PMID- 29933102 OWN - NLM STAT- MEDLINE DCOM- 20190903 LR - 20190903 IS - 1878-5905 (Electronic) IS - 0142-9612 (Linking) VI - 178 DP - 2018 Sep TI - Elimination of melanoma by sortase A-generated TCR-like antibody-drug conjugates (TL-ADCs) targeting intracellular melanoma antigen MART-1. PG - 158-169 LID - S0142-9612(18)30437-X [pii] LID - 10.1016/j.biomaterials.2018.06.017 [doi] AB - Most tumor-associated proteins are located inside tumor cells and thus are not accessible to current marketed therapeutic monoclonal antibodies or their cytotoxic conjugates. Human leukocyte antigen (HLA) class I can present peptides derived from intracellular tumor-associated proteins and somatically mutated proteins on the cell's surface, forming an HLA/peptide complex as tumor-specific antigens for T cell receptor (TCR) recognition. Therefore, HLA-mediated presentation of intracellular tumor antigen peptides provides a viable way to distinguish tumor cells from normal cells, which is important for broadening antigen selection, especially for antibody-drug conjugates (ADCs) regarding their highly cytotoxic payload. We applied sortase A-mediated conjugation to develop TCR-like ADCs (i.e., EA1 HL-vcMMAE) targeting intracellular MART-1 protein, a melanocyte-differentiating antigen specific for metastatic melanomas, via the cell surface HLA-A2/MART-1(26-35) peptide complex. Homogenous EA1 HL-vcMMAE (drug to antibody ratio of 4) efficiently eliminated melanoma cells in xenograft mouse models with no obvious toxicity at the therapeutic dosage. Trametinib, an MEK inhibitor serving as an HLA expression enhancing agent, augmented the TL-ADCs' efficacy both in vitro and in vivo by upregulating MART-1(26-35) peptide presentation, thus providing a strategy for overcoming the limitation of antigen presentation level for TL-ADCs. Hence, our findings validate the strategy of using sortase A-generated TL-ADCs to target tumor-specific intracellular proteins, with or without agents present, to increase presenting TCR epitope peptides. CI - Copyright (c) 2018 Elsevier Ltd. All rights reserved. FAU - Lai, Jun AU - Lai J AD - Institute of Drug Metabolism and Pharmaceutical Analysis, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, 310058, China. FAU - Wang, Yun AU - Wang Y AD - Institute of Drug Metabolism and Pharmaceutical Analysis, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, 310058, China. FAU - Wu, Shan-Shan AU - Wu SS AD - Institute of Drug Metabolism and Pharmaceutical Analysis, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, 310058, China. FAU - Ding, Ding AU - Ding D AD - Noeantigen Therapeutics (HangZhou) Co., Ltd, Hangzhou, 310058, China. FAU - Sun, Ze-Yu AU - Sun ZY AD - State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infection Diseases, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, 310003, China. FAU - Zhang, Ying AU - Zhang Y AD - Institute of Drug Metabolism and Pharmaceutical Analysis, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, 310058, China. FAU - Zhou, Jie AU - Zhou J AD - Institute of Drug Metabolism and Pharmaceutical Analysis, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, 310058, China. FAU - Zhou, Zhan AU - Zhou Z AD - Institute of Drug Metabolism and Pharmaceutical Analysis, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, 310058, China. FAU - Xu, Ying-Chun AU - Xu YC AD - Institute of Drug Metabolism and Pharmaceutical Analysis, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, 310058, China. FAU - Pan, Li-Qiang AU - Pan LQ AD - Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA 02115, United States. Electronic address: lpan@crystal.harvard.edu. FAU - Chen, Shu-Qing AU - Chen SQ AD - Institute of Drug Metabolism and Pharmaceutical Analysis, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, 310058, China. Electronic address: chenshuqing@zju.edu.cn. LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20180615 PL - Netherlands TA - Biomaterials JT - Biomaterials JID - 8100316 RN - 0 (Antineoplastic Agents) RN - 0 (Bacterial Proteins) RN - 0 (Histocompatibility Antigens Class I) RN - 0 (Immunoconjugates) RN - 0 (MART-1 Antigen) RN - 0 (Peptides) RN - 0 (Pyridones) RN - 0 (Pyrimidinones) RN - 0 (Receptors, Antigen, T-Cell) RN - 33E86K87QN (trametinib) RN - EC 2.3.2.- (Aminoacyltransferases) RN - EC 2.3.2.- (sortase A) RN - EC 3.4.22.- (Cysteine Endopeptidases) SB - IM MH - Aminoacyltransferases/*metabolism MH - Animals MH - Antibody Specificity/drug effects MH - Antigen Presentation/drug effects MH - Antineoplastic Agents/pharmacology MH - Bacterial Proteins/*metabolism MH - Cell Line, Tumor MH - Cysteine Endopeptidases/*metabolism MH - Endocytosis/drug effects MH - Female MH - Histocompatibility Antigens Class I/metabolism MH - Immunoconjugates/*metabolism MH - Intracellular Space/*metabolism MH - MART-1 Antigen/*metabolism MH - Melanoma/*pathology MH - Mice, SCID MH - Peptides/chemistry MH - Protein Binding/drug effects MH - Pyridones/pharmacology MH - Pyrimidinones/pharmacology MH - Receptors, Antigen, T-Cell/*metabolism OTO - NOTNLM OT - Intracellular antigen OT - Sortase A mediated conjugation OT - Specific targeting OT - TCR-Like antibody-drug conjugates EDAT- 2018/06/23 06:00 MHDA- 2019/09/04 06:00 CRDT- 2018/06/23 06:00 PHST- 2018/03/28 00:00 [received] PHST- 2018/06/08 00:00 [revised] PHST- 2018/06/11 00:00 [accepted] PHST- 2018/06/23 06:00 [pubmed] PHST- 2019/09/04 06:00 [medline] PHST- 2018/06/23 06:00 [entrez] AID - S0142-9612(18)30437-X [pii] AID - 10.1016/j.biomaterials.2018.06.017 [doi] PST - ppublish SO - Biomaterials. 2018 Sep;178:158-169. doi: 10.1016/j.biomaterials.2018.06.017. Epub 2018 Jun 15.