| Status | 已發表Published |
| Affinity maturation of T-cell receptor-like antibodies for Wilms tumor 1 peptide greatly enhances therapeutic potential | |
Zhao, Q.; Ahmed, M.; Tassev, D.; Hansen, A.; Kuo, T.; Guo, H.; OReilly, R.; Cheung, N.
| |
| 2015-05-19 | |
| Source Publication | Leukemia
 |
| ISSN | 0887-6924 |
| Pages | 2238-2247 |
| Abstract | WT1126 (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 (KD)=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 (KD=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. |
| Keyword | Affinity maturation T-cell receptor-like antibody WT1 |
| URL | View the original |
| Language | 英語English |
| The Source to Article | PB_Publication |
| PUB ID | 55323 |
| Document Type | Journal article |
| Collection | DEPARTMENT OF BIOMEDICAL SCIENCES |
| Corresponding Author | Cheung, N. |
| Recommended Citation GB/T 7714 | Zhao, Q.,Ahmed, M.,Tassev, D.,et al. Affinity maturation of T-cell receptor-like antibodies for Wilms tumor 1 peptide greatly enhances therapeutic potential[J]. Leukemia, 2015, 2238-2247. |
| APA | Zhao, Q.., Ahmed, M.., Tassev, D.., Hansen, A.., Kuo, T.., Guo, H.., OReilly, R.., & Cheung, N. (2015). Affinity maturation of T-cell receptor-like antibodies for Wilms tumor 1 peptide greatly enhances therapeutic potential. Leukemia, 2238-2247. |
| MLA | Zhao, Q.,et al."Affinity maturation of T-cell receptor-like antibodies for Wilms tumor 1 peptide greatly enhances therapeutic potential".Leukemia (2015):2238-2247. |
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