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A microbial-inspired antibody-drug conjugate for cancer immunotherapy

ABSTRACT: A microbial-inspired antibody-drug conjugate for cancer immunotherapy

PROVIDER: PRJNA1077275 | ENA |

REPOSITORIES: ENA

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A microbial-inspired antibody-drug conjugate for cancer immunotherapy

Project description:Generating antitumor immune responses requires the phagocytosis of tumor cells and subsequent cross-presentation of tumor-derived antigens by antigen-presenting cells. However, these processes are impeded by phagocytosis checkpoints and inefficient cytosolic transport of antigenic peptides from phagolysosomes. Here, using a microbial-inspired strategy, we engineered an antibody-drug conjugate (ADC) that targets the “don’t eat me” signal CD47 linked to the bacterial toxin listeriolysin O from the intracellular bacterium Listeria monocytogenes via a cleavable linker (CD47-LLO). CD47-LLO promotes the phagocytosis of cancer cells followed by the release and activation of LLO to form pores on phagolysosomal membranes that allow cytosolic entry of tumor-derived contents, leading to enhanced antigen cross-presentation of tumor-derived peptides and activation of cytosolic immune sensors. CD47-LLO treatment in vivo significantly inhibited the growth of both localized and metastatic tumors and improved animal survival as monotherapy or in combination with checkpoint blockade. Together, these results demonstrate that designing ADCs to promote immune recognition of tumor cells represents a promising therapeutic strategy for treating multiple cancers.

2024-12-01 | GSE255937 | GEO

TD-MS analysis of single-domain antibody and anti-EGFR single-domain antibody-drug conjugate

Project description:Analysis of the intact single-domain antibody and its associated anti-EGFR single-domain antibody-drug conjugate. Optimizations of conditions with various fragmentation methods.

2025-02-11 | PXD058380 | JPOST Repository

A Dual-Payload Antibody-Drug Conjugate Targeting CD276/B7-H3 Elicits Cytotoxicity and Immune Activation in Triple-Negative Breast Cancer

Project description:Triple-negative breast cancer (TNBC) is a highly aggressive and heterogeneous disease that often relapses following treatment with standard radiotherapies and cytotoxic chemotherapies. Combination therapies have potential for treating refractory metastatic TNBC. Here, we aimed to develop an antibody-drug conjugate with dual payloads (DualADC) as a chemo-immunotherapy for TNBC. The overexpression of an immune checkpoint transmembrane CD276 (also known as B7-H3) was associated with angiogenesis, metastasis, and immune tolerance, in over 60% of TNBC patients. Development of a monoclonal antibody (mAb) capable of targeting the extracellular domain of surface CD276 enabled delivery of payloads to tumors, and a platform was established for concurrent conjugation of a traditional cytotoxic payload and an immunoregulating toll-like receptor 7/8 agonist to the CD276 mAb. The DualADC effectively killed multiple TNBC subtypes, significantly enhanced immune functions in the tumor microenvironment, and reduced tumor burden by up to 90-100% in animal studies. Single-cell RNA-sequencing, multiplex cytokine analysis, and histology elucidated the impact of treatment on tumor cells and the immune landscape. This study suggests that the developed DualADC could represent a promising targeted chemo-immunotherapy for TNBC.

2024-08-21 | GSE274871 | GEO

RPPA profiling of ES8 Ewing sarcoma xenografts after Endoglin-targeting antibody-drug conjugate treatments

Project description:RPPA profiling of ES8 Ewing sarcoma xenografts after Endoglin-targeting antibody-drug conjugate treatments

| PRJNA472943 | ENA

Identification of MUC1-C Dependence in Drug-Resistant Advanced Prostate Cancer Uncovers a New Target for Antibody-Drug Conjugate Therapy

Project description:Androgen receptor positive prostate cancer (PC), castration resistant prostate cancer (CRPC) and neuroendocrine prostate cancer (NEPC) represent a spectrum of malignancies that invariably become resistant to treatment with targeted and cytotoxic agents. There is no known common pathway responsible for these pleotropic mechanisms of resistance. The MUC1 gene is aberrantly expressed in CRPC and NEPC in association with poor clinical outcomes. The present results demonstrate that the oncogenic MUC1-C protein is necessary for resistance of (i) PC cells to enzalutamide (ENZ), and (ii) CRPC and NEPC cells to docetaxel (DTX). We show that MUC1-C-mediated ENZ and DTX resistance is conferred by upregulation of aerobic glycolysis and suppression of reactive oxygen species (ROS) necessary for self-renewal capacity. Common dependence of these drug-resistant phenotypes on MUC1-C for the cancer stem cell (CSC) state thus identified a potential new target for their treatment. cIn this context, we further demonstrate that targeting MUC1-C with an antibody-drug conjugate (ADC) is highly effective in suppressing (i) self-renewal of drug-resistant CRPC and NEPC CSCs and (ii) growth of t-NEPC tumor xenografts derived from drug-resistant cells and a patient with refractory disease. These findings reveal a shared MUC1-C-dependent pathway in drug-resistant CRPC and NEPC progression and identify MUC1-C as a target for their treatment with an ADC.

2025-01-02 | GSE276750 | GEO

Identification of MUC1-C Dependence in Drug-Resistant Advanced Prostate Cancer Uncovers a New Target for Antibody-Drug Conjugate Therapy

2025-01-02 | GSE276890 | GEO

Identification of MUC1-C Dependence in Drug-Resistant Advanced Prostate Cancer Uncovers a New Target for Antibody-Drug Conjugate Therapy

Project description:Identification of MUC1-C Dependence in Drug-Resistant Advanced Prostate Cancer Uncovers a New Target for Antibody-Drug Conjugate Therapy

| PRJNA1158796 | ENA

Identification of MUC1-C Dependence in Drug-Resistant Advanced Prostate Cancer Uncovers a New Target for Antibody-Drug Conjugate Therapy

Project description:Identification of MUC1-C Dependence in Drug-Resistant Advanced Prostate Cancer Uncovers a New Target for Antibody-Drug Conjugate Therapy

| PRJNA1159347 | ENA

RNA-seq tumor immunome analysis of murine breast cancer model EMT6-hHER2 responsive to novel antibody drug conjugate T-PNU

Project description:An orthotopic murine breast cancer model was created by transfecting the human HER2 gene into the breast cancer cell line EMT6 resulting in EMT6-hHER2. Previous in vivo tumor treatments with trastuzumab, trastuzumab-emtansine (T-DM1) and a novel antibody drug conjugate (ADC) T-PNU (provided by NBE therapeutics and carrying the highly potent anthracycline analogue PNU-159682) revealed that EMT6-hHER2 tumors are unresponsive to standard therapy treatments of trastuzumab and T-DM1, but respond well to the novel ADC T-PNU. Identifying immunogenic cell death properties of T-PNU, we postulated a therapeutic relevance for T-PNU mediated immune modulation of the tumor microenvironment. In order to identify the transcriptional pathways underlying the T-PNU anti-tumor response, we performed RNA-sequencing analysis of CD45+ tumor-derived cells from differently treated cohorts (untreated, trastuzumab, T-DM1, T-PNU; n=6).

2018-10-06 | GSE120888 | GEO

Tumor-derived biomarkers beyond antigen expression enhance efficacy of CD276/B7H3 antibody-drug conjugate in metastatic prostate cancer

Project description:Tumor-derived biomarkers beyond antigen expression enhance efficacy of CD276/B7H3 antibody-drug conjugate in metastatic prostate cancer

| PRJNA992487 | ENA

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