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Open AccessArticle

The Antitumor Activity of TCR-Mimic Antibody-Drug Conjugates (TCRm-ADCs) Targeting the Intracellular Wilms Tumor 1 (WT1) Oncoprotein

Laboratory of Precision Medicine and Biopharmaceutics & Zhejiang Province Key Laboratory of Anti-Cancer Drug Research, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, China
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Int. J. Mol. Sci. 2019, 20(16), 3912; https://doi.org/10.3390/ijms20163912
Received: 1 July 2019 / Revised: 2 August 2019 / Accepted: 8 August 2019 / Published: 12 August 2019
Wilms tumor 1 (WT1) oncoprotein is an intracellular oncogenic transcription factor which is barely expressed in normal adult tissues but over expressed in a variety of leukemias and solid cancers. WT1-derived HLA-A*02:01 T cell epitope, RMFPNAPYL (RMF), is a validated target for T cell-based immunotherapy. We generated two T cell receptor mimic antibody-drug conjugates (TCRm-ADCs), ESK-MMAE, and Q2L-MMAE, against WT1 RMF/HLA-A*02:01 complex with distinct affinities, which mediate specific antitumor activity. Although ESK-MMAE showed higher tumor growth inhibition ratio in vivo, the efficacy of them was not so promising, which might be due to low expression of peptide/HLA targets. Therefore, we explored a bispecific TCRm-ADC that exerted more potent tumor cytotoxicity compared with TCRm-ADCs. Hence, our findings validate the feasibility of the presenting intracellular peptides as the targets of ADCs, which broadens the antigen selection range of antibody-based drugs and provides new strategies for precision medicine in tumor therapy. View Full-Text
Keywords: TCR-mimic antibody; antibody-drug conjugates; Wilms tumor 1; human leukocyte antigen class I molecule; bispecific TCR-mimic antibody TCR-mimic antibody; antibody-drug conjugates; Wilms tumor 1; human leukocyte antigen class I molecule; bispecific TCR-mimic antibody
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Shen, Y.; Li, Y.-M.; Zhou, J.-J.; Zhou, Z.; Xu, Y.-C.; Zhao, W.-B.; Chen, S.-Q. The Antitumor Activity of TCR-Mimic Antibody-Drug Conjugates (TCRm-ADCs) Targeting the Intracellular Wilms Tumor 1 (WT1) Oncoprotein. Int. J. Mol. Sci. 2019, 20, 3912.

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