Therapeutic Targeting of Osteosarcoma and Lung Metastases in Preclinical Models Using a CD24 Antibody‐Drug Conjugate

Abstract Pulmonary metastases present a significant clinical challenge in the treatment of osteosarcoma (OS). The current therapeutic landscape for metastatic OS is limited by the lack of effective targeted therapies. Here, the development and preclinical evaluation of a novel CD24 antibody‐drug conjugate (ADC) designed for the targeted ablation of primary OS tumors and pulmonary metastases are reported. An unbiased, quantitative screening of cancer‐related cell surface markers on human OS cells identifies CD24 as a novel target for ADC therapy in OS, owing to its disease‐specific overexpression and rapid antigen‐mediated internalization. Based on these findings, a proof‐of‐concept ADC, comprising a humanized CD24 antibody conjugated with mertansine (CD24‐DM1), was designed and constructed. CD24‐DM1 demonstrated potent cytotoxicity against a panel of human OS cell lines while sparing normal human osteoblasts. In an orthotopic OS model, CD24‐DM1 induced complete and durable tumor regression. Additionally, CD24‐DM1 significantly delayed tumor growth in a lung‐metastatic OS model, providing robust in vivo evidence of CD24 as a promising ADC target for OS therapy. In conclusion, CD24‐DM1 exhibits a favorable therapeutic index for the treatment of metastatic OS in preclinical models, highlighting its potential as an effective targeted therapeutic option.