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A T cell redirection platform for co-targeting dual antigens on solid tumors.

ABSTRACT: In order to direct T cells to specific features of solid cancer cells, we engineered a bispecific antibody format, named Dual Antigen T cell Engager (DATE), by fusing a single-chain variable fragment targeting CD3 to a tumor-targeting antigen-binding fragment. In this format, multiple novel paratopes against different tumor antigens were able to recruit T-cell cytotoxicity to tumor cells in vitro and in an in vivo pancreatic ductal adenocarcinoma xenograft model. Since unique surface antigens in solid tumors are limited, in order to enhance selectivity, we further engineered "double-DATEs" targeting two tumor antigens simultaneously. The double-DATE contains an additional autonomous variable heavy-chain domain, which binds a second tumor antigen without itself eliciting a cytotoxic response. This novel modality provides a strategy to enhance the selectivity of immune redirection through binary targeting of native tumor antigens. The modularity and use of a common, stable human framework for all components enables a pipeline approach to rapidly develop a broad repertoire of tailored DATEs and double-DATEs with favorable biophysical properties and high potencies and selectivities.

SUBMITTER: Enderle L

PROVIDER: S-EPMC8253144 | biostudies-literature | 2021 Jan-Dec

REPOSITORIES: biostudies-literature

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A T cell redirection platform for co-targeting dual antigens on solid tumors.

Enderle Leonie L Shalaby Karim H KH Gorelik Maryna M Weiss Alexander A Blazer Levi L LL Paduch Marcin M Cardarelli Lia L Kossiakoff Anthony A Adams Jarrett J JJ Sidhu Sachdev S SS

mAbs 20210101 1

In order to direct T cells to specific features of solid cancer cells, we engineered a bispecific antibody format, named Dual Antigen T cell Engager (DATE), by fusing a single-chain variable fragment targeting CD3 to a tumor-targeting antigen-binding fragment. In this format, multiple novel paratopes against different tumor antigens were able to recruit T-cell cytotoxicity to tumor cells in vitro and in an in vivo pancreatic ductal adenocarcinoma xenogra ...[more]

PMID: 34190031

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Project description:Accumulating evidence indicates that non-coding RNAs including microRNAs (miRs) and long non-coding RNAs (lncRNAs) are aberrantly expressed in cancer, providing promising biomarkers for diagnosis, prognosis and/or therapeutic targets. We aimed in the current work to quantify the expression profile of miR-34a and one of its bioinformatically selected partner lncRNA growth arrest-specific 5 (GAS5) in a sample of Egyptian cancer patients, including three prevalent types of cancer in our region; renal cell carcinoma (RCC), glioblastoma (GB), and hepatocellular carcinoma (HCC) as well as to correlate these expression profiles with the available clinicopathological data in an attempt to clarify their roles in cancer. Quantitative real-time polymerase chain reaction analysis was applied. Different bioinformatics databases were searched to confirm the potential miRNAs-lncRNA interactions of the selected ncRNAs in cancer pathogenesis. The tumor suppressor lncRNA GAS5 was significantly under-expressed in the three types of cancer [0.08 (0.006-0.38) in RCC, p <0.001; 0.10 (0.003-0.89) in GB, p < 0.001; and 0.12 (0.015-0.74) in HCC, p < 0.001]. However, levels of miR-34a greatly varied according to the tumor type; it displayed an increased expression in RCC [4.05 (1.003-22.69), p <0.001] and a decreased expression in GB [0.35 (0.04-0.95), p <0.001]. Consistent to the computationally predicted miRNA-lncRNA interaction, negative correlations were observed between levels of GAS5 and miR-34a in RCC samples (r = -0.949, p < 0.001), GB (r = -0.518, p < 0.001) and HCC (r = -0.455, p = 0.013). Kaplan-Meier curve analysis revealed that RCC patients with down-regulated miR-34a levels had significantly poor overall survival than their corresponding (p < 0.05). Hierarchical clustering analysis showed RCC patients could be clustered by GAS5 and miR-34a co-expression profile. Our results suggest potential applicability of GAS5 and miR-34a with other conventional markers for various types of cancer. Further functional validation studies are warranted to confirm miR-34a/GAS5 interplay in cancer.

Dataset Information

A T cell redirection platform for co-targeting dual antigens on solid tumors.

Publications

A T cell redirection platform for co-targeting dual antigens on solid tumors.

Similar Datasets

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