Abstract
The design, synthesis and pharmacology of novel long-acting exenatide analogs for the treatment of metabolic diseases are described. These molecules display enhanced pharmacokinetic profile and potent glucoregulatory and weight lowering actions compared to native exenatide. [Leu14]exenatide-ABD is an 88 residue peptide amide incorporating an Albumin Binding Domain (ABD) scaffold. [Leu14]exenatide-ABP is a 53 residue peptide incorporating a short Albumin Binding Peptide (ABP). [Leu14]exenatide-ABD and [Leu14]exenatide-ABP exhibited nanomolar functional GLP-1 receptor potency and were metabolically stable in vitro in human plasma and in a pancreatic digestive enzyme mixture. Both molecules displayed picomolar and nanomolar binding association with albumin across multiple species and circulating half lives of 16 and 11 hours, respectively, post a single IV dose in rats. Unlike exenatide, both molecules elicited robust glucose lowering when injected 1 day prior to an oral glucose tolerance test, indicative of their extended duration of action. [Leu14]exenatide-ABD was compared to exenatide in a Lep ob/ob mouse model of diabetes. Twice-weekly subcutaneously dosed [Leu14]exenatide-ABD displayed superior glucose lowering and weight loss in diabetic mice when compared to continuously infused exenatide at the same total weekly dose. A single oral administration of each molecule via an enteric coated capsule to cynomolgus monkeys showed superior pharmacokinetics for [Leu14]exenatide-ABD as compared to [Leu14]exenatide-ABP with detectable exposure longer than 14 days. These studies support the potential use of these novel long acting exenatide analogs with different routes of administration for the treatment of type 2 diabetes.
Highlights
Peptide hormone-based therapeutics deliver significant therapeutic benefits while displaying exquisite receptor selectivity
The result show that both peptides associate with serum albumins of all species with high affinity
The current study describes characterization of two novel longacting exenatide analogs that were designed to have extended plasma circulation by virtue of their tight association with serum albumin, while retaining the key pharmacological actions of their parent hormone. [Leu14]exenatide-Albumin Binding Peptide (ABP) is a fusion molecule that has [Leu14]exenatide conjugated to an albumin binding peptide via a Gly-Gly-Gly linker. [Leu14]exenatide-Albumin Binding Domain (ABD) is comprised of [Leu14]exenatide and an albumin binding domain from bacterial Streptococcus protein G that are linked via a Gly-Gly-Ser sequence
Summary
Peptide hormone-based therapeutics deliver significant therapeutic benefits while displaying exquisite receptor selectivity. With the recent introduction of ByettaTM, VictozaTM, LyxumiaH and BydureonTM, the GLP-1-based drug class has emerged as an important therapeutic regimen for treating patients with type 2 diabetes. These anti-diabetic agents illustrate product differentiation based on differences in efficacy, tolerability, frequency of administration and device presentation. Long-acting injectable peptide drugs, given by injection, afford greater convenience and promote increased compliance due to less frequent administration. The design of such drugs needs to address proteolytic degradation and renal filtration which plays a significant role in their clearance from the bloodstream. Efforts to reduce renal clearance have focused on increasing molecular size beyond the 60 kDa renal threshold [7] through the covalent fusion of the bioactive molecule to molecular scaffolds such as polyethylene glycol (PEG) polymers [8,9,10,11], XTEN [12,13], polysaccharides, large natural proteins such as Fc [14,15,16] and albumin [17]
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