Small Molecule, TLR-4 Ligands as Immunomodulators
• Small molecules are more readily scaled and controlled in drug development (vs. proteins and peptides)• TLR-4 specificity allows one to modulate the immune response in a more cell-specific manner• Small molecules easily modified to enable linking to other TLR-agonists for combined drugs
Compositions may be useful for the treatment of cancer and infectious diseases. Tolerance inducers may be useful for inflammatory and autoimmune disorders, including but not limited to as toxic shock, multiple sclerosis or diabetes. Those that are not inflammatory of cytokines appear to be useful for inducing tolerant.
UC researchers have validated means of using TLR-4-specific small molecules as immunomodulatory compositions. Strong ligands are useful as vaccine adjuvants, anticancer agents and immune-stimulants; more weakly binding compositions have been substantially validated, in vivo, for inducing tolerance.
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State Of Development Inventors have confirmed the molecular target in mouse and human models and have generated structure-activity relationships around hits. For some compositions, activity has been confirmed in vivo. Tolerance induction has been tested in nine distinct murine models of autoimmunity and/or inflammation. Additional animal studies and lead optimization are in process. Other Information Dev, A., et al., (2011), NF-κB and innate immunity, Curr. Top. Microbiol. Immunol., 349, 115-143. Intellectual Property Info Worldwide rights available; Pending patents available under confidentiality. Related Materials Pu, M., et al., (2012) Analysis of high-throughput screening assays using cluster enrichment, Stat Med,1191-1195. Tech ID/UC Case 23140/2013-065-0 Related Cases 2013-065-0, 2014-123-0
Fang, H. et al., (2011), Toll-like receptor 4 (TLR4) is essential for Hsp70-like protein 1 (HSP70L1) to activate dendritic cells and induce Th1 response, J. Biol. Chem., 286, 30393-30400.
Coffman, R. L. et. al., (2010) Vaccine adjuvants: putting innate immunity to work, Immunity, 33, 492-503.
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Goff PH, et al., Synthetic Toll-Like Receptor 4 (TLR4) and TLR7 Ligands as Influenza Virus Vaccine Adjuvants Induce Rapid, Sustained, and Broadly Protective Responses. J Virol. 2015 Mar 15;89(6):3221-35. doi: 10.1128/JVI.03337-14. Epub 2015 Jan 7.
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