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FcγRIIB engagement drives agonistic activity of Fc-engineered αOX40 antibody to stimulate human tumor-infiltrating T cells

ABSTRACT: FcγRIIB engagement drives agonistic activity of Fc-engineered αOX40 antibody to stimulate human tumor-infiltrating T cells

PROVIDER: PRJNA640811 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR12060531_1.fastq.gz	Fastqsanger.gz
	SRR12060531_2.fastq.gz	Fastqsanger.gz
	SRR12060532_1.fastq.gz	Fastqsanger.gz
	SRR12060532_2.fastq.gz	Fastqsanger.gz
	SRR12060533_1.fastq.gz	Fastqsanger.gz

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FcγRIIB engagement drives agonistic activity of Fc-engineered αOX40 antibody to stimulate human tumor-infiltrating T cells

Project description:Background: OX40 (CD134) is a co-stimulatory molecule of the tumor necrosis factor receptor (TNFR) superfamily, that is currently investigated as a target for cancer immunotherapy. However, despite promising results in murine tumor models, the clinical efficacy of agonistic αOX40 antibodies in treatment of cancer patients has fallen short of the high expectation in earlier stage trials. Methods: Using lymphocytes from resected tumor, tumor-free tissue and PBMC of 4 hepatocellular and colorectal cancer patients, we performed RNA-Seq to evaluate OX40-mediated transcriptional changes in CD4+ and CD8+ human tumor-infiltrating lymphocytes (TILs). Results: The transcriptional landscape of CD4+ and CD8+ TILs shifted towards a pro-survival, inflammatory and chemotactic profile upon treatment with αOX40_v12.

2020-06-22 | GSE152904 | GEO

FcγRIIB engagement drives agonistic activity of Fc-engineered αOX40 antibody to stimulate human tumor-infiltrating T cells.

Project description:OX40 (CD134) is a costimulatory molecule of the tumor necrosis factor receptor superfamily that is currently being investigated as a target for cancer immunotherapy. However, despite promising results in murine tumor models, the clinical efficacy of agonistic αOX40 antibodies in the treatment of patients with cancer has fallen short of the high expectation in earlier-stage trials. Using lymphocytes from resected tumor, tumor-free (TF) tissue and peripheral blood mononuclear cells (PBMC) of 96 patients with hepatocellular and colorectal cancers, we determined OX40 expression and the in vitro T-cell agonistic activity of OX40-targeting compounds. RNA-Seq was used to evaluate OX40-mediated transcriptional changes in CD4+ and CD8+ human tumor-infiltrating lymphocytes (TILs). Here, we show that OX40 was overexpressed on tumor-infiltrating CD4+ T cells compared with blood and TF tissue-derived T cells. In contrast to a clinical candidate αOX40 antibody, treatment with an Fc-engineered αOX40 antibody (αOX40_v12) with selectively enhanced FcγRIIB affinity, stimulated in vitro CD4+ and CD8+ TIL expansion, as well as cytokine and chemokine secretions. The activity of αOX40_v12 was dependent on FcγRIIB engagement and intrinsic CD3/CD28 signals. The transcriptional landscape of CD4+ and CD8+ TILs shifted toward a prosurvival, inflammatory and chemotactic profile on treatment with αOX40_v12. OX40 is overexpressed on CD4+ TILs and thus represents a promising target for immunotherapy. Targeting OX40 with currently used agonistic antibodies may be inefficient due to lack of OX40 multimerization. Thus, Fc engineering is a powerful tool in enhancing the agonistic activity of αOX40 antibody and may shape the future design of antibody-mediated αOX40 immunotherapy.

| S-EPMC7478034 | biostudies-literature

IL-15 complex enhances agonistic anti-CD40 + anti-PDL1 by correcting the T-bet to Tox ratio in CD8+ T cells infiltrating pancreatic ductal adenocarcinoma

Project description:Single cell RNA sequencing paired with single cell V(D)J sequenction of immune cells infiltrating orthotopic KPC2a tumors, spleen cells, and CD8 T cells enriched from spleen cells on day 14 posttumor. Cohorts received no treatment, agonistic anti-CD40, anti-PD-L1 or the combination of agonistic anti-CD40 + anti-PDL1. Treatments were initated on day 7 posttumor.

2025-03-05 | GSE285902 | GEO

Fc-optimized CD40 Agonistic Antibody Induces Tertiary Lymphoid Structures and Systemic Antitumor Immunity in Metastatic Cancer Patients

Project description:Fc-optimized CD40 Agonistic Antibody Induces Tertiary Lymphoid Structures and Systemic Antitumor Immunity in Metastatic Cancer Patients

| PRJNA1267139 | ENA

Fc-optimized CD40 Agonistic Antibody Induces Tertiary Lymphoid Structures and Systemic Antitumor Immunity in Metastatic Cancer Patients [Human]

Project description:Fc-optimized CD40 Agonistic Antibody Induces Tertiary Lymphoid Structures and Systemic Antitumor Immunity in Metastatic Cancer Patients [Human]

| PRJNA1267166 | ENA

The effect of a novel form of macrophage colony-stimulating factor (CSF1-Fc) on gene expression in the liver.

Project description:Treatment of mice with daily injections of CSF1-Fc produce a 50% increase in the size of the liver within 5 days. There was extensive proliferation of hepatocytes, similar to that seen following partial hepatectomy. Comparative gene expression profiles of the treated and control livers, alongside macrophages grown in CSF1, indicate extensive infiltration by macrophages in response to CSF1-Fc, and demonstrate that infiltrating macrophages produced several candidate mediators of hepatocyte proliferation.

2013-12-31 | E-GEOD-52636 | biostudies-arrayexpress

Geitlerinema sp. FC II strain:FC II

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Transcriptomic analysis of 4NQO-induced oral squamous cell carcinoma with agonistic anti-CD40 treatment

Project description:To investigate the anti-tumor effect of agonistic anti-CD40, 4NQO-indued OSCC mice with agonistic anti-CD40.

2023-10-23 | GSE217407 | GEO

Mapping of nascent RNA in MLL2 F/F and FC/FC MEF cells

Project description:Global Run-On has been performed in MLL2 F/F and FC/FC MEF cells. The aim of the experiment is to test how the lack of MLL2 affects nascent RNA transcription. Four samples were analyzed - 2 independent replicates. The experiments were performed using immortalized mouse embryonic fibroblasts (MEF) in which both MLL2 alleles were targeted by the loxp system (F/F cells). Tamoxifen treatment of the F/F cells for 24 hours results in the excision of both MLL2 alleles (FC/FC cells).

2016-04-13 | E-GEOD-73126 | biostudies-arrayexpress

Neutralizing antibodies against SARS-CoV-2 require intact Fc effector functions and monocytes for optimal therapeutic activity

Project description:SARS-CoV-2 has spread globally and caused the COVID-19 pandemic. Although passively delivered neutralizing antibodies against SARS-CoV-2 are in clinical trials, their mechanism of action in vivo is incompletely understood. Here, we define correlates of protection of neutralizing human monoclonal antibodies (mAbs) in SARS-CoV-2-infected mice. Whereas Fc effector functions are fully dispensable when mAbs are administered as prophylaxis, they are required for optimal protection as therapy. When given after infection, intact but not LALA-PG loss of Fc effector function variant mAbs reduce SARS-CoV-2 burden and lung disease in mice and hamsters. Fc engagement of neutralizing antibodies mitigates inflammation and improves respiratory mechanics, and transcriptional profiling suggests these phenotypes are associated with diminished innate immune signaling and enhanced tissue repair. Immune cell depletions establish that neutralizing mAbs require monocytes for therapeutic efficacy. Our study demonstrates that therapeutic neutralizing mAbs require Fc effector functions to reduce SARS-CoV-2 infection and modulate protective immune responses.

2021-03-01 | GSE161615 | GEO

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