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Development of antibody-drug conjugates targeting L1CAM to treat metastatic cancer

ABSTRACT: Effective treatments for metastatic disease have eluded precision oncology efforts and represent a major unmet need. The L1 cell adhesion molecule (L1CAM) is a transmembrane protein expressed by populations of Metastasis Stem cells (MetSC), that are enriched for the ability to reinitiate and propel metastatic growth and display phenotypic plasticity and resistance to conventional chemotherapies. Notably, L1CAM+ MetSC have been detected in numerous human solid tumor types and in multiple disseminated organ sites. As a selective marker of MetSC, L1CAM is a promising candidate for molecularly targeted drugs aimed at eliminating metastases, yet strategies to date have not achieved clinical success. Here, we develop antibody-drug conjugates to deliver highly toxic PNU-159682 payloads to L1CAM-expressing cells. We report the generation of monoclonal antibodies (mAb) with high binding affinity, specificity and selectivity for the human L1CAM extracellular domain. After further optimization of the L1CAM mAbs, PNU-159682 was conjugated to generate ADC variants with both cleavable and non-cleavable linkers, with an average drug-antibody-ratio (DAR) of four. The three ADCs (Y-004, Y-005 and Y-006) potently killed cells with varying levels of surface L1CAM expression. L1CAM ADCs given as monotherapy resulted in robust tumor growth control and extended survival in mice harboring subcutaneous L1CAM+ xenografts or L1CAM+ lung metastases, with safety analyses indicating a feasible therapeutic window. Our findings provide strong proof-of-concept to extend preclinical development of these novel L1CAM ADCs as therapeutic agents for advanced cancer.

ORGANISM(S): Homo sapiens

PROVIDER: GSE307811 | GEO | 2025/12/12

REPOSITORIES: GEO

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Project description:In pancreatic cancer the survival rate is low, as the available treatment options usually only extend survival and seldom produce a cure. Drug resistance and disease reoccurrence is the typical reason for death after cancer diagnosis. 5-Fluorouracil (5-FU) is the main chemostatic used in first line therapy. However the majority of the tumors become resistant to treatment. To investigate acquired 5-FU resistance in pancreatic adenocarcinoma, we established chemoresistant monoclonal cell lines from the Panc03.27 cell line by long-term exposure to 5-FU. In addition to increased expression of markers associated with multidrug resistance, the 5-FU resistant clones showed alterations typical of the process of epithelial-to-mesenchymal transition (EMT), including upregulation of mesenchymal markers and increased invasiveness. Microarray analysis revealed the L1CAM pathway as one of the most upregulated pathways in the chemoresistant clones, which was confirmed on RNA and protein levels. Expression of the adhesion molecule L1CAM is associated with a chemoresistant and migratory phenotype of pancreatic cancer. Using esiRNA targeting L1CAM, or by blocking the extracellular part of L1CAM with monoclonal antibodies, we discovered that the increased invasiveness observed in the chemoresistant cells depends on L1CAM. Using esiRNA targeting β-catenin and/or Slug, we discovered that L1CAM expression depends on Slug rather than β-catenin in the 5-FU resistant cells. We demonstrate a functional link between Slug and the expression level of L1CAM in pancreatic cancer cells having undergone EMT following long-term exposure to 5-FU. Our findings provide further insight into the molecular mechanisms leading to a chemoresistant and migratory phenotype in pancreatic cancer cells and indicate the importance of Slug-induced L1CAM in refractory pancreatic cancer. Examination of expression of 5-Fluorouracil (5-FU) Panc03.27 cell line resistant clone versus expression of 5-FU sensitive clones (NT) in 4 replicates per cell lines

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Development of antibody-drug conjugates targeting L1CAM to treat metastatic cancer

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