Development of antibody-drug conjugates targeting L1CAM to treat metastatic cancer
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. Overall design: LUAD PDX tumoroids were generated, dissociated as single cells, FACS-sorted and submitted for single-cell sequencing.