Affinity maturation of T-cell receptor-like antibodies for Wilms tumor 1 peptide greatly enhances therapeutic potential Journal Article
| Authors: | Zhao, Q.; Ahmed, M.; Tassev, D. V.; Hasan, A.; Kuo, T. Y.; Guo, H. F.; O'Reilly, R. J.; Cheung, N. K. V. |
| Article Title: | Affinity maturation of T-cell receptor-like antibodies for Wilms tumor 1 peptide greatly enhances therapeutic potential |
| Abstract: | WT1 126 (RMFPNAPYL) is a human leukocyte antigen-A2 (HLA-A2)-restricted peptide derived from Wilms tumor protein 1 (WT1), which is widely expressed in a broad spectrum of leukemias, lymphomas and solid tumors. A novel T-cell-receptor (TCR)-like single-chain variable fragment (scFv) antibody specific for the T-cell epitope consisting of the WT1/HLA-A2 complex was isolated from a human scFv phage library. This scFv was affinity-matured by mutagenesis combined with yeast display and structurally analyzed using a homology model. This monovalent scFv showed a 100-fold affinity improvement (dissociation constant (K D)=3 nm) and exquisite specificity towards its targeted epitope or HLA-A2 + /WT1 + tumor cells. Bivalent scFv-huIgG1-Fc fusion protein demonstrated an even higher avidity (K D =2 pm) binding to the T-cell epitope and to tumor targets and was capable of mediating antibody-dependent cell-mediated cytotoxicity or tumor lysis by chimeric antigen receptor-expressing human T- or NK-92-MI-transfected cells. This antibody demonstrated specific and potent cytotoxicity in vivo towards WT1-positive leukemia xenograft that was HLA-A2 restricted. In summary, T-cell epitopes can provide novel targets for antibody-based therapeutics. By combining phage and yeast displays and scFv-Fc fusion platforms, a strategy for developing high-affinity TCR-like antibodies could be rapidly explored for potential clinical development. © 2015 Macmillan Publishers Limited. |
| Keywords: | controlled study; protein expression; leukemia; unclassified drug; human cell; nonhuman; binding affinity; t lymphocyte; animal cell; mouse; cell maturation; animal model; in vivo study; cytotoxicity; drug potency; in vitro study; tumor xenograft; acute lymphoblastic leukemia; monoclonal antibody; hybrid protein; genetic transfection; epitope; tumor protein; tumor cell line; tumor cell; chimeric antigen receptor; natural killer cell; yeast; mutagenesis; single chain fragment variable antibody; phage display; peripheral blood mononuclear cell; peptide library; nephroblastoma; antibody dependent cellular cytotoxicity; tumor cell destruction; dissociation constant; human; male; priority journal; article; scfv hulgg1 fc fusion protein; t cell receptor like antibody; wilms tumor 1 protein |
| Journal Title: | Leukemia |
| Volume: | 29 |
| Issue: | 11 |
| ISSN: | 0887-6924 |
| Publisher: | Nature Publishing Group |
| Date Published: | 2015-11-01 |
| Start Page: | 2238 |
| End Page: | 2247 |
| Language: | English |
| DOI: | 10.1038/leu.2015.125 |
| PROVIDER: | scopus |
| PUBMED: | 25987253 |
| PMCID: | PMC4788467 |
| DOI/URL: | |
| Notes: | Export Date: 2 December 2015 -- Source: Scopus |
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