1. Introduction 2. TLR agonists 3. Conclusion 4. Expert opinion Review Toll-like receptor agonists: a patent review (2011 -- 2013) Waleed M Hussein, Tzu-Yu Liu, Mariusz Skwarczynski & Istvan Toth † † The University of Queensland, School of Chemistry and Molecular Biosciences, Brisbane, Australia Introduction: Toll-like receptors (TLRs) are a crucial part of the innate immu- nity and present the first line of defense against pathogens. In humans, there are ten TLRs, with TLR3, 7, 8 and 9 located in intracellular vesicles and the remaining expressed on the cell surface. These transmembrane protein recep- tors recognize a wide range of pathogen components. A large number of TLR agonists, either derived from pathogen components or modified synthetic molecules, were developed and investigated for their ability to stimulate an immune response. Areas covered: This review includes an updated summary (2011 -- 2013) of TLR agonists that have been published in patent applications and/or progressed to clinical studies, with an emphasis on their chemical structure, immune response, prophylactic and therapeutic outcomes. Expert opinion: A number of factors have contributed to the design and development of TLR agonists such as solving the crystal structures of TLR bound to their ligands, improvements in our understanding of the signaling pathway activated after TLR stimulation and the identification of the native ligands of all human TLRs. Some of the TLR agonists have been approved for human use by the FDA while others have reached clinical studies in Phases I, II and III. Generally, immunotherapy based on TLR agonists is very promising for the prevention and/or treatment of several disorders including cancer, allergy and microbial infections. However, many TLR agonists were withdrawn from further studies as they either lacked efficacy or caused serious side effects. Keywords: adjuvant, agonist, clinical study, immune response, immunostimulatory, innate immunity, patent, Toll-like receptor, vaccine Expert Opin. Ther. Patents (2014) 24(4):453-470 1. Introduction Innate and adaptive immunities are the two arms of the vertebrate defense system against pathogen infections [1-4]. Toll-like receptors (TLRs) are one of the most important regulators of both innate and adaptive immune responses because they have the ability to detect pathogen associated molecular patterns and danger associ- ated molecular patterns (DAMPs) [5,6]. TLR was first described in the fruitfly, Drosophila melanogaster. TLRs are a family of conserved type 1 transmembrane pro- teins that comprise an extracellular domain containing leucine-rich repeats (LxxLxLxxN, LRRs) and an intracellular Toll/IL-1 receptor (TIR) domain. The cloning of a mammalian TLR homologue, currently known as TLR4, was first reported by Janeway and coworkers in 1997 [7,8]. TLRs are highly conserved in both vertebrates and invertebrates. TLRs 1, 2, 4, 5, 6 and 10 are located on the cell surface, while TLRs 3, 7, 8, 9, 11, 12 and 13 are localized to endosomal/ lysosomal vesicles. The ten TLRs in humans (TLR1 -- 10) are expressed by B cells, dendritic cells (DCs), T cells, monocytes and macrophages [9-12]. The native ligands of TLR1 -- 9 were identified while TLR10 ligand is still unknown. The capacity of TLRs to recognize specific components expressed by bacteria, fungi, protozoa and 10.1517/13543776.2014.880691 © 2014 Informa UK, Ltd. ISSN 1354-3776, e-ISSN 1744-7674 453 All rights reserved: reproduction in whole or in part not permitted Expert Opin. Ther. Patents Downloaded from informahealthcare.com by University of Queensland on 03/24/14 For personal use only.