Protein Engineering Strategies for Sustained Glucagon-Like Peptide-1 Receptor–Dependent Control of Glucose Homeostasis
Open Access
- 1 July 2008
- journal article
- Published by American Diabetes Association in Diabetes
- Vol. 57 (7), 1926-1934
- https://doi.org/10.2337/db07-1775
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.Keywords
This publication has 45 references indexed in Scilit:
- CNTO 530: Molecular pharmacology in human UT-7EPO cells and pharmacokinetics and pharmacodynamics in miceJournal of Biotechnology, 2008
- Effects of Once-Weekly Dosing of a Long-Acting Release Formulation of Exenatide on Glucose Control and Body Weight in Subjects With Type 2 DiabetesDiabetes Care, 2007
- Engineered antibody fragments and the rise of single domainsNature Biotechnology, 2005
- Effects of Exenatide (Exendin-4) on Glycemic Control Over 30 Weeks in Sulfonylurea-Treated Patients With Type 2 DiabetesDiabetes Care, 2004
- Glucagon-like Peptide-1 Receptor Signaling Modulates β Cell ApoptosisJournal of Biological Chemistry, 2003
- From peptides to drugs via phage displayDrug Discovery Today, 1998
- A role for glucagon-like peptide-1 in the central regulation of feedingNature, 1996
- Truncated GLP-1 (proglucagon 78?107-amide) inhibits gastric and pancreatic functions in manDigestive Diseases and Sciences, 1993
- GLUCAGON-LIKE PEPTIDE-1 7-36: A PHYSIOLOGICAL INCRETIN IN MANThe Lancet, 1987
- Truncated glucagon‐like peptide I, an insulin‐releasing hormone from the distal gutFEBS Letters, 1987