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 quite distinct from those of Fc-fusion proteins. CNTO736 is a 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-1R-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-1R-dependent actions while exhibiting significantly improved pharmacokinetics relative to the native GLP-1 peptide.