Antibody-coupled cyclic peptide tyrosine tyrosine compounds as modulators of neuropeptide y receptors

Abstract

The present invention comprises conjugates comprising a monoclonal antibody conjugated to a cyclic PYY peptide. The invention also relates to pharmaceutical compositions and methods for use thereof. The novel conjugates are useful for preventing, treating or ameliorating diseases and disorders disclosed herein.

1 . A conjugate comprising a monoclonal antibody or an antigen binding fragment thereof coupled to a cyclic PYY peptide, wherein the cyclic PYY peptide is represented by Formula I or a derivative or pharmaceutically acceptable salt thereof: 
       
         
           
           
               
               
           
         
         wherein
 p is 0 or 1; 
 m is 0, 1, 2, 3, 4, or 5; 
 n is 1, 2, 3, or 4; 
 q is 0 or 1; provided that q is 1 only when Z 30  is absent; 
 BRIDGE is -Ph-CH 2 —S—, -triazolyl-, —NHC(O)CH 2 S—, —SCH 2 C(O)NH—, —(OCH 2 CH 2 ) 2 NHC(O)CH 2 S, —NHC(O)—, or —CH 2 S—; 
 Z 4  is K, A, E, S, or R; 
 Z 7  is A or K; 
 Z 9  is G or K; 
 Z 11  is D or K; 
 Z 22  is A or K; 
 Z 23  is S or K; 
 Z 26  is A or H; 
 Z 30  is L, W, absent, or K; 
 provided that Z 30  is absent only when q is 1; 
 Z 34  is 
 
       
       
         
           
           
               
               
           
         
         
           Z 35  is 
         
       
       
         
           
           
               
               
           
         
       
       wherein cyclic PYY peptide of Formula I comprises at least one lysine residue (K), in which the amino group of the side chain of the at least one lysine is acylated and is further covalently linked, via a thioether bond, to the monoclonal antibody or the antigen binding fragment. 
     
     
         2 . (canceled) 
     
     
         3 . The conjugate of  claim 1 , wherein the cyclic PYY peptide is represented by Formula I or the derivative or pharmaceutically acceptable salt thereof, wherein:
 p is 0 or 1;   m is 0, 1, 2, 3, 4, or 5;   n is 1, 2, 3, or 4;   q is 0 or 1; provided that q is 1 only when Z 30  is absent;   BRIDGE is -Ph-CH 2 —S—, —NHC(O)CH 2 S—, —SCH 2 C(O)NH 2 —, —(OCH 2 CH 2 ) 2 NHC(O)CH 2 S, —NHC(O)—, or —CH 2 S—;   Z 4  is K, A, E, S, or R;   Z 7  is A or K, wherein the amino side chain of said K is optionally acylated with   
       
         
           
           
               
               
           
         
         wherein i is an integer of 0 to 24, and X=Br, I or Cl, —C(O)CH 2 Br, —C(O)CH 2 I, or —C(O)CH 2 Cl; 
         Z 9  is G or K, wherein the amino side chain of said K is optionally acylated with 
       
       
         
           
           
               
               
           
         
         wherein i is an integer of 0 to 24, and X=Br, I or Cl, —C(O)CH 2 Br, —C(O)CH 2 I, or —C(O)CH 2 Cl; 
         Z 11  is D or K, wherein the amino side chain of said K is optionally acylated with 
       
       
         
           
           
               
               
           
         
         wherein i is an integer of 0 to 24, and X=Br, I or Cl, —C(O)CH 2 Br, —C(O)CH 2 I, or —C(O)CH 2 Cl; 
         Z 22  is A or K, wherein the amino side chain of said K is optionally acylated with 
       
       
         
           
           
               
               
           
         
         wherein i is an integer of 0 to 24, and X=Br, I or Cl, —C(O)CH 2 Br, —C(O)CH 2 I, or —C(O)CH 2 Cl; 
         Z 23  is S or K, wherein the amino side chain of said K is optionally acylated with 
       
       
         
           
           
               
               
           
         
         wherein i is an integer of 0 to 24, and X=Br, I or Cl, —C(O)CH 2 Br, —C(O)CH 2 I, or —C(O)CH 2 Cl; 
         Z 26  is A or H; 
         Z 30  is L or K, wherein the amino side chain of said K is optionally acylated with 
       
       
         
           
           
               
               
           
         
         Z 34  is 
       
       
         
           
           
               
               
           
         
          and 
         Z 35  is 
       
       
         
           
           
               
               
           
         
         wherein at least one of Z 7 , Z 9 , Z 11 , Z 22 , Z 23  and Z 30  in Formula I is lysine (K). 
       
     
     
         4 . The conjugate of  claim 1 , wherein the cyclic PYY peptide is represented by Formula I or the derivative or pharmaceutically acceptable salt thereof, wherein:
 p is 0 or 1;   m is 0, 1, 2, 3, or 5;   n is 1, 2, or 4;   q is 0 or 1; provided that q may be 1 only when Z 30  is absent;   BRIDGE is -Ph-CH 2 —S—, -triazolyl-, —NHC(O)CH 2 S—, —(OCH 2 CH 2 ) 2 NHC(O)CH 2 S, —NHC(O)—, or —CH 2 S—;   Z 4  is K, A, E, S, or R;   Z 7  is A or K, wherein the amino side chain of said K is optionally acylated with   
       
         
           
           
               
               
           
         
         Z 9  is G or K, 
         Z 11  is D or K, wherein the amino side chain of said K is optionally acylated with 
       
       
         
           
           
               
               
           
         
          —C(O)CH 2 Br, 
         Z 22  is A or K, wherein the amino side chain of said K is optionally acylated with 
       
       
         
           
           
               
               
           
         
         Z 23  is S or K, wherein the amino side chain of said K is optionally acylated with 
       
       
         
           
           
               
               
           
         
         Z 26  is A or H, 
         Z 30  is L or K, wherein the amino side chain of said K is optionally acylated with 
       
       
         
           
           
               
               
           
         
         Z 34  is 
       
       
         
           
           
               
               
           
         
         Z 35  is 
       
       
         
           
           
               
               
           
         
         wherein at least one of Z 7 , Z 9 , Z 11 , Z 22 , Z 23  and Z 30  in Formula I is lysine (K). 
       
     
     
         5 . The conjugate of  claim 1 , wherein the cyclic PYY peptide is selected from the group consisting of SEQ ID NOs:1, and 73-100, or a pharmaceutically acceptable salt thereof. 
     
     
         6 . The conjugate of  claim 1 , wherein the monoclonal antibody or the antigen binding fragment thereof comprises a cysteine residue, the sulfhydryl group of which is covalently linked to the cyclic PYY peptide at the at least one lysine residue of the cyclic PYY peptide via a linker. 
     
     
         7 . The conjugate of  claim 6 , wherein the linker comprises one selected from the group consisting of polyethylene glycol (PEG)8-triazolyl-CH 2 CH 2 CO-PEG4, a PEG chain of 2-24 PEG units, an alkyl chain containing 2-10 carbon atoms, (Gly 4 Ser) j  wherein j=1-4, (AlaPro) u  wherein u=1-10, and a bond. 
     
     
         8 . The conjugate of  claim 7 , wherein only one of Z 7 , Z 9 , Z 11 , Z 22  and Z 23  in Formula I is lysine, and the lysine is covalently linked to an engineered cysteine residue of the monoclonal antibody or the antigen binding fragment thereof via the linker. 
     
     
         9 . A conjugate comprising a monoclonal antibody or an antigen binding fragment thereof coupled to a cyclic PYY peptide, wherein the conjugate comprises a sequence selected from the group consisting of SEQ ID NOs: 102-127 or a pharmaceutically acceptable salt thereof,
 wherein mAb represents the monoclonal antibody or the antigen binding fragment thereof, and ] 2  represents that 1 or 2 of the cyclic PYY peptide are covalently conjugated to the mAb.   
     
     
         10 . The conjugate of  claim 1 , wherein the monoclonal antibody or the antigen binding fragment thereof comprises a heavy chain complementarity determining region 1 (HCDR1), HCDR2, HCDR3, and a light chain complementarity determining region 1 (LCDR1), LCDR2, and LCDR3, having the polypeptide sequences of SEQ ID NO: 141, 142, 143, 144, 145, and 146, respectively 
     
     
         11 . The conjugate of  claim 10 , wherein the isolated monoclonal antibody comprises a heavy chain variable domain (VH) having the polypeptide sequence of SEQ ID NO:137, and a light chain variable domain (VL) having the polypeptide sequence of SEQ ID NO:139. 
     
     
         12 . The conjugate of  claim 11 , further comprising a Fc portion. 
     
     
         13 . The conjugate of  claim 12 , comprising a heavy chain (HC) having the polypeptide sequence of SEQ ID NO:138 and a light chain (LC) having the polypeptide sequence of SEQ ID NO:140. 
     
     
         14 .- 15 . (canceled) 
     
     
         16 . A pharmaceutical composition comprising the conjugate of  claim 1  and a pharmaceutically acceptable carrier. 
     
     
         17 . A method for treating or preventing a disease or disorder in a subject in need thereof, wherein said disease or disorder is selected from the group consisting of obesity, type I or type II diabetes, metabolic syndrome, insulin resistance, impaired glucose tolerance, hyperglycemia, hyperinsulinemia, hypertriglyceridemia, hypoglycemia due to congenital hyperinsulinism (CHI), dyslipidemia, atherosclerosis, diabetic nephropathy, and hypertension, unmanaged cholesterol and/or lipid levels, osteoporosis, inflammation, non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), renal disease, and eczema, the method comprising administering to the subject in need thereof an effective amount of the pharmaceutical composition of  claim 16 . 
     
     
         18 . A method of reducing food intake in a subject in need thereof, the method comprising administering to the subject in need thereof an effective amount of the pharmaceutical composition of  claim 16 . 
     
     
         19 . A method of modulating Y2 receptor activity in a subject in need thereof, the method comprising administering to the subject in need thereof an effective amount of the pharmaceutical composition of  claim 16 . 
     
     
         20 . (canceled) 
     
     
         21 . The method of  claim 17 , wherein the pharmaceutical composition is administered in a combination with at least one antidiabetic agent. 
     
     
         22 . The method of  claim 21 , wherein said antidiabetic agent is a glucagon-like-peptide-1 receptor modulator. 
     
     
         23 . The method of  claim 21 , wherein the pharmaceutical composition is administered in combination with liraglutide. 
     
     
         24 . A kit comprising the conjugate of  claim 1 , preferably further comprising a liraglutide and a device for injection. 
     
     
         25 . (canceled)