发现FL-261作为治疗c-MET过表达癌症的诊疗一体化RDC载体

Mesenchymal-epithelial transition factor (c-MET) is an important member in the receptor tyrosine kinase family that is overexpressed and abnormally activated in most malignant tumors, making it an attractive target for radionuclide drug conjugate (RDC) based therapy. Despite the clinical validation of the target by small molecule kinase inhibitors, EGFR/c-MET bispecific antibodies and antibody drug conjugates (ADCs), their efficacy is mostly observed in non-small cell lung cancer (NSCLC). With the aim of developing a novel c-MET targeting RDC vector for the diagnosis and treatment of broader c-MET overexpressing indications, we have applied our UniRDC TM platform technologies and discovered the development candidate FL-261. The binding affinity and selectivity of FL-261 against c-MET was tested by surface plasmon resonance (SPR) protein binding assay. FL-261 was then labelled with 111 In and 225 Ac, and their radiochemical purity (RCP) was determined by radio high-performance liquid chromatography (radio-HPLC). Their in vivo performance, assessed via imaging, ex vivo biodistribution and efficacy studies, was evaluated in xenograft mouse models with varying levels of c-MET overexpression. FL-261 showed potent binding affinity against c-MET with a K D value of 7.5 nM and demonstrated over 450-fold selectivity over structurally similar receptor tyrosine kinases. FL-261 was successfully labeled with 111 In and 225 Ac, with each achieving an RCP of over 95%. After administration of [ 111 In]In-FL-261 in mice implanted with EBC-1 non-small cell lung cancer (NSCLC) xenografts, SPECT/CT images revealed intense and sustained tumor uptake which was significantly higher than that of normal organs. In addition, the tumor uptake was nearly completely blocked when extra mass of unlabeled FL-261 was co-administrated in the imaging study, suggesting in vivo cMET-specificity of FL-261. Separately, ex vivo cut-and-count biodistribution studies were performed after administration of [ 225 Ac]Ac-FL-261 in c-MET overexpressing EBC-1 xenograft model, demonstrating persistent and high tumor uptake from 1-hour to 120-hour post-dosing and rapid clearance from normal organs. Furthermore, in multiple xenograft models with varying levels of c-MET expression and one PDX model derived from a patient who became refractory to c-MET ADC therapy, [ 225 Ac]Ac-FL-261 consistently exhibited significant anti-tumor activity resulting in marked tumor regression. In these studies, there were no notable changes in body weight observed, suggesting a favorable safety profile of [ 225 Ac]Ac-FL-261. In summary, FL-261 demonstrates high theranostic potential, with favorable imaging profile of [ 111 In]In-FL-261 and potent antitumor activity of [²²⁵Ac]Ac-FL-261 across a diverse set of tumor models. This compelling data set supports the further development of FL-261 as a theranostic agent for c-MET overexpressing cancers.