Abstract:
OBJECTIVE:We have developed a novel platform for display and delivery of bioactive peptides that links the biological properties of the peptide to the pharmacokinetic properties of an antibody. Peptides engineered in the MIMETIBODY platform have improved biochemical and biophysical properties that are quite distinct from those of Fc-fusion proteins. CNTO736 is a glucagon-like peptide 1 (GLP-1) receptor agonist engineered in our MIMETIBODY platform. It retains many activities of native GLP-1 yet has a significantly enhanced pharmacokinetic profile. Our goal was to develop a long-acting GLP-1 receptor agonist with sustained efficacy. RESEARCH DESIGN AND METHODS:In vitro and in vivo activity of CNTO736 was evaluated using a variety of rodent cell lines and diabetic animal models. RESULTS:Acute pharmacodynamic studies in diabetic rodents demonstrate that CNTO736 reduces fasting and postprandial glucose, decreases gastric emptying, and inhibits food intake in a GLP-1 receptor-specific manner. Reduction of food intake following CNTO736 dosing is coincident with detection of the molecule in the circumventricular organs of the brain and activation of c-fos in regions protected by the blood-brain barrier. Diabetic rodents dosed chronically with CNTO736 have lower fasting and postprandial glucose and reduced body weight. CONCLUSIONS:Taken together, our data demonstrate that CNTO736 produces a spectrum of GLP-1 receptor-dependent actions while exhibiting significantly improved pharmacokinetics relative to the native GLP-1 peptide.
journal_name
Diabetesjournal_title
Diabetesauthors
Picha KM,Cunningham MR,Drucker DJ,Mathur A,Ort T,Scully M,Soderman A,Spinka-Doms T,Stojanovic-Susulic V,Thomas BA,O'Neil KTdoi
10.2337/db07-1775subject
Has Abstractpub_date
2008-07-01 00:00:00pages
1926-34issue
7eissn
0012-1797issn
1939-327Xpii
db07-1775journal_volume
57pub_type
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