Neonatal Fc Receptor Binding Dimer and Methods of Use

Abstract

The present disclosure relates to dimers of engineered polypeptides having a binding affinity for the neonatal Fc receptor FcRn, and provides an FcRn binding dimer, comprising a first monomer unit, a second monomer unit and an amino acid linker, wherein the first and second monomer units each comprises an FcRn binding motif. The FcRn binding dimer binds FcRn with higher capacity compared to the first monomer unit or second monomer unit alone. The present disclosure also relates to the use of the FcRn binding dimer as an agent for modifying pharmacokinetic and pharmacodynamic properties and as a therapeutic agent.

1 .- 20 . (canceled) 
     
     
         21 . A method of treating a condition selected from the group consisting of auto-immune conditions, allo-immune conditions, epilepsy and seizures in a subject in need thereof, comprising administering a therapeutically effective amount of a neonatal Fc receptor (FcRn) binding dimer, comprising a first monomer unit, a second monomer unit and an amino acid linker, wherein said first and second monomer unit each comprises an FcRn binding motif (BM), which motif consists of the amino acid sequence 
       
         
           
                 
               
                   (SEQ ID NO: 389) 
                 
                 
               
                   EX 2  X 3  X 4  AX 6  X 7  EIR WLPNLX 16 X 17  X 18  QR X 21  AFIX 25   
                 
                     
                 
                   X 26 LX 28  X 29   
                 
             
                
               
            
             
                
                
                
               
            
           
         
         wherein, independently from each other,
 X 2  is selected from A, D, E, F, H, I, K, L, N, Q, R, S, T, V, W and Y; 
 X 3  is selected from A, D, E, F, G, H, I, K, L, M, N, Q, R, S, T, V, W and Y; 
 X 4  is selected from A, D, E, F, G, H, I, K, L, N, Q, R, S, T, V, W and Y; 
 X 6  is selected from A, E, F, G, H, I, K, Q, R, S and V; 
 X 7  is selected from A, F, H, K, N, Q, R, S and V; 
 X 16  is selected from N and T; 
 X 17  is selected from F, W and Y; 
 X 18  is selected from A, D, E and N; 
 X 21  is selected from A, S, V and W; 
 X 25  is selected from D, E, G, H, I, K, L, N, Q, R, S, T, V, W and Y; 
 X 26  is selected from K and S; 
 X 28  is selected from A, D, E, F, H, I, K, L, N, Q, R, S, T, V, W and Y; and 
 X 29  is selected from D and R, 
 
         and wherein said FcRn binding dimer binds FcRn with a higher binding capacity compared to said first monomer or said second monomer alone. 
       
     
     
         22 . The method according to  claim 21 , wherein the BM of at least one of said first and second monomer units consists of an amino acid sequence selected from 
       
         
           
                 
                 
               
                     
                   i) 
                 
                 
               
                   (SEQ ID NO: 391) 
                 
                 
                 
               
                     
                   EX 2  X 3  X 4  AX 6  HEIR WLPNLTX 17  X 18  QR X 21  AFIX 25   
                 
                     
                     
                 
                     
                   KLX 28  D 
                 
             
                
               
            
             
                
               
            
             
                
                
                
               
            
           
         
         wherein, independently from each other, 
         X 2  is selected from A, D, E, F, H, I, K, L, N, Q, R, S, T, V, W and Y; 
         X 3  is selected from A, D, E, G, H, K, L, M, N, Q, R, S, T, V and Y; 
         X 4  is selected from A, D, E, F, G, I, K, L, N, Q, R, S, T, V and Y; 
         X 6  is selected from A, G, K, R, S and V; 
         X 17  is selected from F, W and Y; 
         X 18  is selected from A, D, E and N; 
         X 21  is selected from A, S, V and W; 
         X 25  is selected from D, G, H, K, L, N, R, V and W; 
         X 28  is selected from A, D, E, H, K, L, N, Q, R, S, T, W and Y; and 
         ii) an amino acid sequence which has at least 96% identity to a sequence defined by i). 
       
     
     
         23 . The method according to  claim 21 , wherein said first and second monomer units comprise identical BM sequences. 
     
     
         24 . The method according to  claim 21 , wherein said first and second monomer units comprise different BM sequences. 
     
     
         25 . The method according to  claim 21 , wherein at least one of said first and second monomer units comprises an FcRn binding motif BM corresponding to the sequence from position 8 to position 36 in a sequence selected from the group consisting of SEQ ID NO: 1-353. 
     
     
         26 . The method according to  claim 25 , wherein at least one of said first and second monomer units comprises an FcRn binding motif BM corresponding to the sequence from position 8 to position 36 in a sequence selected from the group consisting of SEQ ID NO:1, SEQ ID NO:20, SEQ ID NO:23, SEQ ID NO:41, SEQ ID NO:44, SEQ ID NO:65, SEQ ID NO:75 and SEQ ID NO:77. 
     
     
         27 . The method according to  claim 21 , wherein at least one of said first and second monomer units comprises a sequence selected from the group consisting of: 
       
         
           
                 
                 
               
                     
                   xi) 
                 
                 
               
                   (SEQ ID NO: 405) 
                 
                 
                 
               
                     
                   AEAKYAK-[BM]-DPSQSSELLSEAKKLNDSQAPK; 
                 
                     
                     
                 
                     
                   xv) 
                 
                 
               
                   (SEQ ID NO: 412) 
                 
                 
                 
               
                     
                   AEAKFAK-[BM]-DPSQSSELLSEAKKLSESQAPK; 
                 
                     
                     
                 
                     
                   xvii) 
                 
                 
               
                   (SEQ ID NO: 427) 
                 
                 
                 
               
                     
                   VDAKYAK-[BM]-DPSQSSELLSEAKKLSESQAPK; 
                 
             
                
               
            
             
                
               
            
             
                
                
                
               
            
             
                
               
            
             
                
                
                
               
            
             
                
               
            
             
                
               
            
           
         
         wherein [BM] is an FcRn binding motif as defined in  claim 21 ; and 
         an amino acid sequence which has at least 94% identity to the sequence defined in xi), xv) or xvii). 
       
     
     
         28 . The method according to  claim 27 , wherein at least one of said first and second monomer units comprises a sequence xi) selected from the group consisting of SEQ ID NO:354-357 and SEQ ID NO:360-367. 
     
     
         29 . The method according to  claim 21 , wherein at least one of said first and second monomer units comprises a sequence selected from the group consisting of: 
       
         
           
                 
                 
               
                     
                   xxi) 
                 
                 
               
                   (SEQ ID NO: 424) 
                 
                 
                 
               
                     
                   VDAKYAK-[BM]-DPSQSSELLSEAKKLNDSQAPK; 
                 
             
                
               
            
             
                
               
            
             
                
               
            
           
         
         wherein [BM] is an FcRn binding motif as defined in  claim 21 ; and 
         xxii) an amino acid sequence which has at least 94% identity to the sequence defined in xxi). 
       
     
     
         30 . The method according to  claim 29 , wherein at least one of said first and second monomer units comprises a sequence xxi) selected from the group consisting of SEQ ID NO:1-353. 
     
     
         31 . The method according to  claim 30 , wherein at least one of said first and second monomer units comprises a sequence xxi) selected from the group consisting of SEQ ID NO:1, SEQ ID NO:20, SEQ ID NO:23, SEQ ID NO:41, SEQ ID NO:44, SEQ ID NO:65, SEQ ID NO:75 and SEQ ID NO:77. 
     
     
         32 . The method according to  claim 28 , wherein said first and second monomer units comprise SEQ ID NO:365 and SEQ ID NO:365; SEQ ID NO:366 and SEQ ID NO:366; or SEQ ID NO:367 and SEQ ID NO:367, respectively. 
     
     
         33 . The method according to  claim 21 , wherein said linker has a general formula selected from
   (GnS m ) p  and (S n G m ) p ,   wherein, independently,   n=1-7,   m=0-7,   n+m≤8 and   p=1-7.   
     
     
         34 . The method according to  claim 21 , wherein said FcRn binding dimer is capable of binding to FcRn with at least 2 times higher capacity than the corresponding first monomer unit or second monomer unit alone. 
     
     
         35 . The method according to  claim 21 , wherein said FcRn binding dimer is comprised in a fusion protein or conjugate comprising
 a first moiety consisting of an FcRn binding dimer as defined in  claim 21 ; and   a second moiety consisting of a polypeptide having a desired biological activity.   
     
     
         36 . The method according to  claim 21 , wherein said FcRn binding dimer inhibits binding of IgG to FcRn. 
     
     
         37 . The method according to  claim 21 , wherein said FcRn binding dimer binds FcRn such that the ability of the FcRn binding dimer to block IgG binding to FcRn is at least 2 times higher compared to the blocking ability of the corresponding first or second monomer unit alone. 
     
     
         38 . The method according to  claim 21 , wherein said FcRn binding dimer is comprised in a composition comprising an FcRn binding dimer as defined in  claim 21  and at least one pharmaceutically acceptable excipient or carrier. 
     
     
         39 . The method according to  claim 35 , wherein said fusion protein or conjugate inhibits binding of IgG to FcRn. 
     
     
         40 . The method according to  claim 35 , wherein said fusion protein or conjugate binds FcRn such that the ability of the FcRn binding dimer to block IgG binding to FcRn is at least 2 times higher compared to the blocking ability of the corresponding first or second monomer unit alone. 
     
     
         41 . The method according to  claim 35 , wherein said fusion protein or conjugate is comprised in a composition comprising a fusion protein or conjugate as defined in  claim 35  and at least one pharmaceutically acceptable excipient or carrier.