JRHDD – Joint Research Hub for Drug Discovery and Delivery

Focus on Infection, Inflammation and Innate Immunity

Immunomodulators for therapy

The central objective of the JRHDD project is to exploit mechanisms of innate immunity in combination with targeted drug delivery for therapy of infections as well as autoimmune and inflammatory diseases. This idea has been fostered by results already achieved in a joint project (ICON project between Fraunhofer IGB and the Hebrew University) [1, 2]. Based on these results, we aim to design immune-modulatory compounds in order to address infections and inflammatory diseases more effectively. Targeting these compounds directly to the site of infection or inflammation will support the healing process significantly. For infections, stimulating the host's owned defense mechanisms should also be effective against pathogens resistant to the current anti-invectives, enhancing “classical” medication efficiently.

As a first target we have identified dermatological disorders, such as atopic dermatitis, psoriasis and lupus, since they show involvement of innate immunity, including toll-like-receptors (TLRs). Currently, the pipeline for mild-to-moderate psoriasis includes at least 22 investigational topical therapies in various stages of development, including IL-17 antagonizing agents, showing that immune-modulating agents have a high potential as medication. Dermatologic disorders often show a complex interplay between defects in skin barrier function, environmental impact and infectious agents as well as changes in immunity.

The second focus is to develop novel drugs and targeted nanomedicine to combat fungal infections caused by fungi such as Candida spp. and viral infections caused by Herpesviridae. Since innate immunity is an essential part of combating infectious diseases, a combination of drug development, stimulation of innate immunity and targeted formulation of the respective compounds is an ideal approach to combat infections. The first compounds with TLR-modulating activities have been introduced in clinical trials as antiviral agents, indicating the feasibility of this approach.

© Fraunhofer IGB

The cell-based reporter gene assay is a tool to identify lead compounds for drug development.

Results

© Fraunhofer IGB

Structure of the human TLR9 when bound to the antagonist oligodeoxynucleotide (receptor-antagonist-complex).

Drug design and selection

Discovery of novel agonists and antagonists of innate immune receptors (pattern recognition receptors, PRRs) or the molecules downstream in the signaling pathway related to the indicated diseases will be performed as previously described [1] using computational methods by our partner, Hebrew University. For example, for TLRs that have a published set of small molecule agonists/antagonist, models are based on physical and chemical properties of ligands and will serve as filters for scoring and picking top candidates from huge (millions) numbers of commercially available molecules. Modeling and docking is performed in iterations, building on experimental screening results [1, 3]. A library of 200–300 compounds is defined initially and smaller libraries are employed for subsequent screenings for each newly addressed PRR or group of PRRs [1]. E.g. ten TLR9 antagonists effective in nanomolecular concentrations have already been verified.

Targeted delivery systems

Liposomes (NP) are potent drug delivery systems that protect the drug from degradation, improve its pharmacokinetic properties and deliver a relatively high drug payload. For efficient NP accumulation at the target site, both long circulation time and efficient particle targeting are critical. True molecular targeting of liposomes can be achieved through ligand linkage to appropriately designed ‘stealth’ NP by our partners [2]. Targeting will be designed specifically to the indications mentioned above.

In vitro and in vivo test systems

Infection models are available for both fungal and viral infections at Fraunhofer IGB [4-6]. These models are used to validate the new immune-modulating compounds as well as the formulations. In a first step, we use cell-based assays [3] to validate the PRR-modulating activity of the compounds identified in silico experimentally (as mentioned above); second, we use complex 3D-tissue models, including components of the immune system [4] to validate both the effect of the IMC on different cell types including immune cells and the formulation in delivering the compounds appropriately. Animal models for further validation of the lead compounds of these indications are available with our partners.

Summary

With this approach, we aim to combine two central ideas supporting the healing processes in infection and inflammatory diseases: (i) modulating innate immunity by supporting clearance of invading pathogens or ameliorating the (auto)inflammatory process and (ii) targeted delivery of known and novel drugs to infected or pathologically-modified tissues/cells.

 

Literature

  1. Zatsepin, M.; Mattes, A.; Rupp, S.; Finkelmeier, D.; Basu, A.; Burger-Kentischer, A.; Goldblum, A. (2016) Computational Discovery and Experimental Confirmation of TLR9 Receptor Antagonist Leads. J Chem Inf Model 56: 1835-1846
  2. Ron-Doitch, S.; Sawodny, B.; Kühbacher, A.; David, M. M.; Samanta, A.; Phopase, J.; Burger-Kentischer, A.; Griffith, M.; Golomb, G.; Rupp, S. (2016) Reduced cytotoxicity and enhanced bioactivity of cationic antimicrobial peptides liposomes in cell cultures and 3D epidermis model against HSV. J Control Release 229: 163-171
  3. Burger-Kentischer, A.; Abele, I. S.; Finkelmeier, D.; Wiesmuller, K. H.; Rupp, S. (2010) A new cell-based innate immune receptor assay for the examination of receptor activity, ligand specificity, signalling pathways and the detection of pyrogens. Journal of immunological methods 358: 93-103
  4. Kühbacher, A.; Sohn, K.; Burger-Kentischer, A.;Rupp, S. (2017) Immune cell-supplemented human skin model for studying fungal infections. Methods in molecular biology 1508: 439-449
  5. Hogk, I.; Rupp, S.; Burger-Kentischer, A. (2013) 3D-tissue model for herpes simplex virus-1 infections. Methods in molecular biology 1064; 239-251
  6. Hogk, I.; Kaufmann, M.; Finkelmeier, D.; Rupp, S.; Burger-Kentischer, A. (2013) An in vitro HSV-1 reactivation model containing quiescently infected PC12 cells. BioResearch open access 2: 250-257

Project information

Project title

JRHDD – Joint Research Hub for Drug Discovery and Delivery

 

Project duration

July 2017 – September 2018

 

Project partners

  • Fraunhofer IGB, Stuttgart (Coordination)
  • Hebrew University, Prof. Gershon Golomb and Prof. Amiram Goldblum, IDR – Institute for Drug Research, Jerusalem, Israel

Funding

We would like to thank the Fraunhofer-Gesellschaft and the Hebrew University for funding the project "Joint Research Hub for Drug Discovery and Delivery" within the ICON program.