Protein engineering strategies for sustained glucagon-like peptide-1 receptor-dependent control of glucose homeostasis.
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.


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.
Picha
Kristen M
KM
Discovery Research, Centocor R&D, Radnor, Pennsylvania. USA.
Cunningham
Mark R
MR
Drucker
Daniel J
DJ
Mathur
Ashok
A
Ort
Tatiana
T
Scully
Michael
M
Soderman
Avery
A
Spinka-Doms
Tracy
T
Stojanovic-Susulic
Vedrana
V
Thomas
Beth Ann
BA
O'Neil
Karyn T
KT
D000273:Adipose Tissue / Q000187:drug effects / Q000378:metabolism*; D000595:Amino Acid Sequence; D000821:Animal Feed; D000818:Animals; D002460:Cell Line; D000067757:Glucagon-Like Peptide-1 Receptor; D005947:Glucose / Q000378:metabolism*; D006706:Homeostasis; D006801:Humans; D007668:Kidney; D007781:Lactoferrin / Q000494:pharmacology*; D051379:Mice; D008810:Mice, Inbred C57BL; D008969:Molecular Sequence Data; D009765:Obesity / Q000209:etiology / Q000503:physiopathology; D015202:Protein Engineering / Q000379:methods*; D018027:Receptors, Glucagon / Q000819:agonists / Q000187:drug effects / Q000502:physiology*; D014168:Transferrin / Q000494:pharmacology*
C000593833:GLP1R protein, human; C000593834:Glp1r protein, mouse; D000067757:Glucagon-Like Peptide-1 Receptor; D018027:Receptors, Glucagon; D014168:Transferrin; D007781:Lactoferrin; D005947:Glucose