Engineering of a GLP-1 Analogue Peptide/anti-PCSK9 Antibody Fusion for Type 2 Diabetes Treatment

Overview

Journal Sci Rep

Specialty Science

Date 2018 Dec 5

PMID 30510163

Citations 7

Authors

Matthieu Chodorge

Anthony J Celeste

Joseph Grimsby

Anish Konkar

Pia Davidsson

David Fairman

Lesley Jenkinson

Jacqueline Naylor

Nicholas White

Jonathan C Seaman

Karen Dickson

Benjamin Kemp

Jennifer Spooner

Emmanuel Rossy

David C Hornigold

James L Trevaskis

Nicholas J Bond

Timothy B London

Andrew Buchanan

Tristan Vaughan

Cristina M Rondinone

Jane K Osbourn

Affiliations

Soon will be listed here.

Abstract

Type 2 diabetes (T2D) is a complex and progressive disease requiring polypharmacy to manage hyperglycaemia and cardiovascular risk factors. However, most patients do not achieve combined treatment goals. To address this therapeutic gap, we have developed MEDI4166, a novel glucagon-like peptide-1 (GLP-1) receptor agonist peptide fused to a proprotein convertase subtilisin/kexin type 9 (PCSK9) neutralising antibody that allows for glycaemic control and low-density lipoprotein cholesterol (LDL-C) lowering in a single molecule. The fusion has been engineered to deliver sustained peptide activity in vivo in combination with reduced potency, to manage GLP-1 driven adverse effects at high dose, and a favourable manufacturability profile. MEDI4166 showed robust and sustained LDL-C lowering in cynomolgus monkeys and exhibited the anticipated GLP-1 effects in T2D mouse models. We believe MEDI4166 is a novel molecule combining long acting agonist peptide and neutralising antibody activities to deliver a unique pharmacology profile for the management of T2D.

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