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The PTPN2/N1 inhibitor ABBV-CLS-484 unleashes potent anti-tumour immunity [PTPN2i-MS-TCRseq]

ABSTRACT: To assess TCR diversity in AC484-treated tumors we profiled the TCRβ chain repertoire from untreated, anti-PD-1-treated, or AC484-treated B16 tumours

ORGANISM(S): Mus musculus

PROVIDER: GSE237374 | GEO | 2023/07/14

REPOSITORIES: GEO

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The PTPN2/N1 inhibitor ABBV-CLS-484 unleashes potent anti-tumour immunity[PTPN2i-MS-scRNAseq]

Project description:To examine the effect of AC484 inhibition on the tumor immune microenvironment, we performed scRNA-seq on CD45+ cells from B16 and KPC tumors from mice treated with vehicle, anti-PD-1, or AC484.

2023-07-14 | GSE237375 | GEO

The PTPN2/N1 inhibitor ABBV-CLS-484 unleashes potent anti-tumour immunity [TIL_ATACseq]

Project description:Immune checkpoint blockade is effective for some cancer patients, but most are refractory to current immunotherapies and new approaches are needed to overcome resistance. The protein tyrosine phosphatases PTPN2 and PTPN1 are central regulators of inflammation, and their genetic deletion in either tumour or immune cells promotes anti-tumour immunity. However, phosphatases are challenging drug targets and in particular, the active site has been considered undruggable. Here, we present the discovery and characterization of ABBV-CLS-484 (AC484), a first-in-class, orally bioavailable, potent PTPN2/N1 active site inhibitor. AC484 treatment in vitro amplifies the response to interferon and promotes the activation and function of several immune cell subsets. In murine cancer models resistant to PD-1 blockade, AC484 monotherapy generates potent anti-tumour immunity. We show that AC484 inflames the tumour microenvironment and promotes NK and CD8+ T cell function by enhancing JAK-STAT signaling and reducing T cell dysfunction. PTPN2/N1 inhibitors offer a promising new strategy for cancer immunotherapy and are currently being evaluated in patients with advanced solid tumours (NCT04777994). More broadly, our study shows that small molecule inhibitors of key intracellular immune regulators can achieve efficacy comparable to or exceeding antibody-based immune checkpoint blockade in preclinical models. Finally, to our knowledge, AC484 represents the first active-site phosphatase inhibitor to enter clinical evaluation for cancer immunotherapy and may pave the way for additional therapeutics targeting this important class of enzymes.

2023-07-14 | GSE237376 | GEO

The PTPN2/N1 inhibitor ABBV-CLS-484 unleashes potent anti-tumour immunity [TIL_RNAseq]

2023-07-14 | GSE237377 | GEO

The PTPN2/PTPN1 inhibitor ABBV-CLS-484 unleashes potent anti-tumour immunity [SK_RNAseq]

Project description:AC484 is a first-in-class, orally bioavailable, potent PTPN2/N1 active site inhibitor. In order to investigate the response of AC484 and IFNg treatment on wild type and PTPN2/N1 dual deletion B16F10 cells, these tumours were transcriptionally profiled.

2023-07-14 | GSE237371 | GEO

The PTPN2/PTPN1 inhibitor ABBV-CLS-484 unleashes potent anti-tumour immunity

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

2023-07-14 | GSE237378 | GEO

CFTR Rescue in Intestinal Organoids with GLPG/ABBV-2737, ABBV/GLPG-2222 and ABBV/GLPG-2451 Triple Therapy.

Project description:Cystic fibrosis transmembrane conductance regulator (CFTR) modulators have transformed the treatment of cystic fibrosis (CF) by targeting the basis of the disease. In particular, treatment regimen consisting of multiple compounds with complementary mechanisms of action have been shown to result in optimal efficacy. Here, we assessed the efficacy of combinations of the CFTR modulators ABBV/GLPG-2222, GLPG/ABBV-2737 and ABBV/GLPG-2451, and compared it to VX-770/VX-809 in 28 organoid lines heterozygous for F508del allele and a class I mutation and seven homozygous F508del organoid lines. The combination ABBV/GLPG-2222/ABBV-2737/ABBV/GLPG-2451 showed increased efficacy over VX-770/VX-809 for most organoids, despite considerable variation in efficacy between the different organoid cultures. These differences in CFTR restoration between organoids with comparable genotypes underline the relevance of continuing to optimize the ABBV/GLPG-Triple therapy, as well as the in vitro characterization of efficacy in clinically relevant models.

| S-EPMC8479794 | biostudies-literature

TCRβ+ vs. TCRβ- CD11bhighCD14+F4/80+ splenic macrophages (Mf)

Project description:TCRβ+ vs. TCRβ- CD11bhighCD14+F4/80+ splenic macrophages (Mf)

| PRJNA437482 | ENA

Identification of potential ABBV-075 responsive markers in mouse skin

Project description:Determination of transcriptional alterations in skin samples from ABBV-075 treated mice

2017-03-07 | GSE89934 | GEO

Identification of potential ABBV-075 responsive markers in human PBMCs

Project description:To identify genes that are modulated by BET inhibitors in blood, we determined global gene expression changes in ABBV-075-treated human PBMC samples

2017-03-07 | GSE89933 | GEO

Project description:Murine TCRβ repertoire sequencing

| PRJNA400603 | ENA

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