Strategies for targeted immunomodulation
Embargo Date
2024-11-04
OA Version
Citation
Abstract
Many therapies fail in clinical trials due to concerns over efficacy or safety. Untargeted therapies undergo systemic nonspecific biodistribution, usually leading to low uptake in the intended tissue or microenvironment. The use of targeted drug conjugates, such as antibody drug conjugates, is one strategy that has been explored to increase drug uptake in diseased microenvironments. Due to their large size, however, antibodies can be limited by poor tissue penetration. To overcome this challenge, we propose the use of small molecules or small peptide targeting ligands specific to receptors or extracellular proteins for the selective delivery of immunomodulatory drugs.
For treating Type 1 Diabetes, we have developed non-internalizing and internalizing drug conjugates for delivering different classes of therapeutics. Conjugates formulated with Exenatide and Glibenclamide targeting ligands with short synthetic linkers were highly internalized into β cells. Bivalent Glibenclamide conjugates exhibited increased potency for β cell labeling and could be used to selectively deliver β cell protective drugs, such as the Abl-kinase inhibitor imatinib. Conjugates with the exenatide analog, Phe1-Exenatide, and short PEG linkers exhibited reduced internalization while maintaining high potency and selectivity for β cells over other cells. Targeted conjugates with Phe1-Exenatide ligands could be used to deliver immunosuppressants to extracellular space to act directly on the immune cells responsible for β cell destruction.
For treating inflammatory diseases, such as asthma or cancer, we have identified first-in-class small molecule inhibitors to the cytokine Interleukin-4 (IL-4). We combined binding-based high throughput small-molecule microarrays with activity-based cell assays to identify small molecule inhibitors. The lead compound, Nico-52, has micromolar inhibitory potency in multiple cell lines as well micromolar kD as measured with surface plasmon resonance. Preliminary structure activity relationships around the Nico-52 scaffold suggest that the p-fluorophenyl substituent is amenable to changes to improve potency. In addition, Nico-52 or a related analog could be utilized as a targeting ligand to both inhibit IL-4 signaling and deliver an additional therapeutic to an inflammatory, IL-4 enriched microenvironment.
Given our success on identify small molecule inhibitors to IL-4, we then sought to utilize small molecule microarrays to identify small molecule binders to 36 other proteins in the cytokine family. Once generated, this data set can be utilized to generate compound selectivity scores and identify specific inhibitors to cytokines.
In summary, we have developed new strategies for delivering therapeutics to the islet microenvironment and expanded the repertoire of small molecule ligands available for targeted delivery applications.