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Identification of CADM1 as an Immunotherapeutic Target and Evaluation of a Novel CADM1-Targeting Antibody-Drug Conjugate in Preclinical Osteosarcoma Models

ABSTRACT: Due to the paucity of validated cell surface osteosarcoma-specific targets, patients with this condition have long been excluded from the benefits of antibody-drug conjugate (ADC) therapy observed in several solid and hematologic malignancies. Our comprehensive surfaceome and RNA-seq profiling approach identified osteosarcoma-specific cell-surface antigens that are highly expressed in osteosarcomas but minimally expressed in normal tissues. As a result, one such antigen, CADM1, was selected for the generation of an ADC.

ORGANISM(S): Homo sapiens

PROVIDER: GSE309827 | GEO | 2026/02/25

REPOSITORIES: GEO

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Identification of CADM1 as an Immunotherapeutic Target and Evaluation of a Novel CADM1-Targeting Antibody-Drug Conjugate in Preclinical Osteosarcoma Models

Project description:Identification of CADM1 as an Immunotherapeutic Target and Evaluation of a Novel CADM1-Targeting Antibody-Drug Conjugate in Preclinical Osteosarcoma Models

| PRJNA1363778 | ENA

CADM1-overexpression ES-2 cells

Project description:CADM1, an immunoglobulin superfamily member, frequently inactivated but function as a tumor suppressor in many solid tumors. However, how CADM1 expression in ovarian cancer cells and the mechanisms of its tumor suppressor function is not fully understood. We created ovarian cancer ES-2 cell lines in which CADM1 was stably up-regulated. Genes differentially expressed in CADM1-overexpressing ES-2 cells.

2019-11-16 | GSE140453 | GEO

Identification of the Notch ligand DLK1 as an immunotherapeutic target and regulator of tumor cell plasticity and chemoresistance in adrenocortical carcinoma

Project description:While immunotherapeutic targeting of cell surface proteins is an increasingly effective cancer therapy, identification of new surface proteins, particularly those with biological importance, is critical. Here, we uncover delta-like non-canonical Notch ligand 1 (DLK1) as a cell surface protein with limited normal tissue expression and high expression in multiple refractory adult metastatic cancers including small cell lung cancer (SCLC) and adrenocortical carcinoma (ACC), a rare cancer with few effective therapies. In ACC, ADCT-701, a DLK1 targeting antibody-drug conjugate (ADC), shows in vitro and in vivo activity but is overall limited due to high expression and activity of the drug efflux protein ABCB1 (MDR1, P-glycoprotein). In contrast, ADCT-701 induces complete responses in DLK1+ ACC and SCLC in vivo models with low or no ABCB1 expression. Genetic deletion of DLK1 in ACC dramatically downregulates ABCB1 and increases ADC payload and chemotherapy sensitivity through NOTCH1-mediated transdifferentiation. This work identifies DLK1 as an immunotherapeutic target that regulates tumor cell plasticity and chemoresistance in ACC and supports an active phase I clinical trial targeting DLK1 with an ADC in ACC and neuroendocrine neoplasms (NCT06041516).

2025-05-19 | GSE294644 | GEO

Effects of CADM1 expression in human melanoma

Project description:CADM1 expression in non-adherent conditions was found to potently induce caspase-independent cell death. We sought to use microarray analysis to glean insights to the mechanism associated with CADM1 induced non-adherent cell death.

2019-04-03 | GSE128954 | GEO

CADM1-overexpression ES-2 cells

Project description:CADM1-overexpression ES-2 cells

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Myeloid Cell Adhesion Molecule 1 (CADM1) promotes pro-inflammatory signaling during Inflammatory Bowel Disease.

Project description:Background and aims: Cytotoxic T cells have long been postulated to facilitate autoimmune destruction of intestinal epithelium; and the precise causal events leading to inflammatory bowel diseases (IBDs) remain unresolved. CADM1, a membrane adhesion protein which can shed its extracellular ectodomain enters the systemic circulation as well as bind the receptor CRTAM present on CD8+ T cells. Methods: We performed RNA and small RNA sequencing on colon tissue from IBD and non-IBD (NIBD) control patients. We performed spatial transcriptomics and stimulated lamina propria mononuclear cells (LPMCs) with the soluble form of CADM (sCADM1) in these patients. Dextran Sulfate Sodium (DSS) was used to induced colitis in a conditional myeloid Cadm1 loss-of-function mouse. Results: MicroRNA-375 was significantly decreased while its direct target CADM1 was markedly up-regulated in UC patients compared to NIBD control subjects. Single cell proteomics data identified CADM1 enrichment in multiple clusters including macrophages and dendritic cells from colonic tissue of human subjects with IBD. An increased number of CADM1+CD68+ cells was detected adjacent to CD8+ T-cells within the intestinal epithelium of colon sections from patients with ulcerative colitis (UC) compared to NIBD subjects. Myeloid Cadm1 conditional knockout mice were protected against DSS-induced colitis indicating Cadm1 may facilitate binding/localization of cytotoxic cell populations within the gut epithelium. Furthermore, we observed that serum levels of the cleaved extracellular ectodomain of CADM1 (sCADM1) are elevated in medically refractory UC patients compared to non-IBD and UC donors in remission and treatment of LPMCs with recombinant sCADM1 enhanced STAT3 phosphorylation. Conclusions: Together these results identify CADM1 as a potent mediator of pro-inflammatory signaling pathways and demonstrate its potential as a diagnostic and therapeutic target for preventing the IBDs.

2024-07-28 | GSE272890 | GEO

Myeloid Cell Adhesion Molecule 1 (CADM1) promotes pro-inflammatory signaling in human Inflammatory Bowel Diseases

Project description:Cytotoxic T cells have been postulated to facilitate the destruction of intestinal epithelium in inflammatory bowel diseases (IBDs). CADM1, which encodes a membrane adhesion protein that can bind the T cell receptor CRTAM, was markedly up regulated in colon of IBD patients compared to non-IBD (NIBD) patients. We then identified CADM1 enrichment in multiple immune cell clusters including macrophages and dendritic cells in the colons of IBD patients. Increased numbers of CADM1+ myeloid cells were measured adjacent to CD8+ T cells within colons of ulcerative colitis patients compared to NIBD patients. Conditional deletion of Cadm1 in myeloid cells resulted in reduced numbers of activated T cell populations and protected mice from chemical-induced colitis. Similarly, administration of a Cadm1 ‘neutralizing’ antibody which binds its extracellular domain reduced tissue inflammation and breakdown of the intestinal epithelium and crypts after induction of colitis in mice. Lastly, serum levels of sCADM1 were elevated in IBD patients compared to NIBD controls and treatment of LPMCs with recombinant sCADM1 enhanced inflammatory STAT3 phosphorylation. Therefore, we concluded that CADM1 is a mediator of pro-inflammatory signaling cascades in the colon and a potential therapeutic target for the IBDs.

2025-10-11 | GSE304649 | GEO

Single dose of CD137-Antibody Drug Conjugate protects non-human primate allogeneic HCT recipients against acute GVHD

Project description:Rapid CD137 upregulation on alloreactive T-cells upon allogeneic stimulation suggests that their selective elimination could prevent acute graft-versus-host disease (aGVHD) after allogeneic hematopoietic stem cell transplantation (HCT). Here, we developed a novel aGVHD prophylactic regimen consisting of a single dose of an anti-CD137 antibody-drug conjugate (CD137-ADC) administered on the day of transplant without additional immunosuppression. The CD137-ADC depleted both human and non-human primate (NHP) activated T-cells and proved highly effective in preventing xenogeneic aGVHD in mice receiving human hematopoietic stem cell grafts, as well as in NHP undergoing MHC-haploidentical HCT. Flow cytometry analysis of NHP T-cells indicated specific depletion of activated PD-1+ CD4 and CD8 T-cells, while sparing naïve and PD-1-OX40+ memory T-cell subsets. CD137-ADC-treated NHP recipients demonstrated robust hematopoietic and immune reconstitution. Hallmarks of T-cell recovery after CD137-ADC, which were associated with long-term aGVHD-free survival, included reconstitution of CD4 memory T-cells expressing TRAIL, terminally-differentiated CD8 T-cells expressing CX3CR1, and CD4 FoxP3+ Tregs – cell types not expected to be involved in aGVHD pathogenesis. CD137-ADC-treated recipients demonstrated a higher risk of reactivation of rhLCV (the rhesus macaque EBV analogue), which was associated with reconstitution of follicular helper T-cells, interferon signaling-associated memory, and gamma-delta T-cell subsets. This reactivation was controllable with rituximab administration. These results document effective depletion of alloreactive T-cells and prevention of aGVHD following a single dose of CD137-ADC, suggesting that clinical translation should be carefully explored.

2025-05-27 | GSE298158 | GEO

CD276-DM1 Antibody drug conjugate with cmLumiOpto gene therapy to treat triple negative breast cancer.

Project description:Triple-negative breast cancer (TNBC) is a highly aggressive subtype characterized by resistance to chemotherapy, elevated metastatic potential, and frequent relapse. This study investigated the therapeutic impact of combining an antibody-drug conjugate (ADC) with mitochondria-targeted gene therapy. A CD276-directed monoclonal antibody conjugated to mertansine when paired with cmLumiOpto gene therapy, exhibited potent synergistic activity across three TNBC cell lines, impairing mitochondrial function and amplifying tumor-associated cytokine responses. In vivo experiments further demonstrated that the ADC/cmLumiOpto combination effectively suppressed metastasis in metastatic models and achieved high tumor growth inhibition in patient-derived xenograft mouse models. Mechanistic studies revealed that this dual approach downregulated metastatic signaling pathways, disrupted the tumor microenvironment, and triggered apoptosis. Importantly, histological assessments of normal tissues and body weight monitoring indicated negligible toxicity. Collectively, these findings highlight the therapeutic promise of CD276-targeted ADCs combined with gene therapy as a strategy for treating TNBC.

2025-12-20 | GSE313892 | GEO

Proteotranscriptomic decoding of the surface-endocytome in primary glioblastoma cells identifies potential target antigens in the hypoxic tumor niche [U87_mRNA_Norm_Hyp]

Project description:Background: Antibody and cell-based immunotherapies, e.g., antibody-drug-conjugates and CAR-T cells, targeted at cell-surface proteins, currently revolutionize clinical oncology. However, target selection warrants a better understanding of the surface-endocytome and how it is modulated by the tumor microenvironment. Here, we unravel the surface-endocytome landscape and its remodeling by hypoxia in primary cultures from glioblastoma (GBM) patients that currently lack targeted therapies. Methods. We employed a comprehensive approach for global and dynamic mapping of surfaceome and endocytosed (endocytome) proteins in primary GBM cultures at normoxia or hypoxia. Selected target candidates were validated by immunofluorescence analyses in patient tumor sections, spheroids, and 2D cultures, and were finally confronted by ADC cytotoxicity studies. Results: We reveal a heterogeneous surface-endocytome profile across GBM cultures from three patients representing different transcriptional subtypes. CD44 emerged as a commonly abundant surfaceome antigen across GBM cultures, and we established a direct correlation between CD44 endocytic activity and ADC cytotoxicity. We elucidate how hypoxia profoundly reshapes the global surface-endocytome, and identify several hypoxia-induced antigens (CXADR, CD47, BSG, CD81, FXYD6), unique to or shared among GBM cultures. Importantly, we highlight the limited correlation between transcriptomics and proteomics, emphasizing the critical role of membrane protein enrichment strategies and targeted mass spectrometry. Conclusions: These studies provide a comprehensive map of the surface-endocytome and its remodeling by hypoxia in GBM as a resource for target discovery. As a proof-of-concept, we validate several proteins, either abundantly expressed in normoxia or induced by hypoxia, for further exploration as potential targets of immunotherapeutic approaches in GBM.

2023-10-28 | GSE245800 | GEO

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