Fc fusion to glucagon-like peptide-1 inhibits degradation by human DPP-IV, increasing its half-life in serum and inducing a potent activity for human GLP-1 receptor activation.
The short in vivo half-life of GLP-1 prevents it from being used clinically. This short half-life occurs because GLP-1 is rapidly degraded by dipeptidyl peptidases such as DPP-IV. To overcome this obstacle, a GLP-1/Fc was constructed and evaluated to determine if it was degraded by DPP-IV and in serum. When the degradation of GLP-1/Fc by human DPP-IV and rabbit serum was compared with that of GLP-1 it was found to be reduced by approximately 5- and 4-fold, respectively. Furthermore, GLP-1/Fc showed a potent activity for human GLP-1 receptor activation (EC50 approximately 6 nM). Taken together, these results indicate that GLP-1/Fc may have an extended half-life in vivo that occurs as a result of inhibition of degradation by human DPP-IV. Due to the extended half life, GLP-1/Fc may be useful for clinical treatments.
Kim
Dong-Myung
DM
LG Life Sciences, Ltd. R&D Park, Daejeon 305-701, Korea. dmkima@kaist.ac.kr
Chu
Seoung-Ho
SH
Kim
Semi
S
Park
Young-Woo
YW
Kim
Sung-Seob
SS
D000818:Animals; D001483:Base Sequence; D016466:CHO Cells; D002460:Cell Line; D006224:Cricetinae; D003412:Cricetulus; D018819:Dipeptidyl Peptidase 4 / Q000378:metabolism*; D052216:Glucagon-Like Peptide 1 / Q000097:blood / Q000235:genetics / Q000378:metabolism*; D000067757:Glucagon-Like Peptide-1 Receptor; D006801:Humans; D007141:Immunoglobulin Fc Fragments / Q000097:blood / Q000235:genetics / Q000378:metabolism*; D018027:Receptors, Glucagon / Q000378:metabolism*; D011993:Recombinant Fusion Proteins / Q000097:blood / Q000235:genetics / Q000378:metabolism*; D018411:Spodoptera
C000593833:GLP1R protein, human; D000067757:Glucagon-Like Peptide-1 Receptor; D007141:Immunoglobulin Fc Fragments; D018027:Receptors, Glucagon; D011993:Recombinant Fusion Proteins; D052216:Glucagon-Like Peptide 1; C042807:DPP4 protein, human; D018819:Dipeptidyl Peptidase 4