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T cell dependent bispecific antibodies (TDBs) promote T cell redistribution through organ-specific alteration of vascular endothelial cell (bulk RNAseq)

ABSTRACT: T cell dependent bispecific antibodies (TDBs) promote T cell redistribution through organ-specific alteration of vascular endothelial cell (bulk RNAseq)

PROVIDER: PRJNA817212 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR18357287.fastq.gz	Fastqsanger.gz
	SRR18357288.fastq.gz	Fastqsanger.gz
	SRR18357289.fastq.gz	Fastqsanger.gz
	SRR18357290.fastq.gz	Fastqsanger.gz
	SRR18357291.fastq.gz	Fastqsanger.gz

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T cell dependent bispecific antibodies (TDBs) promote T cell redistribution through organ-specific alteration of vascular endothelial cell

Project description:T cell dependent bispecific antibodies (TDBs) promote T cell redistribution through organ-specific alteration of vascular endothelial cell

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T cell dependent bispecific antibodies (TDBs) promote T cell redistribution through organ-specific alteration of vascular endothelial cell (scRNAseq)

Project description:T cell dependent bispecific antibodies (TDBs) promote T cell redistribution through organ-specific alteration of vascular endothelial cell (scRNAseq)

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T cell dependent bispecific antibodies (TDBs) promote T cell redistribution through organ-specific alteration of vascular endothelial cell (scRNAseq)

Project description:TDBs (T cell dependent bispecific antibodies) have an agonistic anti-CD3 arm paired with a tumor-targeting arm that recognizes tumor-restricted/enriched cell-surface proteins. Preclinical and clinical studies demonstrated that TDBs can induce systemic changes in addition to their expected action in tumors, including transient loss of circulating leukocytes (margination), systemic cytokine release, and accumulation of lymphocytes in normal tissues. These reactions can lead to undesirable symptoms including cytokine release syndrome and liver enzyme elevation. Here, we report for the first-time an in-depth characterization of acute responses in tumor and liver upon TDB treatment. We observed rapid and substantial accumulation of lymphocytes around large blood vessels in normal organs such as the liver, accompanied by elevated vascular endothelial cell (EC) activation markers. We hypothesized that organ-specific EC phenotypes may account for the differential T cell accumulation in normal tissues versus tumors. Despite ongoing efforts to better characterize specific properties of ECs, the underlying transcriptional changes of specific endothelial cell subtypes influencing the T cell trafficking and accumulation in non-target-expressing organs (like here liver) upon TDB treatment are unknown. The purpose of the study is to investigate the effect of anti-HER2/CD3 TDB treatment on the endothelial cells in the liver and characterize possible transcriptional changes occurring.

2022-12-09 | GSE198868 | GEO

T cell dependent bispecific antibodies (TDBs) promote T cell redistribution through organ-specific alteration of vascular endothelial cell (bulk RNAseq)

2022-12-09 | GSE198867 | GEO

Bispecific antibodies increase the therapeutic window of CD40 agonists through selective dendritic cell targeting

Project description:Therapeutic use of agonistic anti-CD40 antibodies is a potentially powerful approach for activating the immune response to eradicate tumors. However, the translation of this approach to clinical practice has been significantly restricted due to the severe dose-limiting toxicities observed in multiple clinical trials. Here, we demonstrate that conventional type-1 dendritic cells are essential for triggering antitumor immunity but not toxicity by CD40 agonists, while macrophages, platelets, and monocytes lead to the toxic events. Therefore, we designed bispecific antibodies that target CD40 activation preferentially to dendritic cells. These bispecific reagents demonstrate a superior safety profile compared to their parental CD40 monospecific antibody, while triggering potent anti-tumor activity. We suggest such cell-selective bispecific agonistic antibodies as a drug platform to bypass the dose-limiting toxicities of anti-CD40, and of additional types of agonistic antibodies used for cancer immunotherapy.

2021-12-12 | GSE184009 | GEO

T cell dependent bispecific antibodies (TDBs) promote T cell redistribution through organ-specific alteration of vascular endothelial cell

Project description:This SuperSeries is composed of the SubSeries listed below.

2022-12-09 | GSE198869 | GEO

Schropp2019 - Target-Mediated Drug Disposition Model for Bispecific Antibodies

Project description:This model presents a general target-mediated drug disposition (TMDD) model for bispecific antibodies (BsAbs), which bind to two different targets on different cell membranes. The model includes four different binding events for BsAbs, turnover of the targets, and internalization of the complexes. In addition, a quasi-equilibrium (QE) approximation with decreased number of binding parameters is also present.

2024-09-02 | BIOMD0000000788 | BioModels

Simultaneous substrate and ubiquitin modification recognition by bispecific antibodies allows detection of ubiquitinated RIP1 and RIP2

Project description:Ubiquitination is crucial for the dynamic regulation of diverse signaling pathways. To enhance understanding of ubiquitination mediated signaling, we generated a new class of bispecific antibodies which combine recognition of ubiquitination substrates and specific polyubiquitin linkages. RIP1-K63 or RIP1-linear (Lin) linkage polyubiquitin bispecific antibodies can detect linkage-specific RIP1 ubiquitination in cells and in tissues, and also reveal RIP1 ubiquitination by immunofluorescence. In a similar fashion, RIP2 ubiquitination with K63 or linear linkages can be specifically detected with RIP2-K63 and RIP2-Lin bispecific antibodies. Furthermore, using RIP2-K63 and RIP2- Lin bispecific antibodies we examined IBD patient samples and found prominent K63- linked and linear RIP2 ubiquitination in ulcerative colitis and Crohn's disease patient samples. We also developed a bispecific antibody (K63-Lin) that can simultaneously recognize K63-linked and linear ubiquitination in a variety of signaling pathways. Collectively, these bispecific antibodies provide a novel conceptual paradigm for potential future development of inflammatory markers.

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A CRISPR Screen Reveals Resistance Mechanisms to CD3-Bispecific Antibody Therapy

Project description:CD3-bispecific antibodies represent an important therapeutic strategy in oncology. These molecules work by redirecting cytotoxic T cells to antigen-bearing tumor cells. Although CD3-bispecific antibodies have been developed for several clinical indications, cases of cancer-derived resistance are an emerging limitation to the more generalized application of these molecules. Here, we devised whole-genome CRISPR screens to identify cancer resistance mechanisms to CD3-bispecific antibodies across multiple targets and cancer types. By validating the screen hits, we found that deficiency in IFNγ signaling has a prominent role in cancer resistance. Interestingly, IFNγ functions by stimulating the expression of T cell killing-related molecules in a cell type-specific manner. Additionally, by assessing resistance to the clinical CD3-bispecific antibody flotetuzumab, we identified core fucosylation as a novel and critical pathway to regulate flotetuzumab binding to the CD123 antigen. Disruption of this pathway resulted in significant resistance to flotetuzumab treatment. Moreover, proper fucosylation of CD123 is required for its normal biological functions. In order to treat the resistance associated with fucosylation loss, flotetuzumab in combination with an alternative targeting CD3-bispecific antibody demonstrated superior efficacy. Together, our study reveals multiple mechanisms that can be targeted to enhance the clinical potential of current and future T cell engaging CD3-bispecific antibody therapies.

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Bispecific antibodies increase the therapeutic window of CD40 agonists through selective dendritic cell targeting

Project description:Bispecific antibodies increase the therapeutic window of CD40 agonists through selective dendritic cell targeting

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