|
|||||
|
|
Simplified Monopalmitoyl Toll-like Receptor 2 Ligand Mini-UPam for Self-Adjuvanting Neoantigen-Based Synthetic Cancer Vaccines |
|
| Authors: | Thomas C. van den Ende Jeroen M. M. Heuts Dr. Geoffroy P. P. Gential Marten Visser Michel J. van de Graaff Dr. Nataschja I. Ho Prof. Dr. Wim Jiskoot Dr. A. Rob P. M. Valentijn Nico J. Meeuwenoord Prof. Dr. Herman S. Overkleeft Prof. Dr. Jeroen D. C. Codée Prof. Dr. Sjoerd H. van der Burg Dr. Els M. E. Verdegaal Prof. Dr. Gijsbert A. van der Marel Prof. Dr. Ferry Ossendorp Dr. Dmitri V. Filippov |
| Affiliation: | 1. Leiden Institute of Chemistry, Leiden University, Einsteinweg 55, 2333 CC Leiden, The Netherlands These authors contributed equally to this work.;2. Department of Immunology, Leiden University Medical Center, Albinusdreef 2, 2333 ZA Leiden, The Netherlands These authors contributed equally to this work.;3. Leiden Institute of Chemistry, Leiden University, Einsteinweg 55, 2333 CC Leiden, The Netherlands;4. Department of Medical Oncology and Oncode Institute, Leiden University Medical Center, Albinusdreef 2, 2333 ZA Leiden, The Netherlands;5. Department of Immunology, Leiden University Medical Center, Albinusdreef 2, 2333 ZA Leiden, The Netherlands;6. Division of BioTherapeutics, Leiden Academic Centre for Drug Research (LACDR), Leiden University, Einsteinweg 55, 2333 CC Leiden, The Netherlands;7. Clinical Pharmacy and Toxicology, Leiden University Medical Center, Albinusdreef 2, 2333 ZA Leiden, The Netherlands |
| Abstract: | Synthetic vaccines, based on antigenic peptides that comprise MHC−I and MHC-II T-cell epitopes expressed by tumors, show great promise for the immunotherapy of cancer. For optimal immunogenicity, the synthetic peptides (SPs) should be adjuvanted with suitable immunostimulatory additives. Previously, we have shown that improved immunogenicity in vivo is obtained with vaccine modalities in which an SP is covalently connected to an adjuvanting moiety, typically a ligand to Toll-like receptor 2 (TLR2). SPs were covalently attached to UPam, which is a derivative of the classic TLR2 ligand Pam3CysSK4. A disadvantage of the triply palmitoylated UPam is its high lipophilicity, which precludes universal adoption of this adjuvant for covalent modification of various antigenic peptides as it renders the synthetic vaccine insoluble in several cases. Here, we report a novel conjugatable TLR2 ligand, mini-UPam, which contains only one palmitoyl chain, rather than three, and therefore has less impact on the solubility and other physicochemical properties of a synthetic peptide. In this study, we used SPs that contain the clinically relevant neoepitopes identified in a melanoma patient who completely recovered after T-cell therapy. Homogeneous mini-UPam-SP conjugates have been prepared in good yields by stepwise solid-phase synthesis that employed a mini-UPam building block pre-prepared in solution and the standard set of Fmoc-amino acids. The immunogenicity of the novel mini-UPam-SP conjugates was demonstrated by using the cancer patient's T-cells. |
| Keywords: | cancer vaccines dendritic cells lipopeptides neoepitopes solid-phase synthesis TLR2 ligand |