Aptamers/Tolerogenic protein complexes

The platform “Aptamers/Tolerogenic Protein Complexes” aims to create cross-institutional structures and networks for research and development of MHCII-glycopeptide complexes for the treatment of rheumatoid arthritis (RA) and aptamers for the early detection of glycosylation defects in autoimmune diseases or their precursors.

Treatment options for long-term disease control are needed

For (auto)immune-mediated diseases such as RA, there is a great need for new therapeutic options. With available treatment options such as cytokine blockers, remission or even cure of the disease is rarely achieved. At the same time, these diseases are often diagnosed only after manifestation of irreversible damage. There is therefore a great need for new methods for early diagnosis and for treatment options for the long-term control of the disease-sustaining autoimmunity.

Preliminary work

In extensive preliminary work, a recombinant complex consisting of the MHC II (DRA / DRB1 * 0401) molecule and a galactosylated collagen II peptide has already been developed as an antirheumatic agent and its immunoregulatory potential has been demonstrated in numerous preclinical data. At the same time, methods for glycan isolation and the synthesis of biotinylated glycan structures were established, which can be used for aptamer selection.

Optimization of the formulation and glycosylation of MHC-II complexes

The main objectives of the project are to optimize the formulation and glycosylation of MHC-II glycopeptide complexes, to study them in a humanized mouse model of RA and to identify aptamers for the development of a detection system for glycosylation changes.

Improved treatment of rheumatoid arthritis

The development of a completely new class of substances to restore immunological self-tolerance by inducing regulatory lymphocyte populations can significantly improve the treatment of patients with RA. The work in the therapy platform forms the basis for the preclinical proof of the efficacy of these molecules in a humanized mouse model. An aptamer-based detection system for the identification and quantification of glycosylation defects could lay the foundation for a novel diagnostic tool for the early detection and monitoring of immune disorders.

Bringing together complementary skills

The platform “Aptamers/Tolerogenic Protein Complexes” combines the expertise of the Fraunhofer ITMP in the section of rheumatological diseases and their preclinical models with the experience of the Fraunhofer IGB and the Fraunhofer ITEM-R in the characterization of immune cells using bulk or single-cell RNA sequence analysis, the expertise of the IZI-BB in the generation, synthesis and functionalization of aptamers, established methods at the Fraunhofer IAP for the isolation and synthetic and semisynthetic production of glycan target structures

Outlook

After completion of the preclinical studies to demonstrate the efficacy of the prototypical recombinant immunomodulatory HLADR4/CII peptide complex in the established humanized murine arthritis model of collagen II (CII) induced arthritis (CIA), the establishment of a GMP-compliant manufacturing process and preclinical toxicity studies are in preparation for the clinical phase 1b studies of the innovative active agent for the treatment of rheumatoid arthritis. The CII T cell receptor-specific aptamers selected through collaboration on the project platform are to be developed into assays for the immune monitoring of cellular CII autoimmunity in peripheral blood for clinical applications. Analogously, following the successful identification of aptamers with specificity for post-translationally modified immunoglobulin structures and for metabolites of congenital glycosylation defects, optimized analytical test systems will be developed for improved clinical laboratory diagnostics.

The experience gained in the ongoing projects will be used to develop new applications for aptamer technology, in particular for the selective modulation of receptors in the immune system. To this end, further research is needed in target identification and drug design, particularly in the section of optimizing pharmacokinetic properties.