Novel Therapeutic Intervention in Crohn's disease

Crohns disease (CD) is a chronic inflammatory condition affecting the gastrointestinal tract, and which is thought to be an overt reaction of the immune system towards the commensal flora of the gut. As the mechanism is unknown, no disease-specific and durable therapy exists. Disease mechanism delineation is imperative for developing improved therapeutic intervention, which today is based on generic inhibition of the pro-inflammatory response. Current treatment is therefore not curative; therapy failure is common and suffers from potentially severe side effects due to generic immunesuppression of the patient. Several seminal studies point to mycobacteria as the etiological component causing the inflammation in CD through aberrant activation of T helper cells (TH). The human leukocyte antigen (HLA) molecule is the key component of the adaptive immune system mediating recognition of foreign substances through a complex process where proteolytically derived fragments (epitopes) are displayed on the surface of antigen presenting cells (APC) in complex with HLA (pHLA). Such pHLA are visible to TH, which then may initiate an appropriate immune response. Infecting mycobacteria reside inside APCs, and though visible to TH through pHLA, escape the immune response through as of yet unknown mechanisms. The primary objective of the project is to identify targets specific for Mycobacterium avium subspecies paratuberculosis (MAP) that can be used in future development of novel immunotherapeutic intervention of CD. The project is sub-divided into several work packages (WP1-4) and we are now in WP4. Through comparative genomics (WP1), pHLA reactivity profiling of TH from CD patients (WP2) and epitope array screening (WP3) using Phagemer technology (http://www.nextera.no/nextera-technology), we have identified a range of epitope candidates in the context of the major HLA haplotypes of Caucasians. Among these, we have de novo isolated an epitope candidate based on TH with unknown specificity, which was one of the major goals of the project. Currently, we are investigating the reactivity of the epitope candidates towards TH from selected CD patients in comparison with healthy controls (WP4). In addition, we have cloned several relevant TCRs - the receptor that renders the pHLA specificity to the TH - which now are used to validate epitope candidates assigned to putative antigens (targets) from MAP. This epitope validation and the cloned TCRs may form the basis for future development of novel drug candidates.

Nextera is a drug discovery company that aims to identify new drug targets by means of a unique and proprietary technology. The technology was initially invented by researchers in Professor Inger Sandlie's group at the University of Oslo, and the company was established in 2009 to exploit the inventions commercially. The core technology is based on a novel phage display platform which forms a complete set of protein engineering tools providing a unique ability to perform MHC class II epitope discovery to delineate CD4+ TH cell responses. Nextera's business goal is to identify a set of "first-in-class" drug candidates in the field of autoimmune diseases and develop these in collaboration with a large pharmaceutical company. The company collaborates with w orld class research groups at the Centre for Immune Regulation (CIR) at Oslo University Hospital / University of Oslo, and has a team of four skilled and dedicated employees that have taken the technology and the business several steps forward since the c ompany was established. A group of professional investors has established an ownership in the company, prepared to contribute to the further development. The technology is well protected through five different patent filings, all found novel and inventive in PCT examinations. The objective for this project is to identify and develop new candidate drugs for the treatment of Crohn's disease (CD).