Ontology highlight
ABSTRACT:
PROVIDER: PRJNA667149 | ENA |
REPOSITORIES: ENA
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Project description:The study's objective is to investigate the mode of action of a bispecific CD19-targeted CD28 agonist (RG6333, CD19-CD28) in combination with the glofitamab through bulk RNA sequencing of tumor tissue from humanized mice over time. This analysis aims to describe the molecular and immunological changes induced by the combination therapy, which is designed to potentiate T cell-mediated antitumor activity. Glofitamab, a T cell bispecific antibody, targets CD20-expressing malignant B cells and engages CD3ε to deliver a robust TCR signal. To enhance this effect, CD19-CD28 was developed to provide a necessary costimulatory signal by binding to CD19 on tumor-infiltrating T cells. This agent is engineered to require concurrent TCR signaling and CD19 target presence, avoiding the issues associated with previous superagonistic antibodies. In this study, we explore the synergistic potential of CD19-CD28 with glofitamab in activating T cell responses and inducing tumor regression in humanized mouse models. The RNA-Seq analysis identified gene expression signatures and immune pathways activated by the treatment. These findings underscore the promise of CD19-CD28 as an effective combination partner to glofitamab.
2024-03-03 | GSE260674 | GEO
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.
2020-11-12 | GSE159547 | GEO
Project description:Local administration of IFN-α-producing proliferating myeloid cells (IFN-α-iPSC-pMCs) inhibited the tumor growth not only at the treatment site but also at the distant site (left). T cell receptor (TCR)-β chain repertoire and complementarity determining region 3 (CDR3) gene sequence analyses of tumor-infiltrating lymphocytes (TILs) showed marked enrichment of T cells with identical TCR-β chains in bilateral tumor tissues.
2019-02-13 | GSE126278 | GEO
Project description:The data corresponds to the analysis of T cell receptor (TCR) repertoires of FACS-purified Tstem, Tpex and TEM cells of six individuals. The analysis of the TCR beta chain (TRB) demonstrated the differences between Tstem and Tpex repertoire properties. In total, 36 samples were analyzed using the Human TCR Profiling Kit (MiLaboratory LLC) for sequencing libraries preparation and Illumina NextSeq 550 sequencing (150+150bp) followed by the demultiplexing procedure using MIGEC software.
2020-08-01 | E-MTAB-8892 | biostudies-arrayexpress
Project description:We used single cell RNA sequencing (scRNAseq) to compare gene expression in human T cells following stimulation with antibodies directed against a CD3 subunit (CD3ε) versus the TCRβ chain variable (V) domain
2023-10-31 | GSE229626 | GEO
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
Project description:Fibrosis is the final path of nearly every form of chronic disease and accounts for up to 45% of all deaths in the developed world. However, antifibrotic therapies that target fibrogenic cells are lacking. We tested whether specific immunization against ADAM12 can elicit an antigen-specific cytotoxic T cell response to ameliorate liver fibrosis. In this study, we performed T cell receptor (TCR) alpha- and beta-chain repertoire sequencing on fibrotic livers to further characterize the T cell response and to detect potential TCR clonotypes. We observed TCR clonality of liver-infiltrating T cells from v-A12- and control-vaccinated mice with minimal overlap to v-CTRL mice in two α-chain sequences. However, the vast majority of expanded clones from v-A12-vaccinated animals showed a unique sequence pattern. Moreover, there was no overlap in the β-chain sequences between v-A12-vaccinated and control mice, suggesting a vaccination-induced expansion of antigen-specific TCR clonotypes.
2022-09-15 | GSE208635 | GEO
Project description:To study the development and function of “natural-arising” T regulatory (nTreg) cells, we developed a novel nTreg model on pure nonobese diabetic background using epigenetic reprogramming via somatic cell nuclear transfer. On RAG1-deficient background, we found that monoclonal FoxP3+ CD4+ Treg cells developed in the thymus in the absence of other T cells. Adoptive transfer experiments revealed that the thymic niche is not a limiting factor in nTreg development. In addition, we showed that the T-cell receptor (TCR) β-chain of our nTreg model was not only sufficient to bias T-cell development toward the CD4 lineage, but we also demonstrated that this TCR β-chain was able to provide stronger TCR signals. This TCR-β–driven mechanism would thus unify former per se contradicting hypotheses of TCR-dependent and -independent nTreg development. Strikingly, peripheral FoxP3− CD4+ T cells expressing the same TCR as this somatic cell nuclear transfer nTreg model had a reduced capability to differentiate into Th1 cells but were poised to differentiate better into induced nTreg cells, both in vitro and in vivo, representing a novel peripheral precursor subset of nTreg cells to which we refer to as pre-nTreg cells.
2016-04-04 | GSE70156 | GEO
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.
2019-08-12 | BIOMD0000000788 | BioModels
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.
2023-01-24 | MSV000091134 | MassIVE