Bovine antibody BLV1H12 possesses a unique "stalk-knob" architecture in its ultralong heavy chain CDR3, allowing substitutions of the "knob" domain with protein agonists to generate functional antibody chimeras. We have generated a humanized glucagon-like peptide-1 (GLP-1) receptor agonist antibody by first introducing a coiled-coil "stalk" into CDR3H of the antibody herceptin. Exendin-4 (Ex-4), a GLP-1 receptor agonist, was then fused to the engineered stalk with flexible linkers, and a Factor Xa cleavage site was inserted immediately in front of Ex-4 to allow release of the N-terminus of the fused peptide. The resulting clipped herceptin-Ex-4 fusion protein is more potent in vitro in activating GLP-1 receptors than the Ex-4 peptide. The clipped herceptin-Ex-4 has an extended plasma half-life of approximately four days and sustained control of blood glucose levels for more than a week in mice. This work provides a novel approach to the development of human or humanized agonist antibodies as therapeutics.
Download full-text PDF |
Source |
|---|---|
| http://dx.doi.org/10.1002/anie.201410049 | DOI Listing |
Publication Analysis
Top Keywords
Similar Publications
Pathways to Sustainable GLP-1 Receptor Agonist Off-Ramping.
JAMA Intern Med
January 2025
Virta Health, Denver, Colorado.
Varenicline Attenuates Memory Impairment in Amyloid-Beta-Induced Rat Model of Alzheimer's Disease.
Neurochem Res
January 2025
Neurosciences Research Center, Tabriz University of Medical Sciences, Tabriz, Iran.
Alzheimer's disease (AD) is the most prevalent neurodegenerative disorder characterized by cognitive decline. Despite extensive research, therapeutic options remain limited. Varenicline, an αβ nicotinic acetylcholine receptor agonist, shows promise in enhancing cognitive function.
View Article and Find Full Text PDFConsiderations for Perioperative Management Guidance Regarding GLP-1 Receptor Agonists: Evaluation of Current Practices and Future Directions.
Mil Med
January 2025
Department of Anesthesiology, Brooke Army Medical Center, Fort Sam Houston, TX 78234, USA.
Introduction: Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) have become increasingly prevalent and have the potential to delay gastric emptying. The American Society of Anesthesiologists (ASA) released guidance regarding the perioperative management of patients receiving GLP-1 RAs, but it is unclear the extent to which hospitals in the U.S.
View Article and Find Full Text PDFPurpose Of Review: Proliferative vitreoretinopathy (PVR) is a severe complication of retinal detachment and trauma, posing significant challenges to surgical success and visual prognosis. Despite advancements in vitreoretinal surgery, PVR incidence remains unchanged, this review presents a synthesis of the principal clinical and preclinical research findings from recent years.
Recent Findings: Recent research has focused on anti-inflammatory, antiproliferative, and antifibrotic agents.
The use of incretin analogues has emerged in recent years as an effective approach to achieve both enhanced insulin secretion and weight loss in type 2 diabetes (T2D) patients. Agonists which bind and stimulate multiple receptors have shown particular promise. However, off target effects, including nausea and diarrhoea, remain a complication of using these agents, and modified versions with optimized pharmacological profiles and/or biased signaling at the cognate receptors are increasingly sought.
View Article and Find Full Text PDFWant AI Summaries of new PubMed Abstracts delivered to your In-box?
Enter search terms and have AI summaries delivered each week - change queries or unsubscribe any time!