To generate a high affinity anti-CD40 antibody/transferrin molecule (CD40-Mab/Tf) with improved access to the central nervous system (CNS) for immunotherapy of multiple sclerosis (MS) patients.
To determine access of the CD40-Mab/Tf to the CNS of healthy and EAE (experimental autoimmune encephalomyelitis) rodents.
To determine access of CD40-Mab/Tf to the CNS of healthy and EAE marmosets.
To demonstrate feasibility of therapy with CD40-Mab/Tf in chronic relapsing EAE in marmoset monkeys and identification of effector mechanisms.
In Europe more than 200,000 people suffer from multiple sclerosis (MS) a severe neurological autoimmune disease for which at present time no adequate therapy exists. This project aims to develop a novel immunotherapy for MS based on the modulation of antigen-specific activated T cells that infiltrate the central nervous system (CNS), provoking disease exacerbations through as yet unidentified mechanisms. The interaction of CD40 ligand (CD40L, exclusively expressed on activated T lymphocytes), with the CD40 molecule (expressed on antigen presenting cells) has recently been identified as a novel and accessible target for immunotherapy of MS. During exacerbations of MS, the CD40 molecule is highly upregulated on endothelial cells and mononuclear cells present in perivascular infiltrates. CD40L-CD40 interactions can activate a number of pathological effector mechanisms contributing to the inflammatory process of MS. A crucial role for these molecules was recently confirmed by showing that monoclonal antibodies blocking the CD40L-CD40 interaction effectively reduce disease severity in mice suffering from experimental autoimmune encephalomyelitis (EAE, an acute MS-like disease).
This project aims to generate prototype high affinity anti-human CD40 antibody constructs that are able to cross the blood-brain barrier and gain access to the CNS by means of the transferrin molecule and the transferrin receptor on the endothelium of the blood-brain barrier. Access of these constructs to the CNS of healthy as well as EAE rodents and marmosets will be assessed. These constructs will be evaluated for their therapeutic activity and clinical potential in a recently established chronic demyelinating EAE model in non-human primates (marmoset monkeys: Callithrix jacchus). In addition, the mechanism of action of prototype constructs will be evaluated in these animals.
Funding SchemeCSC - Cost-sharing contracts
2288 GJ Rijswijk Zh
220 07 Lund
1105 BE Amsterdam