The delivery of 150 kDa antibodies to the brain

Lead Research Organisation: University of Exeter
Department Name: Physics

Abstract

Over the last three decades a new therapeutic, the antibody has been introduced. Antibodies are large molecules which are at least 300 times larger than the molecules that are usually used to treat patients. These antibodies are very successful therapies and form the basis of the pharmaceutical industry's recent prosperity. However there are two key problems associated with antibody medicines. One problem is that antibodies have to be given by injection as they are destroyed in the stomach and intestines and cannot cross the intestinal wall to get into the blood; antibodies need to be in the blood to act on their therapeutic target. This makes antibody medicines expensive. However a more important problem is that when antibodies are in the blood, they cannot cross the blood vessels in the brain to get to the brain tissue. This inability to access the brain is due to their large size and good solubility in the blood. Exclusion from the brain makes it hard for antibodies to be used to treat brain diseases such as Alzheimer's disease (AD) and brain tumours and yet these are diseases that are becoming more widespread in our populations, e.g. there are almost half a million AD sufferers in the UK. The current consortium aims to develop antibody medicines that are active in the brain and hence useful for the treatment of conditions such as dementia and brain cancer. In previous collaborations (grant reference numbers - EP/G061483/1 and EP/G028362/1), the applicants had identified a key technological advance that underpins the current application. They found that a particular type of nanoparticle, with a diameter 1/1000th of the thickness of a human hair, is able to cause delicate drugs known as peptides to be absorbed from the intestines; peptides are not normally absorbed when taken by mouth. These tiny particles act by protecting the peptide from degradation in the intestines and stomach and transporting the encapsulated peptide from the intestine to the blood. This former work is pertinent to the current initiative as in the current work, the applicants hypothesise that antibody particles of a similar chemistry should be able to deliver antibodies to the brain via the nose. The applicants have shown that when peptides are dosed in these same particles through the nose the particles are taken up by the brain and the peptides act almost exclusively in the brain. This exciting finding forms the bases of the nasal antibody dosage forms that the group wish to develop.
Nanomerics Ltd, a UCL spin out company and member of the current consortium is actually developing an analgesic for the treatment of chronic pain, based on the peptides studied in the earlier funded projects. Chronic pain is a condition suffered by an estimated 20% of European adults and it is poorly served by current drugs. Only a quarter of patients, suffering from the extremely painful chronic neuropathic pain, experience any relief from their symptoms with existing therapies.
The group thus has experience in activities aimed at translating scientific findings into real world solutions and the antibody delivery project is aimed at new therapeutics for dementia and cancer patients. The project will be delivered by scientists at UCL, Exeter University, Nanomerics and H. Lundbeck. H. Lundbeck, a global pharmaceutical company with annual revenues of £2 billion, specialises in the treatment of brain diseases. The combination of Nanomerics (which has an exclusive licence to the delivery system's intellectual property), H. Lundbeck (with experience of taking products to market) and academic scientists is ideal for taking a new concept from early stage testing on to a marketed product. The project will involve chemical reactions, nanoscience experiments, microscopical examinations with specialist lasers, cell based tests and animal testing.

Publications

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Belsey NA (2014) Evaluation of drug delivery to intact and porated skin by coherent Raman scattering and fluorescence microscopies. in Journal of controlled release : official journal of the Controlled Release Society

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Chiu WS (2015) Drug delivery into microneedle-porated nails from nanoparticle reservoirs. in Journal of controlled release : official journal of the Controlled Release Society

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Chiu WS (2015) Molecular diffusion in the human nail measured by stimulated Raman scattering microscopy. in Proceedings of the National Academy of Sciences of the United States of America

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Lalatsa A (2015) Chitosan amphiphile coating of peptide nanofibres reduces liver uptake and delivers the peptide to the brain on intravenous administration. in Journal of controlled release : official journal of the Controlled Release Society

 
Description We have further developed non-linear optical imaging technologies based on coherent Raman scattering to image the fate of polymeric nanomedicines in ex-vivo animal tissues to provide new sights into the mechanisms of enhanced drug uptake.
Exploitation Route Project is running in partnership with Nanomerics Ltd (UCL spin-out company) and Lundbeck, who plan to exploit and commercialise and IP resulting from this project.

Syngenta are exploring agrochemical applications of the imaging technology that was developed during this project. We have been awarded an EPRSC iCASE project to explore this unexpected direction.

We have been awarded an EPSRC strategic equipment award to establish the first UK user facility for coherent Raman scattering microscopy so that other researcher may access the imaging techniques developed on this award
Sectors Agriculture, Food and Drink,Healthcare,Manufacturing, including Industrial Biotechology,Pharmaceuticals and Medical Biotechnology

 
Description The ability to visualise the environmental fate of microplastics at the cellular level in marine animals played a key role in both the elucidating mechanisms by which they harm organisms and in convincing policy makers to ban their use in cosmetic products. The unique strength of the techniques developed and implemented by the Moger Group was the ability to, for the first time, unequivocally identify microplastics in marine organisms based on the intrinsic chemical signatures of the polymers from which the particles were composed. The research underpinning these imaging techniques originally aimed to develop label-free microscopy for monitoring the uptake of nanomedicines in mammalian tissues. Nanoparticle drug delivery was known to greatly improve the efficacy of pharmaceuticals however; the mechanisms by which nanoparticles improved drug performance was unclear. Research in the Moger Group developed and applied techniques based on coherent Raman scattering (CRS) to image polymeric nanoparticles in animals dosed with nanomedicines based on their intrinsic vibrational signature. The ability to track nanomedicines at the cellular level without using fluorescent labels represented a major advance in drug developmental capability and allowed, for the first time, clarification of the delivery mechanisms which aided the rational engineering of particles for the appropriate clinical condition. This capability, serendipitously, turned out to be extremely important for visualising microplastics since particles in organisms collected from the marine environment are by their nature unlabelled.
First Year Of Impact 2017
Sector Pharmaceuticals and Medical Biotechnology
Impact Types Societal,Economic

 
Description EPSRC Programme Grant
Amount £5,752,646 (GBP)
Funding ID EP/R020965/1 
Organisation Engineering and Physical Sciences Research Council (EPSRC) 
Sector Academic/University
Country United Kingdom
Start 02/2018 
End 01/2023
 
Description EPSRC iCASE
Amount £75,000 (GBP)
Organisation University of Leeds 
Department Faculty of Engineering
Sector Academic/University
Country United Kingdom
Start 10/2015 
End 10/2019
 
Description Exploring Industry R&D Applications of Frequency Modulated SRS Imaging 
Organisation Unilever
Department Unilever UK R&D Centre Port Sunlight
Country United Kingdom 
Sector Private 
PI Contribution Feasibility study to explore the application of frequency modulated SRS for visualising the uptake of low molecular weight compounds in to human hair
Collaborator Contribution Financial support of postDoctoral salary for 6 months
Impact academic publication in preparation
Start Year 2015
 
Description Next Generation Optical Analysis for Agrochemical Research & Development 
Organisation Syngenta International AG
Department Syngenta Ltd (Bracknell)
Country United Kingdom 
Sector Private 
PI Contribution Translation of SRS techniques developed at Exeter into an analytical tool for agrochemical R&D
Collaborator Contribution Access to state of the art standard analytical tools that are not available at Exeter
Impact none yet.
Start Year 2015