Controlling the bioactivity of a peptide hormone in vivo by reversible self-assembly

Myriam M. Ouberai, Ana L. Gomes Santos, Sonja Kinna, Shimona Madalli, David C. Hornigold, David Baker, Jacqueline Naylor, Laura Sheldrake, Dominic J. Corkill, John Hood, Paolo Vicini, Shahid Uddin, Steven Bishop, Paul G. Varley and Mark E. Welland ()
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Myriam M. Ouberai: University of Cambridge
Ana L. Gomes Santos: Biopharmaceutical Development, MedImmune Ltd.
Sonja Kinna: University of Cambridge
Shimona Madalli: Cardiovascular and Metabolic Diseases, MedImmune Ltd.
David C. Hornigold: Cardiovascular and Metabolic Diseases, MedImmune Ltd.
David Baker: Cardiovascular and Metabolic Diseases, MedImmune Ltd.
Jacqueline Naylor: Cardiovascular and Metabolic Diseases, MedImmune Ltd.
Laura Sheldrake: Invivo Sciences UK, MedImmune Ltd.
Dominic J. Corkill: Respiratory, Inflammation and Autoimmunity, MedImmune Ltd.
John Hood: Clinical Pharmacology, Drug Metabolism and Pharmacokinetics, MedImmune Ltd.
Paolo Vicini: Clinical Pharmacology, Drug Metabolism and Pharmacokinetics, MedImmune Ltd.
Shahid Uddin: Biopharmaceutical Development, MedImmune Ltd.
Steven Bishop: Biopharmaceutical development, MedImmune LLC Gaithersburg Headquarters
Paul G. Varley: Biopharmaceutical Development, MedImmune Ltd.
Mark E. Welland: University of Cambridge

Nature Communications, 2017, vol. 8, issue 1, 1-9

Abstract: Abstract The use of peptides as therapeutic agents is undergoing a renaissance with the expectation of new drugs with enhanced levels of efficacy and safety. Their clinical potential will be only fully realised once their physicochemical and pharmacokinetic properties have been precisely controlled. Here we demonstrate a reversible peptide self-assembly strategy to control and prolong the bioactivity of a native peptide hormone in vivo. We show that oxyntomodulin, a peptide with potential to treat obesity and diabetes, self-assembles into a stable nanofibril formulation which subsequently dissociates to release active peptide and produces a pharmacological effect in vivo. The subcutaneous administration of the nanofibrils in rats results in greatly prolonged exposure, with a constant oxyntomodulin bioactivity detectable in serum for at least 5 days as compared to free oxyntomodulin which is undetectable after only 4 h. Such an approach is simple, cost-efficient and generic in addressing the limitations of peptide therapeutics.

Date: 2017
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DOI: 10.1038/s41467-017-01114-1

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