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Affinity maturation of T-cell receptor-like antibodies for Wilms tumor 1 peptide greatly enhances therapeutic potential
Zhao Q.; Ahmed M.; Tassev D.V.; Hasan A.; Kuo T.-Y.; Guo H.-F.; O'Reilly R.J.; Cheung N.-K.V.
2015-11-01
Source PublicationLeukemia
ISSN14765551 08876924
Volume29Issue:11Pages:2238-2247
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.

DOI10.1038/leu.2015.125
URLView the original
Indexed BySCI
Language英语
WOS Research AreaOncology ; Hematology
WOS SubjectOncology ; Hematology
WOS IDWOS:000364527400014
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Cited Times [WOS]:32   [WOS Record]     [Related Records in WOS]
Document TypeJournal article
CollectionFaculty of Health Sciences
AffiliationMemorial Sloan-Kettering Cancer Center
Recommended Citation
GB/T 7714
Zhao Q.,Ahmed M.,Tassev D.V.,et al. Affinity maturation of T-cell receptor-like antibodies for Wilms tumor 1 peptide greatly enhances therapeutic potential[J]. Leukemia,2015,29(11):2238-2247.
APA Zhao Q..,Ahmed M..,Tassev D.V..,Hasan A..,Kuo T.-Y..,...&Cheung N.-K.V..(2015).Affinity maturation of T-cell receptor-like antibodies for Wilms tumor 1 peptide greatly enhances therapeutic potential.Leukemia,29(11),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 29.11(2015):2238-2247.
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