Towards a targeted therapy for arthritis

Lead Research Organisation: Queen Mary, University of London
Department Name: William Harvey Research Institute

Abstract

We have developed a new drug delivery technology that allows the drug to be protected from being degraded in the body and targets it to the site of disease. The drug delivery system is composed of a shell derived from a naturally occurring molecule called latency associated peptide (LAP). LAP forms a shell around the drug and is therefore protecting the drug from degradation within the body. The shell is opened through an enzyme-sensitive cleavage site. The enzymes that can open the shell are found at sites of inflammation particularly in joints affected by arthritis. The shell is therefore only opened and it?s contents released at the sites of disease.
This technology has many advantages over current biological drugs as it targets the release of the drug only to sites of disease thus preventing side effects, and the drug can be used in small doses. In this study we will produce and purify sufficient material of different forms of the shell and drug that can be tested, pharmaceutically assessed, and compared in a model of arthritis. In this way, we will obtain data that is essential to allow us bring this novel technology to clinical trials in humans. The success of this project will enable us to expand the use of this technology to other diseases that have a destructive/inflammatory component such as Crohn?s disease, multiple sclerosis and atherosclerosis.

Technical Summary

To enable targeting of cytokines and other therapeutic molecules to sites of disease, we have developed a novel platform technology that harnesses the pathological process to release the therapeutic moiety in situ and provides for longer half-life. We built a stable ?shell? by fusing the latency associated peptide precursor part of transforming growth factor beta, through a linker with a matrix metalloproteinase- or aggrecanase-sensitive site (thus targeting release/activation to inflammatory sites) to a therapeutic cytokine (IFN beta) for arthritis treatment. In this study we will express and biochemically purify sufficient recombinant protein to provide data on pharmacokinetics, pharmacodynamics, immunogenicity, toxicology and therapeutic efficacy in an arthritis model. This work is essential to produce preclinical data and bring this technology to the level of a phase I/II clinical trial.

Publications

10 25 50
 
Description project grant
Amount £103,000 (GBP)
Funding ID PG/09/093 
Organisation British Heart Foundation (BHF) 
Sector Charity/Non Profit
Country United Kingdom
Start 07/2010 
End 06/2011
 
Description project grant
Amount £213,000 (GBP)
Organisation Breast Cancer Campaign (BCC) 
Sector Charity/Non Profit
Country United Kingdom
Start 03/2011 
End 02/2013
 
Title mLAP-aggrecanase-IFN beta 
Description This material is cleaved specifically by aggreacanase and synovila fluid from osteoarthritic patients 
Type Of Material Technology assay or reagent 
Provided To Others? No  
Impact This material has shown better therapeutic efficacy in a collagen-induced arthritis model than that obtained with a MMP cleavable fusion protein 
 
Title mouse LAP-IFN beta 
Description CHO expressed glycosylated material with murine sequences in various isoforms for testing in vivo 
Type Of Material Technology assay or reagent 
Provided To Others? No  
Impact Better PK data expected than originally planned in original application 
 
Description Crystal structure of LAP-IL-10 
Organisation Amgen Inc
Country United States 
Sector Private 
PI Contribution We are expressing LAp-IL-10 in a baculovirus system with a view to crystalise and define its structure with colleagues at Birbeck College. This study is funded by Amgen Corp. USA
Collaborator Contribution I spend a mini sabbatical at Amgen in Seattle (3 months) that as a result this collaboration was set up
Impact NA
Start Year 2011
 
Description In vivo real time pharmacodynamic imaging using a transgenic mouse 
Organisation Helmholtz Association of German Research Centres
Department Helmholtz Centre for Infection Research (HZI)
Country Germany 
Sector Academic/University 
PI Contribution We are starting to image these Mx2-luciferase Tg mice after administration of IFN beta followed by luciferin substrate and imaging the PK/PD
Collaborator Contribution this is allowing us to measure in real time delivery of LAP-IFN constructs to sites of disease
Impact na
Start Year 2011
 
Title Latency associated protein construct with aggrecanase-sensitive cleavage site 
Description The discovery describes a cytokine delivery technology that targets delivery to sites high in aggrecanase activity such as the arthritic joint 
IP Reference US2010310515 
Protection Patent granted
Year Protection Granted 2010
Licensed No
Impact N/A
 
Title Modified Latency Associated Protein Construct 
Description We have designed a method of closing the LAP shell enabling the delivery of antibody fragments and soluble cytokine receptors in a latent form to sites of disease where they get released through cleavage by matrix metalloproteinases. 
IP Reference WO2015198072 
Protection Patent application published
Year Protection Granted 2015
Licensed Commercial In Confidence
Impact see above