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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: Not available

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Fc-optimized GITR antibody enhances a CD4 T cell-dendritic cell crosstalk to promote anti-tumor immunity

Project description:Targeting the stimulatory immune checkpoint glucocorticoid-induced TNFR-related protein (GITR) using agonistic monoclonal antibodies (mAbs) is a promising strategy for cancer immunotherapy that activates effector T cells and eliminates regulatory T cells (Treg). The pre-clinical anti-tumor activity of GITR mAbs depends on activating Fcγ receptors (FcγRs). However, the human Fc-FcgR interactions in the activity of GITR mAbs have not been comprehensively investigated. To this end, we employed Fc protein and glycan engineering to modify the FcγR interactions of anti-GITR human mAbs and characterized them in humanized FcgR mice. We identified an Fc-optimized human IgG scaffold that enhances anti-tumor efficacy through multiple FcgR-mediated mechanisms, including Treg depletion and mutual engagement and activation of CD4+ T cells and dendritic cells, leading to anti-tumor cytotoxicity of CD4+ T cells and enhanced CD8+ T cell activity. Our findings suggest a strategy to optimize human GITR mAbs, harnessing beneficial immune pathways to improve their therapeutic potential.

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Project description:Targeting the stimulatory immune checkpoint glucocorticoid-induced TNFR-related protein (GITR) using agonistic monoclonal antibodies (mAbs) is a promising strategy for cancer immunotherapy that involves increased effector T cell activity and regulatory T cell (Treg) elimination. The pre-clinical anti-tumor activity of GITR mAbs depends on activating Fcγ receptors (FcγRs). However, the role of human Fc-FcγR interactions in the activity of GITR mAbs has not been comprehensively addressed. To this end, we employed Fc protein and glycan engineering to modify the FcγR interactions of anti-GITR human mAbs and characterized them in humanized FcγR mice. We identified an Fc-optimized human IgG scaffold that increased binding to activating FcγRIIa and FcγRIIIa, enhancing anti-tumor efficacy. This Fc-optimized activity was mediated by multiple mechanisms that are unique to GITR mAb, including FcγR-mediated Treg depletion and mutual engagement and activation of CD4+ T cells and dendritic cells, leading to anti-tumor cytotoxic activity of CD4+ T cells and enhanced CD8+ T cell activity. Our findings suggest a strategy to optimize human GITR mAbs, harnessing beneficial immune pathways to improve their therapeutic potential.

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

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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]

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Gene expression profile of tumour-infiltrating immune cells in murine PDAC

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