Non-small cell lung cancers (NSCLCs) are highly aggressive and heterogenous, which has high recurrent post standard chemotherapy, radiotherapy, and biological therapies. The objective of this study is to develop a translation antibody-drug conjugate for NSCLC treatment. First, we humanized our previously developed anti-CD276 monoclonal antibody (mAb) and developed a stable Chinese Hamster Ovarian (CHO) production cell line. The generated humanized CD276 mAb was used to construct antibody-drug conjugate, which showed high circulation stability and in vivo NSCLC targeting specificity. Further evaluation demonstrated that this ADC can effectively reduce tumor burden in cell line xenografted mouse models and patient-derived xenograft mouse models which cover all the three major subtypes. Metastasis was significantly reduced and inhibited in distant metastatic models. Post treatment mechanism studies using histology and single cell RNA sequencing analysis indicated that NSCLC heterogeneity was reduced, metastasis signaling were downregulated, proliferation was inhibited, and apoptosis cell death was induced. Taken together, this CD276-targeted ADC has great potential for NSCLC treatment.
