GLP-1R is a class B G-protein coupled receptor and a major therapeutic target for type 2 diabetes and obesity.  Several GLP-1 analog drugs have been approved for T2DM to achieve excellent glycemic control and improved β-cell function with hypoglycemia rarely.  However, the on-target toxicity limited their dosage and any further improvement to the patients. 

To overcome the shortcomings of the existing drugs, we constructed Glutazumab, a humanized anti-GLP-1R monoclonal antibody carrying a GLP-1 fragment.  It could serve as a biased GLP-1 in the hope of having less on-target toxicity.  A first-in-human, placebo-controlled, double-blinded, dose-escalation phase 1 study was carried out to investigate the safety, tolerability and pharmacokinetics of a single subcutaneous dose of Glutazumab in healthy male volunteers.  Phase 1 data showed that Glutazumab has fewer and milder common adverse effects like nausea and vomiting of GLP-1R agonists, while the maximum tolerated dose is multiple-fold higher than that of dulaglutide.  On the other hand, similar efficacy were demonstrated in a monkey OGTT study of Glutazumab and dulaglutide at similar molar dosage.  Glutazumab, dosing either once a week or two-week, could be the first long-acting GLP-1 drug with the biased activity and the best-in-class with a well-tolerated safety profile.

A phase I study to investigate the safety, tolerability and pharmacokinetics of a biased GLP-1R antibody Glutazumab