Structure of a TCR-mimic antibody with target predicts pharmacogenetics Journal Article
| Authors: | Ataie, N.; Xiang, J.; Cheng, N.; Brea, E. J.; Lu, W.; Scheinberg, D. A.; Liu, C.; Ng, H. L. |
| Article Title: | Structure of a TCR-mimic antibody with target predicts pharmacogenetics |
| Abstract: | Antibody therapies currently target only extracellular antigens. A strategy to recognize intracellular antigens is to target peptides presented by immune HLA receptors. ESK1 is a human, T-cell receptor (TCR)-mimic antibody that binds with subnanomolar affinity to the RMF peptide from the intracellular Wilms tumor oncoprotein WT1 in complex with HLA-A∗02:01. ESK1 is therapeutically effective in mouse models of WT1+ human cancers. TCR-based therapies have been presumed to be restricted to one HLA subtype. The mechanism for the specificity and high affinity of ESK1 is unknown. We show in a crystal structure that ESK1 Fab binds to RMF/HLA-A∗02:01 in a mode different from that of TCRs. From the structure, we predict and then experimentally confirm high-affinity binding with multiple other HLA-A∗02 subtypes, broadening the potential patient pool for ESK1 therapy. Using the crystal structure, we also predict potential off-target binding that we experimentally confirm. Our results demonstrate how protein structure information can contribute to personalized immunotherapy. © 2015 Elsevier Ltd. All rights reserved. |
| Keywords: | oncoprotein; nonhuman; drug targeting; binding affinity; animal cell; protein binding; immunotherapy; crystal structure; pharmacogenetics; protein structure; hla a antigen; nephroblastoma; hla system; purification; antibody structure; human; female; priority journal; article; abbreviations tcr t-cell receptor; b2m β2-microglobulin; cdr complementarity-determining region; mab monoclonal antibody; mhc major histocompatibility complex; nih national institutes of health; pmhc peptide/mhc; ssrl stanford synchrotron radiation laboratory; tcrm tcr mimic |
| Journal Title: | Journal of Molecular Biology |
| Volume: | 428 |
| Issue: | 1 |
| ISSN: | 0022-2836 |
| Publisher: | Academic Press Inc., Elsevier Science |
| Date Published: | 2016-01-16 |
| Start Page: | 194 |
| End Page: | 205 |
| Language: | English |
| DOI: | 10.1016/j.jmb.2015.12.002 |
| PROVIDER: | scopus |
| PMCID: | PMC4738012 |
| PUBMED: | 26688548 |
| DOI/URL: | |
| Notes: | Article -- Export Date: 4 April 2016 -- Source: Scopus |
