                               SEQUENCE LISTING

<110> REGENERON PHARMACEUTICALS, INC.
 
<120> METHODS FOR TREATING HYPERLIPIDEMIA WITH AN 
      ANGPTL8 INHIBITOR AND AN ANGPTL3 INHIBITOR

<130> 0431.25PCT

<140>
<141>

<150> 62/453,110
<151> 2017-02-01

<150> 62/319,980
<151> 2016-04-08

<160> 19    

<170> PatentIn version 3.5

<210> 1
<211> 120
<212> PRT
<213> Artificial Sequence

<220>
<221> source
<223> /note="Description of Artificial Sequence: Synthetic
      polypeptide"

<220>
<221> source
<223> /note="HCVR"

<400> 1
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 
1               5                   10                  15      


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


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


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


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


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


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


Gly Thr Leu Val Thr Val Ser Ser 
        115                 120 


<210> 2
<211> 8
<212> PRT
<213> Artificial Sequence

<220>
<221> source
<223> /note="Description of Artificial Sequence: Synthetic
      peptide"

<220>
<221> source
<223> /note="HCDR1"

<400> 2
Gly Phe Thr Phe Asn Asn His Glu 
1               5               


<210> 3
<211> 8
<212> PRT
<213> Artificial Sequence

<220>
<221> source
<223> /note="Description of Artificial Sequence: Synthetic
      peptide"

<220>
<221> source
<223> /note="HCDR2"

<400> 3
Ile Ser Ser Ser Gly Asn Thr Val 
1               5               


<210> 4
<211> 13
<212> PRT
<213> Artificial Sequence

<220>
<221> source
<223> /note="Description of Artificial Sequence: Synthetic
      peptide"

<220>
<221> source
<223> /note="HCDR3"

<400> 4
Ala Arg Asp His Leu Ser Gly Thr Ser Pro Leu Ser Tyr 
1               5                   10              


<210> 5
<211> 107
<212> PRT
<213> Artificial Sequence

<220>
<221> source
<223> /note="Description of Artificial Sequence: Synthetic
      polypeptide"

<220>
<221> source
<223> /note="LCVR"

<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 Gln Ala Ser Gln Asp Ile Asn Asn Tyr 
            20                  25                  30          


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


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


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


Glu Asp Ile Ala Thr Tyr Phe Cys Gln Gln Tyr Glu Asn Leu Pro Tyr 
                85                  90                  95      


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


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

<220>
<221> source
<223> /note="Description of Artificial Sequence: Synthetic
      peptide"

<220>
<221> source
<223> /note="LCDR1"

<400> 6
Gln Asp Ile Asn Asn Tyr 
1               5       


<210> 7
<211> 3
<212> PRT
<213> Artificial Sequence

<220>
<221> source
<223> /note="Description of Artificial Sequence: Synthetic
      peptide"

<220>
<221> source
<223> /note="LCDR2"

<400> 7
Asp Ala Ser 
1           


<210> 8
<211> 9
<212> PRT
<213> Artificial Sequence

<220>
<221> source
<223> /note="Description of Artificial Sequence: Synthetic
      peptide"

<220>
<221> source
<223> /note="LCDR3"

<400> 8
Gln Gln Tyr Glu Asn Leu Pro Tyr Thr 
1               5                   


<210> 9
<211> 413
<212> PRT
<213> Artificial Sequence

<220>
<221> source
<223> /note="Description of Artificial Sequence: Synthetic
      polypeptide"

<220>
<221> source
<223> /note="hANGPTL8-mFc
      aa 1-177: amino acids 22-198 of NP_061157.3
      aa 178-413: GPG linker and mouse IgG2a Fc tag"

<400> 9
Ala Pro Met Gly Gly Pro Glu Leu Ala Gln His Glu Glu Leu Thr Leu 
1               5                   10                  15      


Leu Phe His Gly Thr Leu Gln Leu Gly Gln Ala Leu Asn Gly Val Tyr 
            20                  25                  30          


Arg Thr Thr Glu Gly Arg Leu Thr Lys Ala Arg Asn Ser Leu Gly Leu 
        35                  40                  45              


Tyr Gly Arg Thr Ile Glu Leu Leu Gly Gln Glu Val Ser Arg Gly Arg 
    50                  55                  60                  


Asp Ala Ala Gln Glu Leu Arg Ala Ser Leu Leu Glu Thr Gln Met Glu 
65                  70                  75                  80  


Glu Asp Ile Leu Gln Leu Gln Ala Glu Ala Thr Ala Glu Val Leu Gly 
                85                  90                  95      


Glu Val Ala Gln Ala Gln Lys Val Leu Arg Asp Ser Val Gln Arg Leu 
            100                 105                 110         


Glu Val Gln Leu Arg Ser Ala Trp Leu Gly Pro Ala Tyr Arg Glu Phe 
        115                 120                 125             


Glu Val Leu Lys Ala His Ala Asp Lys Gln Ser His Ile Leu Trp Ala 
    130                 135                 140                 


Leu Thr Gly His Val Gln Arg Gln Arg Arg Glu Met Val Ala Gln Gln 
145                 150                 155                 160 


His Arg Leu Arg Gln Ile Gln Glu Arg Leu His Thr Ala Ala Leu Pro 
                165                 170                 175     


Ala Gly Pro Gly Glu Pro Arg Gly Pro Thr Ile Lys Pro Cys Pro Pro 
            180                 185                 190         


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


Phe Pro Pro Lys Ile Lys Asp Val Leu Met Ile Ser Leu Ser Pro Ile 
    210                 215                 220                 


Val Thr Cys Val Val Val Asp Val Ser Glu Asp Asp Pro Asp Val Gln 
225                 230                 235                 240 


Ile Ser Trp Phe Val Asn Asn Val Glu Val His Thr Ala Gln Thr Gln 
                245                 250                 255     


Thr His Arg Glu Asp Tyr Asn Ser Thr Leu Arg Val Val Ser Ala Leu 
            260                 265                 270         


Pro Ile Gln His Gln Asp Trp Met Ser Gly Lys Glu Phe Lys Cys Lys 
        275                 280                 285             


Val Asn Asn Lys Asp Leu Pro Ala Pro Ile Glu Arg Thr Ile Ser Lys 
    290                 295                 300                 


Pro Lys Gly Ser Val Arg Ala Pro Gln Val Tyr Val Leu Pro Pro Pro 
305                 310                 315                 320 


Glu Glu Glu Met Thr Lys Lys Gln Val Thr Leu Thr Cys Met Val Thr 
                325                 330                 335     


Asp Phe Met Pro Glu Asp Ile Tyr Val Glu Trp Thr Asn Asn Gly Lys 
            340                 345                 350         


Thr Glu Leu Asn Tyr Lys Asn Thr Glu Pro Val Leu Asp Ser Asp Gly 
        355                 360                 365             


Ser Tyr Phe Met Tyr Ser Lys Leu Arg Val Glu Lys Lys Asn Trp Val 
    370                 375                 380                 


Glu Arg Asn Ser Tyr Ser Cys Ser Val Val His Glu Gly Leu His Asn 
385                 390                 395                 400 


His His Thr Thr Lys Ser Phe Ser Arg Thr Pro Gly Lys 
                405                 410             


<210> 10
<211> 126
<212> PRT
<213> Artificial Sequence

<220>
<221> source
<223> /note="Description of Artificial Sequence: Synthetic
      polypeptide"

<220>
<221> source
<223> /note="Evinacumab HCVR"

<400> 10
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Val Ile Gln Pro Gly Gly 
1               5                   10                  15      


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


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


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


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


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


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


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


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

<220>
<221> source
<223> /note="Description of Artificial Sequence: Synthetic
      peptide"

<220>
<221> source
<223> /note="Evinacumab HCDR1"

<400> 11
Gly Phe Thr Phe Asp Asp Tyr Ala 
1               5               


<210> 12
<211> 8
<212> PRT
<213> Artificial Sequence

<220>
<221> source
<223> /note="Description of Artificial Sequence: Synthetic
      peptide"

<220>
<221> source
<223> /note="Evinacumab HCDR2"

<400> 12
Ile Ser Gly Asp Gly Gly Ser Thr 
1               5               


<210> 13
<211> 19
<212> PRT
<213> Artificial Sequence

<220>
<221> source
<223> /note="Description of Artificial Sequence: Synthetic
      peptide"

<220>
<221> source
<223> /note="Evinacumab HCDR3"

<400> 13
Ala Lys Asp Leu Arg Asn Thr Ile Phe Gly Val Val Ile Pro Asp Ala 
1               5                   10                  15      


Phe Asp Ile 
            


<210> 14
<211> 108
<212> PRT
<213> Artificial Sequence

<220>
<221> source
<223> /note="Description of Artificial Sequence: Synthetic
      polypeptide"

<220>
<221> source
<223> /note="Evinacumab LCVR"

<400> 14
Asp Ile Gln Met Thr Gln Ser Pro Ser Thr Leu Ser Ala Ser Val Gly 
1               5                   10                  15      


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


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


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


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


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


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


<210> 15
<211> 6
<212> PRT
<213> Artificial Sequence

<220>
<221> source
<223> /note="Description of Artificial Sequence: Synthetic
      peptide"

<220>
<221> source
<223> /note="Evinacumab LCDR1"

<400> 15
Gln Ser Ile Arg Ser Trp 
1               5       


<210> 16
<211> 3
<212> PRT
<213> Artificial Sequence

<220>
<221> source
<223> /note="Description of Artificial Sequence: Synthetic
      peptide"

<220>
<221> source
<223> /note="Evinacumab LCDR2"

<400> 16
Lys Ala Ser 
1           


<210> 17
<211> 9
<212> PRT
<213> Artificial Sequence

<220>
<221> source
<223> /note="Description of Artificial Sequence: Synthetic
      peptide"

<220>
<221> source
<223> /note="Evinacumab LCDR3"

<400> 17
Gln Gln Tyr Asn Ser Tyr Ser Tyr Thr 
1               5                   


<210> 18
<211> 460
<212> PRT
<213> Artificial Sequence

<220>
<221> source
<223> /note="Description of Artificial Sequence: Synthetic
      polypeptide"

<220>
<221> source
<223> /note="hANGPTL3"

<400> 18
Met Phe Thr Ile Lys Leu Leu Leu Phe Ile Val Pro Leu Val Ile Ser 
1               5                   10                  15      


Ser Arg Ile Asp Gln Asp Asn Ser Ser Phe Asp Ser Leu Ser Pro Glu 
            20                  25                  30          


Pro Lys Ser Arg Phe Ala Met Leu Asp Asp Val Lys Ile Leu Ala Asn 
        35                  40                  45              


Gly Leu Leu Gln Leu Gly His Gly Leu Lys Asp Phe Val His Lys Thr 
    50                  55                  60                  


Lys Gly Gln Ile Asn Asp Ile Phe Gln Lys Leu Asn Ile Phe Asp Gln 
65                  70                  75                  80  


Ser Phe Tyr Asp Leu Ser Leu Gln Thr Ser Glu Ile Lys Glu Glu Glu 
                85                  90                  95      


Lys Glu Leu Arg Arg Thr Thr Tyr Lys Leu Gln Val Lys Asn Glu Glu 
            100                 105                 110         


Val Lys Asn Met Ser Leu Glu Leu Asn Ser Lys Leu Glu Ser Leu Leu 
        115                 120                 125             


Glu Glu Lys Ile Leu Leu Gln Gln Lys Val Lys Tyr Leu Glu Glu Gln 
    130                 135                 140                 


Leu Thr Asn Leu Ile Gln Asn Gln Pro Glu Thr Pro Glu His Pro Glu 
145                 150                 155                 160 


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


Asp Leu Leu Gln Thr Val Glu Asp Gln Tyr Lys Gln Leu Asn Gln Gln 
            180                 185                 190         


His Ser Gln Ile Lys Glu Ile Glu Asn Gln Leu Arg Arg Thr Ser Ile 
        195                 200                 205             


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


Thr Thr Pro Phe Leu Gln Leu Asn Glu Ile Arg Asn Val Lys His Asp 
225                 230                 235                 240 


Gly Ile Pro Ala Glu Cys Thr Thr Ile Tyr Asn Arg Gly Glu His Thr 
                245                 250                 255     


Ser Gly Met Tyr Ala Ile Arg Pro Ser Asn Ser Gln Val Phe His Val 
            260                 265                 270         


Tyr Cys Asp Val Ile Ser Gly Ser Pro Trp Thr Leu Ile Gln His Arg 
        275                 280                 285             


Ile Asp Gly Ser Gln Asn Phe Asn Glu Thr Trp Glu Asn Tyr Lys Tyr 
    290                 295                 300                 


Gly Phe Gly Arg Leu Asp Gly Glu Phe Trp Leu Gly Leu Glu Lys Ile 
305                 310                 315                 320 


Tyr Ser Ile Val Lys Gln Ser Asn Tyr Val Leu Arg Ile Glu Leu Glu 
                325                 330                 335     


Asp Trp Lys Asp Asn Lys His Tyr Ile Glu Tyr Ser Phe Tyr Leu Gly 
            340                 345                 350         


Asn His Glu Thr Asn Tyr Thr Leu His Leu Val Ala Ile Thr Gly Asn 
        355                 360                 365             


Val Pro Asn Ala Ile Pro Glu Asn Lys Asp Leu Val Phe Ser Thr Trp 
    370                 375                 380                 


Asp His Lys Ala Lys Gly His Phe Asn Cys Pro Glu Gly Tyr Ser Gly 
385                 390                 395                 400 


Gly Trp Trp Trp His Asp Glu Cys Gly Glu Asn Asn Leu Asn Gly Lys 
                405                 410                 415     


Tyr Asn Lys Pro Arg Ala Lys Ser Lys Pro Glu Arg Arg Arg Gly Leu 
            420                 425                 430         


Ser Trp Lys Ser Gln Asn Gly Arg Leu Tyr Ser Ile Lys Ser Thr Lys 
        435                 440                 445             


Met Leu Ile His Pro Thr Asp Ser Glu Ser Phe Glu 
    450                 455                 460 


<210> 19
<211> 198
<212> PRT
<213> Homo sapiens

<400> 19
Met Pro Val Pro Ala Leu Cys Leu Leu Trp Ala Leu Ala Met Val Thr 
1               5                   10                  15      


Arg Pro Ala Ser Ala Ala Pro Met Gly Gly Pro Glu Leu Ala Gln His 
            20                  25                  30          


Glu Glu Leu Thr Leu Leu Phe His Gly Thr Leu Gln Leu Gly Gln Ala 
        35                  40                  45              


Leu Asn Gly Val Tyr Arg Thr Thr Glu Gly Arg Leu Thr Lys Ala Arg 
    50                  55                  60                  


Asn Ser Leu Gly Leu Tyr Gly Arg Thr Ile Glu Leu Leu Gly Gln Glu 
65                  70                  75                  80  


Val Ser Arg Gly Arg Asp Ala Ala Gln Glu Leu Arg Ala Ser Leu Leu 
                85                  90                  95      


Glu Thr Gln Met Glu Glu Asp Ile Leu Gln Leu Gln Ala Glu Ala Thr 
            100                 105                 110         


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


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


Ala Tyr Arg Glu Phe Glu Val Leu Lys Ala His Ala Asp Lys Gln Ser 
145                 150                 155                 160 


His Ile Leu Trp Ala Leu Thr Gly His Val Gln Arg Gln Arg Arg Glu 
                165                 170                 175     


Met Val Ala Gln Gln His Arg Leu Arg Gln Ile Gln Glu Arg Leu His 
            180                 185                 190         


Thr Ala Ala Leu Pro Ala 
        195             


