675                 680                 685             


Asn Phe Ala Gln Val Trp Cys Gly Thr Tyr Arg Pro Glu Tyr Ala Val 
    690                 695                 700                 


Asn Ser Ile Lys Thr Asp Val His Ser Pro Gly Asn Phe Arg Ile Ile 
705                 710                 715                 720 


Gly Thr Leu Gln Asn Ser Ala Glu Phe Ser Glu Ala Phe His Cys Arg 
                725                 730                 735     


Lys Asn Ser Tyr Met Asn Pro Glu Lys Lys Cys Arg Val Trp 
            740                 745                 750 


<210>  2
<211>  699
<212>  PRT
<213>  Homo sapiens

<400>  2

Tyr Asp Asp Gly Ile Cys Lys Ser Ser Asp Cys Ile Lys Ser Ala Ala 
1               5                   10                  15      


Arg Leu Ile Gln Asn Met Asp Ala Thr Thr Glu Pro Cys Thr Asp Phe 
            20                  25                  30          


Phe Lys Tyr Ala Cys Gly Gly Trp Leu Lys Arg Asn Val Ile Pro Glu 
        35                  40                  45              


Thr Ser Ser Arg Tyr Gly Asn Phe Asp Ile Leu Arg Asp Glu Leu Glu 
    50                  55                  60                  


Val Val Leu Lys Asp Val Leu Gln Glu Pro Lys Thr Glu Asp Ile Val 
65                  70                  75                  80  


Ala Val Gln Lys Ala Lys Ala Leu Tyr Arg Ser Cys Ile Asn Glu Ser 
                85                  90                  95      


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


Ile Tyr Gly Trp Pro Val Ala Thr Glu Asn Trp Glu Gln Lys Tyr Gly 
        115                 120                 125             


Ala Ser Trp Thr Ala Glu Lys Ala Ile Ala Gln Leu Asn Ser Lys Tyr 
    130                 135                 140                 


Gly Lys Lys Val Leu Ile Asn Leu Phe Val Gly Thr Asp Asp Lys Asn 
145                 150                 155                 160 


Ser Val Asn His Val Ile His Ile Asp Gln Pro Arg Leu Gly Leu Pro 
                165                 170                 175     


Ser Arg Asp Tyr Tyr Glu Cys Thr Gly Ile Tyr Lys Glu Ala Cys Thr 
            180                 185                 190         


Ala Tyr Val Asp Phe Met Ile Ser Val Ala Arg Leu Ile Arg Gln Glu 
        195                 200                 205             


Glu Arg Leu Pro Ile Asp Glu Asn Gln Leu Ala Leu Glu Met Asn Lys 
    210                 215                 220                 


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


Asp Arg Asn Asp Pro Met Leu Leu Tyr Asn Lys Met Thr Leu Ala Gln 
                245                 250                 255     


Ile Gln Asn Asn Phe Ser Leu Glu Ile Asn Gly Lys Pro Phe Ser Trp 
            260                 265                 270         


Leu Asn Phe Thr Asn Glu Ile Met Ser Thr Val Asn Ile Ser Ile Thr 
        275                 280                 285             


Asn Glu Glu Asp Val Val Val Tyr Ala Pro Glu Tyr Leu Thr Lys Leu 
    290                 295                 300                 


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


Ser Trp Arg Phe Ile Met Asp Leu Val Ser Ser Leu Ser Arg Thr Tyr 
                325                 330                 335     


Lys Glu Ser Arg Asn Ala Phe Arg Lys Ala Leu Tyr Gly Thr Thr Ser 
            340                 345                 350         


Glu Thr Ala Thr Trp Arg Arg Cys Ala Asn Tyr Val Asn Gly Asn Met 
        355                 360                 365             


Glu Asn Ala Val Gly Arg Leu Tyr Val Glu Ala Ala Phe Ala Gly Glu 
    370                 375                 380                 


Ser Lys His Val Val Glu Asp Leu Ile Ala Gln Ile Arg Glu Val Phe 
385                 390                 395                 400 


Ile Gln Thr Leu Asp Asp Leu Thr Trp Met Asp Ala Glu Thr Lys Lys 
                405                 410                 415     


Arg Ala Glu Glu Lys Ala Leu Ala Ile Lys Glu Arg Ile Gly Tyr Pro 
            420                 425                 430         


Asp Asp Ile Val Ser Asn Asp Asn Lys Leu Asn Asn Glu Tyr Leu Glu 
        435                 440                 445             


Leu Asn Tyr Lys Glu Asp Glu Tyr Phe Glu Asn Ile Ile Gln Asn Leu 
    450                 455                 460                 


Lys Phe Ser Gln Ser Lys Gln Leu Lys Lys Leu Arg Glu Lys Val Asp 
465                 470                 475                 480 


Lys Asp Glu Trp Ile Ser Gly Ala Ala Val Val Asn Ala Phe Tyr Ser 
                485                 490                 495     


Ser Gly Arg Asn Gln Ile Val Phe Pro Ala Gly Ile Leu Gln Pro Pro 
            500                 505                 510         


Phe Phe Ser Ala Gln Gln Ser Asn Ser Leu Asn Tyr Gly Gly Ile Gly 
        515                 520                 525             


Met Val Ile Gly His Glu Ile Thr His Gly Phe Asp Asp Asn Gly Arg 
    530                 535                 540                 


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


Ala Ser Asn Phe Lys Glu Gln Ser Gln Cys Met Val Tyr Gln Tyr Gly 
                565                 570                 575     


Asn Phe Ser Trp Asp Leu Ala Gly Gly Gln His Leu Asn Gly Ile Asn 
            580                 585                 590         


Thr Leu Gly Glu Asn Ile Ala Asp Asn Gly Gly Leu Gly Gln Ala Tyr 
        595                 600                 605             


Arg Ala Tyr Gln Asn Tyr Ile Lys Lys Asn Gly Glu Glu Lys Leu Leu 
    610                 615                 620                 


Pro Gly Leu Asp Leu Asn His Lys Gln Leu Phe Phe Leu Asn Phe Ala 
625                 630                 635                 640 


Gln Val Trp Cys Gly Thr Tyr Arg Pro Glu Tyr Ala Val Asn Ser Ile 
                645                 650                 655     


Lys Thr Asp Val His Ser Pro Gly Asn Phe Arg Ile Ile Gly Thr Leu 
            660                 665                 670         


Gln Asn Ser Ala Glu Phe Ser Glu Ala Phe His Cys Arg Lys Asn Ser 
        675                 680                 685             


Tyr Met Asn Pro Glu Lys Lys Cys Arg Val Trp 
    690                 695                 


<210>  3
<211>  116
<212>  PRT
<213>  Artificial

<220>
<223>  humanized variable heavy chain

<400>  3

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


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


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


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


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


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


Ala Arg Arg Gly Leu Leu Leu Asp Tyr Trp Gly Gln Gly Thr Leu Val 
            100                 105                 110         


Thr Val Ser Ser 
        115     


<210>  4
<211>  111
<212>  PRT
<213>  Artificial

<220>
<223>  humanized variable light chain

<400>  4

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 Ser Cys Arg Ala Ser Lys Ser Val Ser Thr Ser 
            20                  25                  30          


Ser Tyr Ser Tyr Met His Trp Tyr Gln Gln Lys Pro Glu Lys Ala Pro 
        35                  40                  45              


Lys Leu Leu Ile Lys Tyr Ala Ser Tyr Leu Gln Ser Gly Val Pro Ser 
    50                  55                  60                  


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


Ser Leu Gln Pro Glu Asp Val Ala Thr Tyr Tyr Cys Gln His Ser Arg 
                85                  90                  95      


Glu Phe Pro Trp Thr Phe Gly Ala Gly Thr Lys Leu Glu Leu Lys 
            100                 105                 110     


<210>  5
<211>  13
<212>  PRT
<213>  Artificial

<220>
<223>  glycine-serine linker

<400>  5

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


<210>  6
<211>  224
<212>  PRT
<213>  Artificial

<220>
<223>  humanized heavy chain Fd

<400>  6

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


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


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


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


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


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


Ala Arg Arg Gly Leu Leu Leu Asp Tyr Trp Gly Gln Gly Thr Leu Val 
            100                 105                 110         


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


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


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


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


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


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


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


<210>  7
<211>  218
<212>  PRT
<213>  Artificial

<220>
<223>  humanized light chain

<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 Ser Cys Arg Ala Ser Lys Ser Val Ser Thr Ser 
            20                  25                  30          


Ser Tyr Ser Tyr Met His Trp Tyr Gln Gln Lys Pro Glu Lys Ala Pro 
        35                  40                  45              


Lys Leu Leu Ile Lys Tyr Ala Ser Tyr Leu Gln Ser Gly Val Pro Ser 
    50                  55                  60                  


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


Ser Leu Gln Pro Glu Asp Val Ala Thr Tyr Tyr Cys Gln His Ser Arg 
                85                  90                  95      


Glu Phe Pro Trp Thr Phe Gly Ala Gly Thr Lys Leu Glu Leu Lys Arg 
            100                 105                 110         


Thr Val Ala Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln 
        115                 120                 125             


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


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


Gly Asn Ser Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr 
                165                 170                 175     


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


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


Val Thr Lys Ser Phe Asn Arg Gly Glu Cys 
    210                 215             


<210>  8
<211>  108
<212>  PRT
<213>  Artificial

<220>
<223>  heavy chain IgG1 CH1 and truncated hinge constant domain

<400>  8

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


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


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


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


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


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


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


<210>  9
<211>  107
<212>  PRT
<213>  Artificial

<220>
<223>  human kappa constant domain of Km3 allotype

<400>  9

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


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


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


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


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


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


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


<210>  10
<211>  8
<212>  PRT
<213>  Artificial

<220>
<223>  heavy chain variable (VH) domain CDR1

<400>  10

Gly Phe Thr Phe Ser Asn Tyr Gly 
1               5               


<210>  11
<211>  8
<212>  PRT
<213>  Artificial

<220>
<223>  heavy chain variable (VH) domain CDR2

<400>  11

Ile Ser Ser Gly Ser Ser Thr Ile 
1               5               


<210>  12
<211>  9
<212>  PRT
<213>  Artificial

<220>
<223>  heavy chain variable (VH) domain CDR3

<400>  12

Ala Arg Arg Gly Leu Leu Leu Asp Tyr 
1               5                   


<210>  13
<211>  10
<212>  PRT
<213>  Artificial

<220>
<223>  light chain variable (VL) domain CDR1

<400>  13

Lys Ser Val Ser Thr Ser Ser Tyr Ser Tyr 
1               5                   10  


<210>  14
<211>  3
<212>  PRT
<213>  Artificial

<220>
<223>  light chain variable (VL) domain CDR2

<400>  14

Tyr Ala Ser 
1           


<210>  15
<211>  9
<212>  PRT
<213>  Artificial

<220>
<223>  light chain variable (VL) domain CDR3

<400>  15

Gln His Ser Arg Glu Phe Pro Trp Thr 
1               5                   


<210>  16
<211>  15
<212>  PRT
<213>  Artificial

<220>
<223>  GS3 linker

<400>  16

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


<210>  17
<211>  116
<212>  PRT
<213>  Artificial

<220>
<223>  murine 3E10 heavy chain variable domain (VH)

<400>  17

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


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


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


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


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


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


Ala Arg Arg Gly Leu Leu Leu Asp Tyr Trp Gly Gln Gly Thr Thr Leu 
            100                 105                 110         


Thr Val Ser Ser 
        115     


<210>  18
<211>  111
<212>  PRT
<213>  Artificial

<220>
<223>  murine 3E10 light chain variable domain (VL)

<400>  18

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


Gln Arg Ala Thr Ile Ser Cys Arg Ala Ser Lys Ser Val Ser Thr Ser 
            20                  25                  30          


Ser Tyr Ser Tyr Met His Trp Tyr Gln Gln Lys Pro Gly Gln Pro Pro 
        35                  40                  45              


Lys Leu Leu Ile Lys Tyr Ala Ser Tyr Leu Glu Ser Gly Val Pro Ala 
    50                  55                  60                  


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


Pro Val Glu Glu Glu Asp Ala Ala Thr Tyr Tyr Cys Gln His Ser Arg 
                85                  90                  95      


Glu Phe Pro Trp Thr Phe Gly Gly Gly Thr Lys Leu Glu Leu Lys 
            100                 105                 110     


<210>  19
<211>  5
<212>  PRT
<213>  Artificial

<220>
<223>  heavy chain variable domain CDR1 of murine 3E10 VH

<400>  19

Asn Tyr Gly Met His 
1               5   


<210>  20
<211>  17
<212>  PRT
<213>  Artificial

<220>
<223>  heavy chain variable domain CDR2 of murine 3E10 VH

<400>  20

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


Gly 
    


<210>  21
<211>  7
<212>  PRT
<213>  Artificial

<220>
<223>  heavy chain variable domain CDR3 of murine 3E10 VH

<400>  21

Arg Gly Leu Leu Leu Asp Tyr 
1               5           


<210>  22
<211>  15
<212>  PRT
<213>  Artificial

<220>
<223>  light chain variable domain CDR1 of murine 3E10 VL

<400>  22

Arg Ala Ser Lys Ser Val Ser Thr Ser Ser Tyr Ser Tyr Met His 
1               5                   10                  15  


<210>  23
<211>  7
<212>  PRT
<213>  Artificial

<220>
<223>  light chain variable domain CDR2 of murine 3E10 VL

<400>  23

Tyr Ala Ser Tyr Leu Glu Ser 
1               5           


<210>  24
<211>  9
<212>  PRT
<213>  Artificial

<220>
<223>  light chain variable domain CDR3 of murine 3E10 VL

<400>  24

Gln His Ser Arg Glu Phe Pro Trp Thr 
1               5                   


<210>  25
<211>  17
<212>  PRT
<213>  Artificial

<220>
<223>  heavy chain variable domain CDR2

<400>  25

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


Gly 
    


<210>  26
<211>  15
<212>  PRT
<213>  Artificial

<220>
<223>  light chain variable domain CDR1

<400>  26

Arg Ala Ser Lys Ser Val Ser Thr Ser Ser Tyr Ser Tyr Leu Ala 
1               5                   10                  15  


<210>  27
<211>  7
<212>  PRT
<213>  Artificial

<220>
<223>  light chain variable domain CDR2

<400>  27

Tyr Ala Ser Tyr Leu Gln Ser 
1               5           


<210>  28
<211>  242
<212>  PRT
<213>  Artificial

<220>
<223>  humanized Fv3E10

<400>  28

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 Ser Cys Arg Ala Ser Lys Ser Val Ser Thr Ser 
            20                  25                  30          


Ser Tyr Ser Tyr Met His Trp Tyr Gln Gln Lys Pro Glu Lys Ala Pro 
        35                  40                  45              


Lys Leu Leu Ile Lys Tyr Ala Ser Tyr Leu Gln Ser Gly Val Pro Ser 
    50                  55                  60                  


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


Ser Leu Gln Pro Glu Asp Val Ala Thr Tyr Tyr Cys Gln His Ser Arg 
                85                  90                  95      


Glu Phe Pro Trp Thr Phe Gly Ala Gly Thr Lys Leu Glu Leu Lys Gly 
            100                 105                 110         


Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Glu Val 
        115                 120                 125             


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


Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Asn Tyr Gly Met 
145                 150                 155                 160 


His Trp Ile Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val Ser Tyr 
                165                 170                 175     


Ile Ser Ser Gly Ser Ser Thr Ile Tyr Tyr Ala Asp Ser Val Lys Gly 
            180                 185                 190         


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


Met Asn Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys Ala Arg 
    210                 215                 220                 


Arg Gly Leu Leu Leu Asp Tyr Trp Gly Gln Gly Thr Leu Val Thr Val 
225                 230                 235                 240 


Ser Ser 
        


<210>  29
<211>  936
<212>  PRT
<213>  Artificial

<220>
<223>  heavy chain + neprilysin ectodomain polypeptide

<400>  29

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


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


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


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


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


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


Ala Arg Arg Gly Leu Leu Leu Asp Tyr Trp Gly Gln Gly Thr Leu Val 
            100                 105                 110         


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


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


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


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


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


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


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


Gly Gly Ser Gly Gly Gly Ser Gly Gly Gly Ser Gly Gly Tyr Asp Asp 
225                 230                 235                 240 


Gly Ile Cys Lys Ser Ser Asp Cys Ile Lys Ser Ala Ala Arg Leu Ile 
                245                 250                 255     


Gln Asn Met Asp Ala Thr Thr Glu Pro Cys Thr Asp Phe Phe Lys Tyr 
            260                 265                 270         


Ala Cys Gly Gly Trp Leu Lys Arg Asn Val Ile Pro Glu Thr Ser Ser 
        275                 280                 285             


Arg Tyr Gly Asn Phe Asp Ile Leu Arg Asp Glu Leu Glu Val Val Leu 
    290                 295                 300                 


Lys Asp Val Leu Gln Glu Pro Lys Thr Glu Asp Ile Val Ala Val Gln 
305                 310                 315                 320 


Lys Ala Lys Ala Leu Tyr Arg Ser Cys Ile Asn Glu Ser Ala Ile Asp 
                325                 330                 335     


Ser Arg Gly Gly Glu Pro Leu Leu Lys Leu Leu Pro Asp Ile Tyr Gly 
            340                 345                 350         


Trp Pro Val Ala Thr Glu Asn Trp Glu Gln Lys Tyr Gly Ala Ser Trp 
        355                 360                 365             


Thr Ala Glu Lys Ala Ile Ala Gln Leu Asn Ser Lys Tyr Gly Lys Lys 
    370                 375                 380                 


Val Leu Ile Asn Leu Phe Val Gly Thr Asp Asp Lys Asn Ser Val Asn 
385                 390                 395                 400 


His Val Ile His Ile Asp Gln Pro Arg Leu Gly Leu Pro Ser Arg Asp 
                405                 410                 415     


Tyr Tyr Glu Cys Thr Gly Ile Tyr Lys Glu Ala Cys Thr Ala Tyr Val 
            420                 425                 430         


Asp Phe Met Ile Ser Val Ala Arg Leu Ile Arg Gln Glu Glu Arg Leu 
        435                 440                 445             


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


Leu Glu Lys Glu Ile Ala Asn Ala Thr Ala Lys Pro Glu Asp Arg Asn 
465                 470                 475                 480 


Asp Pro Met Leu Leu Tyr Asn Lys Met Thr Leu Ala Gln Ile Gln Asn 
                485                 490                 495     


Asn Phe Ser Leu Glu Ile Asn Gly Lys Pro Phe Ser Trp Leu Asn Phe 
            500                 505                 510         


Thr Asn Glu Ile Met Ser Thr Val Asn Ile Ser Ile Thr Asn Glu Glu 
        515                 520                 525             


Asp Val Val Val Tyr Ala Pro Glu Tyr Leu Thr Lys Leu Lys Pro Ile 
    530                 535                 540                 


Leu Thr Lys Tyr Ser Ala Arg Asp Leu Gln Asn Leu Met Ser Trp Arg 
545                 550                 555                 560 


Phe Ile Met Asp Leu Val Ser Ser Leu Ser Arg Thr Tyr Lys Glu Ser 
                565                 570                 575     


Arg Asn Ala Phe Arg Lys Ala Leu Tyr Gly Thr Thr Ser Glu Thr Ala 
            580                 585                 590         


Thr Trp Arg Arg Cys Ala Asn Tyr Val Asn Gly Asn Met Glu Asn Ala 
        595                 600                 605             


Val Gly Arg Leu Tyr Val Glu Ala Ala Phe Ala Gly Glu Ser Lys His 
    610                 615                 620                 


Val Val Glu Asp Leu Ile Ala Gln Ile Arg Glu Val Phe Ile Gln Thr 
625                 630                 635                 640 


Leu Asp Asp Leu Thr Trp Met Asp Ala Glu Thr Lys Lys Arg Ala Glu 
                645                 650                 655     


Glu Lys Ala Leu Ala Ile Lys Glu Arg Ile Gly Tyr Pro Asp Asp Ile 
            660                 665                 670         


Val Ser Asn Asp Asn Lys Leu Asn Asn Glu Tyr Leu Glu Leu Asn Tyr 
        675                 680                 685             


Lys Glu Asp Glu Tyr Phe Glu Asn Ile Ile Gln Asn Leu Lys Phe Ser 
    690                 695                 700                 


Gln Ser Lys Gln Leu Lys Lys Leu Arg Glu Lys Val Asp Lys Asp Glu 
705                 710                 715                 720 


Trp Ile Ser Gly Ala Ala Val Val Asn Ala Phe Tyr Ser Ser Gly Arg 
                725                 730                 735     


Asn Gln Ile Val Phe Pro Ala Gly Ile Leu Gln Pro Pro Phe Phe Ser 
            740                 745                 750         


Ala Gln Gln Ser Asn Ser Leu Asn Tyr Gly Gly Ile Gly Met Val Ile 
        755                 760                 765             


Gly His Glu Ile Thr His Gly Phe Asp Asp Asn Gly Arg Asn Phe Asn 
    770                 775                 780                 


Lys Asp Gly Asp Leu Val Asp Trp Trp Thr Gln Gln Ser Ala Ser Asn 
785                 790                 795                 800 


Phe Lys Glu Gln Ser Gln Cys Met Val Tyr Gln Tyr Gly Asn Phe Ser 
                805                 810                 815     


Trp Asp Leu Ala Gly Gly Gln His Leu Asn Gly Ile Asn Thr Leu Gly 
            820                 825                 830         


Glu Asn Ile Ala Asp Asn Gly Gly Leu Gly Gln Ala Tyr Arg Ala Tyr 
        835                 840                 845             


Gln Asn Tyr Ile Lys Lys Asn Gly Glu Glu Lys Leu Leu Pro Gly Leu 
    850                 855                 860                 


Asp Leu Asn His Lys Gln Leu Phe Phe Leu Asn Phe Ala Gln Val Trp 
865                 870                 875                 880 


Cys Gly Thr Tyr Arg Pro Glu Tyr Ala Val Asn Ser Ile Lys Thr Asp 
                885                 890                 895     


Val His Ser Pro Gly Asn Phe Arg Ile Ile Gly Thr Leu Gln Asn Ser 
            900                 905                 910         


Ala Glu Phe Ser Glu Ala Phe His Cys Arg Lys Asn Ser Tyr Met Asn 
        915                 920                 925             


Pro Glu Lys Lys Cys Arg Val Trp 
    930                 935     


<210>  30
<211>  954
<212>  PRT
<213>  Artificial

<220>
<223>  scFv-neprilysin

<400>  30

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 Ser Cys Arg Ala Ser Lys Ser Val Ser Thr Ser 
            20                  25                  30          


Ser Tyr Ser Tyr Met His Trp Tyr Gln Gln Lys Pro Glu Lys Ala Pro 
        35                  40                  45              


Lys Leu Leu Ile Lys Tyr Ala Ser Tyr Leu Gln Ser Gly Val Pro Ser 
    50                  55                  60                  


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


Ser Leu Gln Pro Glu Asp Val Ala Thr Tyr Tyr Cys Gln His Ser Arg 
                85                  90                  95      


Glu Phe Pro Trp Thr Phe Gly Ala Gly Thr Lys Leu Glu Leu Lys Gly 
            100                 105                 110         


Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Glu Val 
        115                 120                 125             


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


Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Asn Tyr Gly Met 
145                 150                 155                 160 


His Trp Ile Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val Ser Tyr 
                165                 170                 175     


Ile Ser Ser Gly Ser Ser Thr Ile Tyr Tyr Ala Asp Ser Val Lys Gly 
            180                 185                 190         


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


Met Asn Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys Ala Arg 
    210                 215                 220                 


Arg Gly Leu Leu Leu Asp Tyr Trp Gly Gln Gly Thr Leu Val Thr Val 
225                 230                 235                 240 


Ser Ser Gly Gly Ser Gly Gly Gly Ser Gly Gly Gly Ser Gly Gly Tyr 
                245                 250                 255     


Asp Asp Gly Ile Cys Lys Ser Ser Asp Cys Ile Lys Ser Ala Ala Arg 
            260                 265                 270         


Leu Ile Gln Asn Met Asp Ala Thr Thr Glu Pro Cys Thr Asp Phe Phe 
        275                 280                 285             


Lys Tyr Ala Cys Gly Gly Trp Leu Lys Arg Asn Val Ile Pro Glu Thr 
    290                 295                 300                 


Ser Ser Arg Tyr Gly Asn Phe Asp Ile Leu Arg Asp Glu Leu Glu Val 
305                 310                 315                 320 


Val Leu Lys Asp Val Leu Gln Glu Pro Lys Thr Glu Asp Ile Val Ala 
                325                 330                 335     


Val Gln Lys Ala Lys Ala Leu Tyr Arg Ser Cys Ile Asn Glu Ser Ala 
            340                 345                 350         


Ile Asp Ser Arg Gly Gly Glu Pro Leu Leu Lys Leu Leu Pro Asp Ile 
        355                 360                 365             


Tyr Gly Trp Pro Val Ala Thr Glu Asn Trp Glu Gln Lys Tyr Gly Ala 
    370                 375                 380                 


Ser Trp Thr Ala Glu Lys Ala Ile Ala Gln Leu Asn Ser Lys Tyr Gly 
385                 390                 395                 400 


Lys Lys Val Leu Ile Asn Leu Phe Val Gly Thr Asp Asp Lys Asn Ser 
                405                 410                 415     


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


Arg Asp Tyr Tyr Glu Cys Thr Gly Ile Tyr Lys Glu Ala Cys Thr Ala 
        435                 440                 445             


Tyr Val Asp Phe Met Ile Ser Val Ala Arg Leu Ile Arg Gln Glu Glu 
    450                 455                 460                 


Arg Leu Pro Ile Asp Glu Asn Gln Leu Ala Leu Glu Met Asn Lys Val 
465                 470                 475                 480 


Met Glu Leu Glu Lys Glu Ile Ala Asn Ala Thr Ala Lys Pro Glu Asp 
                485                 490                 495     


Arg Asn Asp Pro Met Leu Leu Tyr Asn Lys Met Thr Leu Ala Gln Ile 
            500                 505                 510         


Gln Asn Asn Phe Ser Leu Glu Ile Asn Gly Lys Pro Phe Ser Trp Leu 
        515                 520                 525             


Asn Phe Thr Asn Glu Ile Met Ser Thr Val Asn Ile Ser Ile Thr Asn 
    530                 535                 540                 


Glu Glu Asp Val Val Val Tyr Ala Pro Glu Tyr Leu Thr Lys Leu Lys 
545                 550                 555                 560 


Pro Ile Leu Thr Lys Tyr Ser Ala Arg Asp Leu Gln Asn Leu Met Ser 
                565                 570                 575     


Trp Arg Phe Ile Met Asp Leu Val Ser Ser Leu Ser Arg Thr Tyr Lys 
            580                 585                 590         


Glu Ser Arg Asn Ala Phe Arg Lys Ala Leu Tyr Gly Thr Thr Ser Glu 
        595                 600                 605             


Thr Ala Thr Trp Arg Arg Cys Ala Asn Tyr Val Asn Gly Asn Met Glu 
    610                 615                 620                 


Asn Ala Val Gly Arg Leu Tyr Val Glu Ala Ala Phe Ala Gly Glu Ser 
625                 630                 635                 640 


Lys His Val Val Glu Asp Leu Ile Ala Gln Ile Arg Glu Val Phe Ile 
                645                 650                 655     


Gln Thr Leu Asp Asp Leu Thr Trp Met Asp Ala Glu Thr Lys Lys Arg 
            660                 665                 670         


Ala Glu Glu Lys Ala Leu Ala Ile Lys Glu Arg Ile Gly Tyr Pro Asp 
        675                 680                 685             


Asp Ile Val Ser Asn Asp Asn Lys Leu Asn Asn Glu Tyr Leu Glu Leu 
    690                 695                 700                 


Asn Tyr Lys Glu Asp Glu Tyr Phe Glu Asn Ile Ile Gln Asn Leu Lys 
705                 710                 715                 720 


Phe Ser Gln Ser Lys Gln Leu Lys Lys Leu Arg Glu Lys Val Asp Lys 
                725                 730                 735     


Asp Glu Trp Ile Ser Gly Ala Ala Val Val Asn Ala Phe Tyr Ser Ser 
            740                 745                 750         


Gly Arg Asn Gln Ile Val Phe Pro Ala Gly Ile Leu Gln Pro Pro Phe 
        755                 760                 765             


Phe Ser Ala Gln Gln Ser Asn Ser Leu Asn Tyr Gly Gly Ile Gly Met 
    770                 775                 780                 


Val Ile Gly His Glu Ile Thr His Gly Phe Asp Asp Asn Gly Arg Asn 
785                 790                 795                 800 


Phe Asn Lys Asp Gly Asp Leu Val Asp Trp Trp Thr Gln Gln Ser Ala 
                805                 810                 815     


Ser Asn Phe Lys Glu Gln Ser Gln Cys Met Val Tyr Gln Tyr Gly Asn 
            820                 825                 830         


Phe Ser Trp Asp Leu Ala Gly Gly Gln His Leu Asn Gly Ile Asn Thr 
        835                 840                 845             


Leu Gly Glu Asn Ile Ala Asp Asn Gly Gly Leu Gly Gln Ala Tyr Arg 
    850                 855                 860                 


Ala Tyr Gln Asn Tyr Ile Lys Lys Asn Gly Glu Glu Lys Leu Leu Pro 
865                 870                 875                 880 


Gly Leu Asp Leu Asn His Lys Gln Leu Phe Phe Leu Asn Phe Ala Gln 
                885                 890                 895     


Val Trp Cys Gly Thr Tyr Arg Pro Glu Tyr Ala Val Asn Ser Ile Lys 
            900                 905                 910         


Thr Asp Val His Ser Pro Gly Asn Phe Arg Ile Ile Gly Thr Leu Gln 
        915                 920                 925             


Asn Ser Ala Glu Phe Ser Glu Ala Phe His Cys Arg Lys Asn Ser Tyr 
    930                 935                 940                 


Met Asn Pro Glu Lys Lys Cys Arg Val Trp 
945                 950                 


<210>  31
<211>  699
<212>  PRT
<213>  Artificial

<220>
<223>  G399V/G714K human neprilysin variant

<400>  31

Tyr Asp Asp Gly Ile Cys Lys Ser Ser Asp Cys Ile Lys Ser Ala Ala 
1               5                   10                  15      


Arg Leu Ile Gln Asn Met Asp Ala Thr Thr Glu Pro Cys Thr Asp Phe 
            20                  25                  30          


Phe Lys Tyr Ala Cys Gly Gly Trp Leu Lys Arg Asn Val Ile Pro Glu 
        35                  40                  45              


Thr Ser Ser Arg Tyr Gly Asn Phe Asp Ile Leu Arg Asp Glu Leu Glu 
    50                  55                  60                  


Val Val Leu Lys Asp Val Leu Gln Glu Pro Lys Thr Glu Asp Ile Val 
65                  70                  75                  80  


Ala Val Gln Lys Ala Lys Ala Leu Tyr Arg Ser Cys Ile Asn Glu Ser 
                85                  90                  95      


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


Ile Tyr Gly Trp Pro Val Ala Thr Glu Asn Trp Glu Gln Lys Tyr Gly 
        115                 120                 125             


Ala Ser Trp Thr Ala Glu Lys Ala Ile Ala Gln Leu Asn Ser Lys Tyr 
    130                 135                 140                 


Gly Lys Lys Val Leu Ile Asn Leu Phe Val Gly Thr Asp Asp Lys Asn 
145                 150                 155                 160 


Ser Val Asn His Val Ile His Ile Asp Gln Pro Arg Leu Gly Leu Pro 
                165                 170                 175     


Ser Arg Asp Tyr Tyr Glu Cys Thr Gly Ile Tyr Lys Glu Ala Cys Thr 
            180                 185                 190         


Ala Tyr Val Asp Phe Met Ile Ser Val Ala Arg Leu Ile Arg Gln Glu 
        195                 200                 205             


Glu Arg Leu Pro Ile Asp Glu Asn Gln Leu Ala Leu Glu Met Asn Lys 
    210                 215                 220                 


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


Asp Arg Asn Asp Pro Met Leu Leu Tyr Asn Lys Met Thr Leu Ala Gln 
                245                 250                 255     


Ile Gln Asn Asn Phe Ser Leu Glu Ile Asn Gly Lys Pro Phe Ser Trp 
            260                 265                 270         


Leu Asn Phe Thr Asn Glu Ile Met Ser Thr Val Asn Ile Ser Ile Thr 
        275                 280                 285             


Asn Glu Glu Asp Val Val Val Tyr Ala Pro Glu Tyr Leu Thr Lys Leu 
    290                 295                 300                 


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


Ser Trp Arg Phe Ile Met Asp Leu Val Ser Ser Leu Ser Arg Thr Tyr 
                325                 330                 335     


Lys Glu Ser Arg Asn Ala Phe Arg Lys Ala Leu Tyr Val Thr Thr Ser 
            340                 345                 350         


Glu Thr Ala Thr Trp Arg Arg Cys Ala Asn Tyr Val Asn Gly Asn Met 
        355                 360                 365             


Glu Asn Ala Val Gly Arg Leu Tyr Val Glu Ala Ala Phe Ala Gly Glu 
    370                 375                 380                 


Ser Lys His Val Val Glu Asp Leu Ile Ala Gln Ile Arg Glu Val Phe 
385                 390                 395                 400 


Ile Gln Thr Leu Asp Asp Leu Thr Trp Met Asp Ala Glu Thr Lys Lys 
                405                 410                 415     


Arg Ala Glu Glu Lys Ala Leu Ala Ile Lys Glu Arg Ile Gly Tyr Pro 
            420                 425                 430         


Asp Asp Ile Val Ser Asn Asp Asn Lys Leu Asn Asn Glu Tyr Leu Glu 
        435                 440                 445             


Leu Asn Tyr Lys Glu Asp Glu Tyr Phe Glu Asn Ile Ile Gln Asn Leu 
    450                 455                 460                 


Lys Phe Ser Gln Ser Lys Gln Leu Lys Lys Leu Arg Glu Lys Val Asp 
465                 470                 475                 480 


Lys Asp Glu Trp Ile Ser Gly Ala Ala Val Val Asn Ala Phe Tyr Ser 
                485                 490                 495     


Ser Gly Arg Asn Gln Ile Val Phe Pro Ala Gly Ile Leu Gln Pro Pro 
            500                 505                 510         


Phe Phe Ser Ala Gln Gln Ser Asn Ser Leu Asn Tyr Gly Gly Ile Gly 
        515                 520                 525             


Met Val Ile Gly His Glu Ile Thr His Gly Phe Asp Asp Asn Gly Arg 
    530                 535                 540                 


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


Ala Ser Asn Phe Lys Glu Gln Ser Gln Cys Met Val Tyr Gln Tyr Gly 
                565                 570                 575     


Asn Phe Ser Trp Asp Leu Ala Gly Gly Gln His Leu Asn Gly Ile Asn 
            580                 585                 590         


Thr Leu Gly Glu Asn Ile Ala Asp Asn Gly Gly Leu Gly Gln Ala Tyr 
        595                 600                 605             


Arg Ala Tyr Gln Asn Tyr Ile Lys Lys Asn Gly Glu Glu Lys Leu Leu 
    610                 615                 620                 


Pro Gly Leu Asp Leu Asn His Lys Gln Leu Phe Phe Leu Asn Phe Ala 
625                 630                 635                 640 


Gln Val Trp Cys Gly Thr Tyr Arg Pro Glu Tyr Ala Val Asn Ser Ile 
                645                 650                 655     


Lys Thr Asp Val His Ser Pro Lys Asn Phe Arg Ile Ile Gly Thr Leu 
            660                 665                 670         


Gln Asn Ser Ala Glu Phe Ser Glu Ala Phe His Cys Arg Lys Asn Ser 
        675                 680                 685             


Tyr Met Asn Pro Glu Lys Lys Cys Arg Val Trp 
    690                 695                 


<210>  32
<211>  19
<212>  PRT
<213>  Artificial

<220>
<223>  Native human immunoglobulin signal sequence (VH3-49)

<400>  32

Met Glu Phe Gly Leu Ser Trp Leu Phe Leu Val Ala Ile Leu Lys Gly 
1               5                   10                  15      


Val Gln Cys 
            


<210>  33
<211>  955
<212>  PRT
<213>  Artificial

<220>
<223>  H3 Fab-linker-Neprilysin heavy chain

<400>  33

Met Glu Phe Gly Leu Ser Trp Leu Phe Leu Val Ala Ile Leu Lys Gly 
1               5                   10                  15      


Val Gln Cys Glu Val Gln Leu Gln Glu Ser Gly Gly Gly Val Val Gln 
            20                  25                  30          


Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe 
        35                  40                  45              


Ser Asn Tyr Gly Met His Trp Ile Arg Gln Ala Pro Gly Lys Gly Leu 
    50                  55                  60                  


Glu Trp Val Ser Tyr Ile Ser Ser Gly Ser Ser Thr Ile Tyr Tyr Ala 
65                  70                  75                  80  


Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn 
                85                  90                  95      


Thr Leu Tyr Leu Gln Met Asn Ser Leu Arg Ser Glu Asp Thr Ala Val 
            100                 105                 110         


Tyr Tyr Cys Ala Arg Arg Gly Leu Leu Leu Asp Tyr Trp Gly Gln Gly 
        115                 120                 125             


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


Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu 
145                 150                 155                 160 


Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp 
                165                 170                 175     


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


Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser 
        195                 200                 205             


Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro 
    210                 215                 220                 


Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys Asp Lys 
225                 230                 235                 240 


Thr His Thr Gly Gly Ser Gly Gly Gly Ser Gly Gly Gly Ser Gly Gly 
                245                 250                 255     


Tyr Asp Asp Gly Ile Cys Lys Ser Ser Asp Cys Ile Lys Ser Ala Ala 
            260                 265                 270         


Arg Leu Ile Gln Asn Met Asp Ala Thr Thr Glu Pro Cys Thr Asp Phe 
        275                 280                 285             


Phe Lys Tyr Ala Cys Gly Gly Trp Leu Lys Arg Asn Val Ile Pro Glu 
    290                 295                 300                 


Thr Ser Ser Arg Tyr Gly Asn Phe Asp Ile Leu Arg Asp Glu Leu Glu 
305                 310                 315                 320 


Val Val Leu Lys Asp Val Leu Gln Glu Pro Lys Thr Glu Asp Ile Val 
                325                 330                 335     


Ala Val Gln Lys Ala Lys Ala Leu Tyr Arg Ser Cys Ile Asn Glu Ser 
            340                 345                 350         


Ala Ile Asp Ser Arg Gly Gly Glu Pro Leu Leu Lys Leu Leu Pro Asp 
        355                 360                 365             


Ile Tyr Gly Trp Pro Val Ala Thr Glu Asn Trp Glu Gln Lys Tyr Gly 
    370                 375                 380                 


Ala Ser Trp Thr Ala Glu Lys Ala Ile Ala Gln Leu Asn Ser Lys Tyr 
385                 390                 395                 400 


Gly Lys Lys Val Leu Ile Asn Leu Phe Val Gly Thr Asp Asp Lys Asn 
                405                 410                 415     


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


Ser Arg Asp Tyr Tyr Glu Cys Thr Gly Ile Tyr Lys Glu Ala Cys Thr 
        435                 440                 445             


Ala Tyr Val Asp Phe Met Ile Ser Val Ala Arg Leu Ile Arg Gln Glu 
    450                 455                 460                 


Glu Arg Leu Pro Ile Asp Glu Asn Gln Leu Ala Leu Glu Met Asn Lys 
465                 470                 475                 480 


Val Met Glu Leu Glu Lys Glu Ile Ala Asn Ala Thr Ala Lys Pro Glu 
                485                 490                 495     


Asp Arg Asn Asp Pro Met Leu Leu Tyr Asn Lys Met Thr Leu Ala Gln 
            500                 505                 510         


Ile Gln Asn Asn Phe Ser Leu Glu Ile Asn Gly Lys Pro Phe Ser Trp 
        515                 520                 525             


Leu Asn Phe Thr Asn Glu Ile Met Ser Thr Val Asn Ile Ser Ile Thr 
    530                 535                 540                 


Asn Glu Glu Asp Val Val Val Tyr Ala Pro Glu Tyr Leu Thr Lys Leu 
545                 550                 555                 560 


Lys Pro Ile Leu Thr Lys Tyr Ser Ala Arg Asp Leu Gln Asn Leu Met 
                565                 570                 575     


Ser Trp Arg Phe Ile Met Asp Leu Val Ser Ser Leu Ser Arg Thr Tyr 
            580                 585                 590         


Lys Glu Ser Arg Asn Ala Phe Arg Lys Ala Leu Tyr Gly Thr Thr Ser 
        595                 600                 605             


Glu Thr Ala Thr Trp Arg Arg Cys Ala Asn Tyr Val Asn Gly Asn Met 
    610                 615                 620                 


Glu Asn Ala Val Gly Arg Leu Tyr Val Glu Ala Ala Phe Ala Gly Glu 
625                 630                 635                 640 


Ser Lys His Val Val Glu Asp Leu Ile Ala Gln Ile Arg Glu Val Phe 
                645                 650                 655     


Ile Gln Thr Leu Asp Asp Leu Thr Trp Met Asp Ala Glu Thr Lys Lys 
            660                 665                 670         


Arg Ala Glu Glu Lys Ala Leu Ala Ile Lys Glu Arg Ile Gly Tyr Pro 
        675                 680                 685             


Asp Asp Ile Val Ser Asn Asp Asn Lys Leu Asn Asn Glu Tyr Leu Glu 
    690                 695                 700                 


Leu Asn Tyr Lys Glu Asp Glu Tyr Phe Glu Asn Ile Ile Gln Asn Leu 
705                 710                 715                 720 


Lys Phe Ser Gln Ser Lys Gln Leu Lys Lys Leu Arg Glu Lys Val Asp 
                725                 730                 735     


Lys Asp Glu Trp Ile Ser Gly Ala Ala Val Val Asn Ala Phe Tyr Ser 
            740                 745                 750         


Ser Gly Arg Asn Gln Ile Val Phe Pro Ala Gly Ile Leu Gln Pro Pro 
        755                 760                 765             


Phe Phe Ser Ala Gln Gln Ser Asn Ser Leu Asn Tyr Gly Gly Ile Gly 
    770                 775                 780                 


Met Val Ile Gly His Glu Ile Thr His Gly Phe Asp Asp Asn Gly Arg 
785                 790                 795                 800 


Asn Phe Asn Lys Asp Gly Asp Leu Val Asp Trp Trp Thr Gln Gln Ser 
                805                 810                 815     


Ala Ser Asn Phe Lys Glu Gln Ser Gln Cys Met Val Tyr Gln Tyr Gly 
            820                 825                 830         


Asn Phe Ser Trp Asp Leu Ala Gly Gly Gln His Leu Asn Gly Ile Asn 
        835                 840                 845             


Thr Leu Gly Glu Asn Ile Ala Asp Asn Gly Gly Leu Gly Gln Ala Tyr 
    850                 855                 860                 


Arg Ala Tyr Gln Asn Tyr Ile Lys Lys Asn Gly Glu Glu Lys Leu Leu 
865                 870                 875                 880 


Pro Gly Leu Asp Leu Asn His Lys Gln Leu Phe Phe Leu Asn Phe Ala 
                885                 890                 895     


Gln Val Trp Cys Gly Thr Tyr Arg Pro Glu Tyr Ala Val Asn Ser Ile 
            900                 905                 910         


Lys Thr Asp Val His Ser Pro Gly Asn Phe Arg Ile Ile Gly Thr Leu 
        915                 920                 925             


Gln Asn Ser Ala Glu Phe Ser Glu Ala Phe His Cys Arg Lys Asn Ser 
    930                 935                 940                 


Tyr Met Asn Pro Glu Lys Lys Cys Arg Val Trp 
945                 950                 955 


<210>  34
<211>  22
<212>  PRT
<213>  Artificial

<220>
<223>  Native human immunoglobulin signal sequence

<400>  34

Met Asp Met Arg Val Pro Ala Gln Leu Leu Gly Leu Leu Leu Leu Trp 
1               5                   10                  15      


Leu Arg Gly Ala Arg Cys 
            20          


<210>  35
<211>  240
<212>  PRT
<213>  Artificial

<220>
<223>  L2 light chain

<400>  35

Met Asp Met Arg Val Pro Ala Gln Leu Leu Gly Leu Leu Leu Leu Trp 
1               5                   10                  15      


Leu Arg Gly Ala Arg Cys Asp Ile Gln Met Thr Gln Ser Pro Ser Ser 
            20                  25                  30          


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


Lys Ser Val Ser Thr Ser Ser Tyr Ser Tyr Met His Trp Tyr Gln Gln 
    50                  55                  60                  


Lys Pro Glu Lys Ala Pro Lys Leu Leu Ile Lys Tyr Ala Ser Tyr Leu 
65                  70                  75                  80  


Gln Ser Gly Val Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp 
                85                  90                  95      


Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro Glu Asp Val Ala Thr Tyr 
            100                 105                 110         


Tyr Cys Gln His Ser Arg Glu Phe Pro Trp Thr Phe Gly Ala Gly Thr 
        115                 120                 125             


Lys Leu Glu Leu Lys Arg Thr Val Ala Ala Pro Ser Val Phe Ile Phe 
    130                 135                 140                 


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


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


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


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


Lys Ala Asp Tyr Glu Lys His Lys Val Tyr Ala Cys Glu Val Thr His 
    210                 215                 220                 


Gln Gly Leu Ser Ser Pro Val Thr Lys Ser Phe Asn Arg Gly Glu Cys 
225                 230                 235                 240 


