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Engineering of a GLP-1 analogue peptide/anti-PCSK9 antibody fusion for type 2 diabetes treatment

by Trevaskis, James L. , Celeste, Anthony J. , Konkar, Anish , Fairman, David , Bond, Nicholas J. , Buchanan, Andrew , Kemp, Benjamin , Rondinone, Cristina M. , Hornigold, David C. , Spooner, Jennifer , Jenkinson, Lesley , Chodorge, Matthieu , Dickson, Karen , Davidsson, Pia , Vaughan, Tristan , White, Nicholas , London, Timothy B. , Grimsby, Joseph , Osbourn, Jane K. , Seaman, Jonathan C. , Naylor, Jacqueline , Rossy, Emmanuel

in 631/154/51/1568 / 631/154/51/2313 / 64/110 / 64/60 / 82/1 / 82/103 / 82/58 / Animal models / Cardiovascular diseases / Cholesterol / Combined treatment / Diabetes / Diabetes mellitus / Diabetes mellitus (non-insulin dependent) / GLP-1 receptor agonists / Glucagon / Glucagon-like peptide 1 / Health risks / Humanities and Social Sciences / Hyperglycemia / Kexin / Low density lipoprotein / multidisciplinary / Peptides / Pharmacology / Proprotein convertases / Risk factors / Science / Science (multidisciplinary) / Subtilisin

2018

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Engineering of a GLP-1 analogue peptide/anti-PCSK9 antibody fusion for type 2 diabetes treatment

2018

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Engineering of a GLP-1 analogue peptide/anti-PCSK9 antibody fusion for type 2 diabetes treatment

2018

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Journal Article

Engineering of a GLP-1 analogue peptide/anti-PCSK9 antibody fusion for type 2 diabetes treatment

Trevaskis, James L.,

Celeste, Anthony J.,

Konkar, Anish,

Fairman, David,

Bond, Nicholas J.,

Buchanan, Andrew,

Kemp, Benjamin,

Rondinone, Cristina M.,

Hornigold, David C.,

Spooner, Jennifer,

Jenkinson, Lesley,

Chodorge, Matthieu,

Dickson, Karen,

Davidsson, Pia,

Vaughan, Tristan,

White, Nicholas,

London, Timothy B.,

Grimsby, Joseph,

Osbourn, Jane K.,

Seaman, Jonathan C.,

Naylor, Jacqueline,

Rossy, Emmanuel

2018

Overview

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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Publisher

Nature Publishing Group UK,Nature Publishing Group

Subject

631/154/51/1568

/ 631/154/51/2313

/ 64/110

/ 64/60

/ 82/1

/ 82/103

/ 82/58