Delivering antibodies (molecular weight = 150 kDa) to the brain

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.

The main output from the proposed work will be data and protocols outlining the feasibility of administering therapeutic monoclonal antibodies (mAbs) to the brain. The global therapeutic antibody market was worth US$45 billion in 2011 and there are approximately 40 marketed therapeutic Abs and approximately 350 therapeutic Abs in clinical development. These therapeutic Abs are administered parenterally, such an administration route saddling them with high costs and patient adherence issues. However, more importantly, the lack of mAb access to the brain has been recognized as an impediment to the field's progress; a fact that makes it difficult to develop mAb brain treatments. The impact of the proposed project's findings on the UK's competitiveness cannot be overstated. Development of these technologies will signal a paradigm shift in the way mAbs are developed and will enable therapeutic mAbs to be considered for the treatment of currently excluded disease states, such as brain diseases for example; it is estimated that 1 billion individuals are living with neurological conditions at any time. The direct economic benefits will be experienced by the consortium members, by way of royalties and product sale revenue with the UK benefit derived from royalties to Nanomerics Ltd.
SPECIFIC PROJECT IMPACTS
The project will utilise outputs from a number of EPSRC grants: e.g. GR/M22185, GR/T20410/01 and more recently EP/G061483/1 and EP/G028362/1. These outputs are already being translated by Nanomerics Ltd., a spin out company from University College London (UCL) in the form of the company's headline product - METDoloron, a leucine5-enkephalin based fast acting therapeutic, indicated for the treatment of chronic pain. However there is now a new opportunity, by virtue of the current consortium (UCL, Exeter University, Nanomerics Ltd. and H Lundbeck), to achieve further translation of UK research into new and beneficial products. The expected exploitable outputs arising from the project are as follows: a) data on the synthesis, structural and biological characterisation of mAb-amphiphilic polymer conjugates (the first such mAb - amphiphilic polymer conjugates), b) data on the feasibility of mAb brain delivery by the intranasal administration of mAb nanoparticles.
SKILLS DEVELOPMENT
Research staff working on the project will be working at the cutting edge of translational research and will thus develop the confidence to translate their own ideas into tangible products and services later on in their careers. There will also be valuable cross disciplinary learning between members of the consortium with the academic partners learning about mAb product profiling, mAb pharmacology and translation of ideas to market; while Nanomerics will learn of the downstream processes associated with translational research and H. Lundbeck will learn about the creation and characteristics of the mAb-polymer conjugate/ mAb nanoparticle technology.
PATHWAY TO IMPACT
The consortium, comprising academics from UCL and Exeter University and scientists from H. Lundbeck (a mature global pharmaceutical company) and Nanomerics (a UCL spin out company), is well placed to execute the vision from preclinical proof of concept studies and later on to a commercial clinical product. All intellectual property will be protected, licensed and sub-licensed in order to allow these new mAb neurological medicines to be brought to patients.