JM Bisp61 Nanostring data
Ontology highlight
ABSTRACT:
PROVIDER: PRJEB59108 | ENA |
REPOSITORIES: ENA
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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:A CRISPR Screen Reveals Resistance Mechanisms to CD3-Bispecific Antibody Therapy
| PRJNA669680 | ENA
Project description:This is a phase II Randomized comparison clinical trial of activated CIK armed with anti-CD3-MUC1 bispecific antibody for advanced colorectal cancer. And the aim of this research is to study the clinical efficacy and safety of activated CIK armed with anti-CD3-MUC1 bispecific antibody for colorectal cancer.
| 2272861 | ecrin-mdr-crc
Project description:A novel affinity-tuned dual-checkpoint bispecific antibody with potent PD-L1 and moderate CD47 affinity was designed to improve the selectivity to TME and thus enhance antitumor immunity and efficacy. The gene expression analysis using Nanostring platform was performed to examine the immune cell modulation in TME following the CD47/PD-L1 bispecific treatment.
2021-10-13 | GSE177053 | GEO
Project description:Mass spectrometry-based quantitative proteomics profiling of in vivo signaling changes in 41 therapy resistant (osimertinib or EGFR/Met bispecific antibody treament) tumors from four xenograft NSCLC models.
2017-08-28 | PXD006114 | Pride
Project description:A Multipronged Unbiased Strategy Guides the Development of an anti-EGFR/EPHA2 Bispecific Antibody for Combination Cancer Therapy
| PRJNA721399 | ENA
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:T-cell-recruiting bispecific antibody therapy has yielded promising results in patients with hematologic malignancies, however, resistance and subsequent relapse remains a major challenge. T-cell exhaustion induced by persistent antigen stimulation or tonic receptor signaling has been reported to compromise outcomes of T-cell based immunotherapies. The impact of continuous exposure to bispecifics on T-cell function, however, remains poorly understood. In relapsed/refractory B-cell precursor acute lymphoblastic leukemia patients, 28-day continuous infusion with the CD19xCD3 bispecific antibody blinatumomab led to declining T-cell function. In an in vitro model system, mimicking 28-day continuous infusion with the half-life-extended CD19xCD3 bispecific AMG 562, we identified hallmark features of exhaustion arising over time. Continuous AMG 562 exposure induced progressive loss of T-cell function (day 7 vs day 28 mean specific lysis: 88.4% vs 8.6%; n = 6; p = .0003). Treatment-free intervals (TFIs), achieved by AMG 562 withdrawal, were identified as powerful strategy for counteracting exhaustion. TFIs induced strong functional reinvigoration of T cells (continuous vs TFI specific lysis on day 14: 34.9% vs 93.4%; ± SEM; n = 6; p < .0001) and transcriptional reprogramming. Furthermore, use of a TFI led to improved T-cell expansion and tumor control in vivo. Our data demonstrate the relevance of T-cell exhaustion in bispecific antibody therapy and highlight that T cells can be functionally and transcriptionally rejuvenated with TFIs. In view of the growing number of bispecific molecules being evaluated in clinical trials, our findings emphasize the need to consider and evaluate TFIs in application schedules to improve clinical outcomes.
2022-07-26 | GSE196463 | GEO
Project description:Control of pertussis depends on primary vaccination of infants in combination with booster vaccination of children, adults, and recently also pregnant women. Tetanus-diptheria-acellular pertussis (Tdap) booster vaccines are frequently given in many countries and can be formulated with inactivated poliovirus (Tdap-IPV). Although Tdap-IPV provides clinical protection, both pertussis antibody levels and clinical protection decay shortly after vaccination. This highlights the need for a better understanding of the mechanisms of immunogenicity of aP-containing combination vaccines, which may explain the longevity of the antibody response to vaccination. In order to identify immune signatures that are induced by Tdap-IPV vaccination and which can be associated with humoral responses, we analyzed changes in gene expression.
2024-01-22 | GSE233855 | GEO