A facile approach for preparing dual agonists with long lifetimes and balanced activities

We have developed a chemically controlled ultra long acting delivery system to support once weekly to once monthly administration of peptides In this system the peptide is covalently attached to a hydrogel microsphere depot by a cleavable eliminative linker upon subcutaneous injection the linker slowly cleaves and releases the drug If the same linker is used to attach two different peptides to microspheres they will be released at the same rate the relative amounts released can be controlled by the relative amounts attached to the microspheres Hence this delivery system should be capable of coordinating the pharmacokinetics of dual agonists This Phase I proposal seeks to demonstrate the feasibility of utilizing a two drug delivery system to coordinate the pharmacokinetics of two peptide therapeutics We will attach both the GLP receptor agonist exenatide and a newly discovered glucagon agonist to our hydrogel microspheres using a single linker having a half life of about one week After subcutaneous injection of the microspheres in the mouse we will determine the pharmacokinetics of both these peptides Concurrently we will utilize the DIO mice as a model for obesity and attempt to demonstrate the efficacy of the dual agonist as an anti obesity drug as well as the optimal ratio of the two drugs We have developed a technology platform for half life extension that is chemically controlled by a linker used to connect the drug to a carrier We propose that by using the same linker to attach two different drugs to the same carrier we can confer the same half life to both drugs and coordinate their in vivo concentrations We will develop these concepts and apply them to produce a peptidic dual agonist for treatment of diabetes and obesity