Abstract
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.
Highlights
According to the Global Cancer Report of 2018, the latest global cancer statistics, there are 18.1 million new cancer cases and 9.6 million deaths worldwide
T2 cell is an HLA-A*0201 positive and transporter-associated protein (TAP)-deficient cell line, there is no peptide/MHC complex (pMHC) on its cell surface [24]
antibody-drug conjugates (ADCs), which exert antitumor activity through selectively tumor-targeting and cytotoxicity, are an attractive therapy used in clinical practice
Summary
According to the Global Cancer Report of 2018, the latest global cancer statistics, there are 18.1 million new cancer cases and 9.6 million deaths worldwide. Antibody-drug conjugates (ADCs) are considered as a promising agent for cancer therapy, which link potent cytotoxic agents to monoclonal antibodies (mAbs) through chemical linkages. ADCs deliver cytotoxic agents into the tumor cells to exert antitumor effects and greatly reduce the side effects caused by the cytotoxic agents. Almost all traditional ADCs, including above five marketed ADCs, target extracellular or cell surface proteins which account for only a tiny fraction of the total cellular proteins [2,3]. Due to the existence of cell membranes, it is difficult for ADCs to target intracellular proteins, which makes it invalid for many tumor associated or specific proteins to be chosen as the targets of ADCs
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