Novel compounds capable of antagonizing islet amyloid polypeptide (iapp) induced beta-cell damage and impaired glucose tolerance

Abstract

Described are molecules specifically binding to human islet amyloid polypeptide (hIAPP) also known as amylin, particularly human-derived antibodies as well as fragments, derivatives and variants thereof for antagonizing islet amyloid polypeptide (IAPP) induced β-cell damage and impaired glucose tolerance which are symptoms typically associated with diabetes mellitus type 2 (T2D).

1 - 19 . (canceled) 
     
     
         20 . An antibody or a human islet amyloid polypeptide (hIAPP)-binding fragment thereof, wherein the antibody or the hIAPP-binding fragment thereof comprises an hIAPP-binding domain comprising:
 (i) a heavy chain variable (VH) region comprising three complementarity determining regions (CDRs) of the heavy chain variable (VH) sequence of SEQ ID NO:2 (as depicted in Fig. 1); and   (ii) a light chain variable (VL) region comprising the amino acid sequence of SEQ ID NO:6.   
     
     
         21 . The antibody or hIAPP-binding fragment thereof of  claim 20 , wherein the VH region comprises the amino acid sequence of SEQ ID NO:2. 
     
     
         22 . The antibody or hIAPP-binding fragment thereof of  claim 20 , wherein the antibody or hIAPP-binding fragment thereof comprises a polypeptide sequence which is heterologous to the hIAPP-binding domain. 
     
     
         23 . The antibody or hIAPP-binding fragment thereof of  claim 22 , wherein the polypeptide sequence comprises a constant domain of an antibody or part thereof which is heterologous to the hIAPP-binding domain. 
     
     
         24 . The antibody or hIAPP-binding fragment thereof of  claim 23 , wherein the constant domain is of the IgG type. 
     
     
         25 . The antibody or hIAPP-binding fragment thereof of  claim 24 , wherein the constant domain is of the IgG1 class or isotype. 
     
     
         26 . The antibody or hIAPP-binding fragment thereof of  claim 23 , wherein the constant domain is a human constant domain. 
     
     
         27 . The antibody or hIAPP-binding fragment thereof of  claim 20 , wherein the antibody or hIAPP-binding fragment thereof is (a) detectably labeled or (b) attached to a drug. 
     
     
         28 . The antibody or hIAPP-binding fragment thereof of  claim 27 , which is detectably labeled, and wherein the detectable label is selected from the group consisting of an enzyme, a radioisotope, a fluorophore, and a heavy metal. 
     
     
         29 . The antibody or hIAPP-binding fragment thereof of  claim 20 , wherein the antibody or hIAPP-binding fragment thereof selectively binds aggregated hIAPP in pancreas tissue of a human diabetic subject. 
     
     
         30 . The antibody or hIAPP-binding fragment thereof of  claim 20 , wherein the antibody is a human-derived monoclonal antibody. 
     
     
         31 . A pharmaceutical composition comprising the antibody or hIAPP-binding fragment thereof of  claim 20 . 
     
     
         32 . The pharmaceutical composition of  claim 31 , wherein the composition further comprises an agent capable of preventing or reducing IAPP amyloid formation. 
     
     
         33 . The pharmaceutical composition of  claim 32 , wherein the agent is selected from the group consisting of a flavonoid, an IAPP analog, metformin, and a thiazolidinedione. 
     
     
         34 . The pharmaceutical composition of  claim 33 , wherein the thiazolidinedione is rosiglitazone. 
     
     
         35 . The pharmaceutical composition of  claim 31 , further comprising a pharmaceutically acceptable carrier or diluent. 
     
     
         36 . A method of protecting β-cells from hIAPP induced cell damage and/or islet amyloid toxic effects, the method comprising administering a therapeutically effective amount of an antibody or hIAPP-binding fragment thereof of  claim 20  to a subject in need thereof. 
     
     
         37 . One or more polynucleotide(s) encoding the antibody or hIAPP-binding fragment thereof of  claim 20 . 
     
     
         38 . A cDNA encoding the antibody or hIAPP-binding fragment thereof of  claim 20 .