Growth Hormones with Prolonged In-Vivo Efficacy

Abstract

The present invention relates to polypeptide compound optimized for subcutaneous administration, exemplified by growth hormone conjugates having a linker providing non-covalent binding to albumin.

1 . A growth hormone conjugate which comprises a growth hormone compound (GH) linked to an albumin binding residue via a hydrophilic spacer, or a pharmaceutically acceptable salt, solvate or prodrug thereof. 
     
     
         2 . The conjugate of  claim 1  wherein the growth hormone conjugate has the formula (I):
   A-W—B-GH  (I)
 
 wherein: 
 GH is a growth hormone compound, 
 B is a hydrophilic spacer, 
 W is a chemical group linking A and B, and 
 A is an albumin binding residue. 
 
     
     
         3 . The conjugate of  claim 1 , wherein GH is hGH (SEQ ID NO:1). 
     
     
         4 . The conjugate of  claim 2  wherein B has the formula
   —X 1 —X 2 —X 3 —X 4 —
 
 wherein 
 X 1  is —W 1 —[(CHR 1 ) l1 —W 2 ] m1 —{[(CH 2 ) n1 E1] m2 —[(CHR 2 ) l2 —W 3 ] m3 } n2 —; 
 X 2  is —[(CHR 3 ) l3 —W 4 ] m4 —{[(CH 2 ) n3 E2] m5 —[(CHR 4 ) l4 —W 5 ] m6 } n4 —; 
 X 3  is —[(CHR 5 ) l5 —W 6 ] m7 —; 
 X 4  is F-D1-(CH 2 ) l6 -D2-; 
 l1, l2, l3, l4, l5 and l6 independently are selected from 0-16; 
 m1, m3, m4, m6 and m7 independently are selected from 0-10; 
 m2 and m5 independently are selected from 0-25; 
 n1, n2, n3 and n4 independently are selected from 0-16; 
 F is aryl, hetaryl, pyrrolidine-2,5-dione or a valence bond, wherein the aryl and hetaryl groups are optionally substituted with halogen, —CN, —OH, —C(O)OH, —C(O)NH 2 , —S(O) 2 OH or C 1-6 -alkyl; 
 R 1 , R 2 , R 3 , R 4  and R 5  independently are selected from hydrogen, —C(O)OH, —C(O)NH 2 , —S(O)OH, —S(O) 2 OH, —NH—C(═NH)—NH 2 , C 1-6 -alkyl, aryl or hetaryl; 
 wherein 
 the alkyl, aryl and hetaryl groups optionally are substituted with halogen, —C(O)OH, —C(O)NH 2 , —S(O)OH, —S(O) 2 OH, —CN or —OH; 
 D1, D2, E1 and E2 independently are selected from —O—, —NR 6 —, —N(COR 7 )— or a valence bond, wherein R 6  and R 7  independently represent hydrogen or C 1-6 -alkyl; W 1  to W 6  independently are selected from —C(O)NH—, —NHC(O)—, —C(O)NHCH 2 —, —CH 2 NHC(O)—, —C(O)NHS(O) 2 —, —S(O) 2 NHC(O)—, —OC(O)NH—, —NHC(O)O—, —C(O)CH 2 —, —CH 2 C(O)—, —C(O)CH═CH—, —CH═CHC(O)—, —(CH 2 ) s2 —, —C(O)—, —C(O)O—, —OC(O)—, or a valence bond, wherein s2 is 0 or 1. 
 
     
     
         5 . The conjugate of  claim 2 , wherein W has the formula
   —W 7 —Y—,
   wherein   Y is —(CH 2 ) l7 —C 3-10 -cycloalkyl-W 8 — or a valence bond,   l7 is 0-6,   W 7  is selected from the group consisting of —C(O)NH—, —NHC(O)—, —C(O)NHCH 2 —, —CH 2 NHC(O)—, —C(O)NHS(O) 2 —, —S(O) 2 NHC(O)—, —OC(O)NH—, —NHC(O)O—, —C(O)CH 2 —, —CH 2 C(O)—, —C(O)CH═CH—, —CH═CHC(O)—, —(CH 2 ) s3 —, —C(O)—, —C(O)O—, —OC(O)—, or a valence bond, wherein s3 is 0 or 1;   W 8  is selected from the group consisting of —C(O)NH—, —NHC(O)—, —C(O)NHCH 2 —, —CH 2 NHC(O)—, —C(O)NHS(O) 2 —, —S(O) 2 NHC(O)—, —OC(O)NH—, —NHC(O)O—, —C(O)CH 2 —, —CH 2 C(O)—, —C(O)CH═CH—, —CH═CHC(O)—, —(CH 2 ) s4 —, —C(O)—, —C(O)O—, —OC(O)—, or a valence bond, wherein s4 is 0 or 1.   
     
     
         6 . The conjugate of  claim 4 , wherein
 l1, l2, l3, l4, l5 and l6 independently are 0-6,   m1, m3, m4, m6 and m7 independently are 0-6,   m2 and m5 independently are 0-10, and   n1, n2, n3 and n4 independently are 0-10.   
     
     
         7 . The conjugate of  claim 4 , wherein D1 and D2 are independently selected from —O— or —NR 6 — or a valence bond. 
     
     
         8 . The conjugate of  claim 4 , wherein E1 and E2 are independently selected from —O— or —NR 6 — or a valence bond. 
     
     
         9 . The conjugate of  claim 4 , wherein W1 through W8 independently are selected from the group consisting of —C(O)NH—, —NHC(O)—, —C(O)NHCH 2 —, —CH 2 NHC(O)—, —C(O)NHS(O) 2 —, —S(O) 2 NHC(O)— and a valence bond. 
     
     
         10 . The conjugate of  claim 4 , wherein R 1 , R 2 , R 3 , R 4  and R 5  independently are selected from the group consisting of hydrogen, —C(O)OH, —C(O)NH 2 , —S(O) 2 OH and C 1-6 -alkyl, wherein the alkyl group optionally is substituted with —C(O)OH, —C(O)NH 2 , or —S(O) 2 OH. 
     
     
         11 . The conjugate of  claim 2 , wherein A is selected from 
       
         
           
           
               
               
           
         
         wherein * denotes the attachment to B through W. 
       
     
     
         12 . The conjugate of  claim 1 , wherein the albumin binding residue via a hydrophilic spacer is attached to the glutamine residue in the position corresponding to position 40 in SEQ ID No. 1, or the glutamine residue in the position corresponding to position 141 in SEQ ID No. 1, or the N-terminal residue of the growth hormone compound. 
     
     
         13 . The conjugate of  claim 1 , wherein said compound is selected from the group consisting of 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
     
     
         14 . A pharmaceutical composition comprising a conjugate of  claim 1 , optionally in combination with a pharmaceutically acceptable excipient. 
     
     
         15 . A method of treating one a disease or condition treatable with an increased amount of circulating growth hormone comprising administering an effective amount of the growth hormone conjugate of  claim 1 . 
     
     
         16 . The method of  claim 15  wherein the disease or condition is selected from the group consisting of growth hormone deficiency (GHD), Turner Syndrome, Prader-Willi syndrome (PWS), Noonan syndrome and idiopathic short stature (ISS).