Presenter(s)
J. Liu1, S. Xu1, B. Li2, S. Wang1, K. Zhao1, J. Yu1, and X. Chen1; 1Department of Radiation Oncology and Shandong Provincial Key Laboratory of Precision Oncology, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, China, 2College of Basic Medicine and Forensic Medicine, Henan University of Science and Technology, Luoyang, China
Purpose/Objective(s): Radioresistance remains a major challenge in NSCLC treatment. CUB domain-containing protein 1 (CDCP1), a transmembrane oncogenic signaling hub overexpressed in aggressive cancers and associated with therapy resistance, represents a potential theranostic target. This study aimed to investigate CDCP1 as a theranostic target to overcome radioresistance using 89Zr/177Lu-labeled antibody.
Materials/Methods: CDCP1 expression was validated in radioresistant A549-R cells and xenografts by flow cytometry and IHC. A humanized anti-CDCP1 monoclonal antibody (mAb1) was radiolabeled with 89Zr for PET imaging and 177Lu for targeted radionuclide therapy. In vitro specificity was assessed by binding assays, cellular uptake and SPR. PET/CT imaging and biodistribution were performed in NSCLC models with graded CDCP1 expression (A549/low, H1975/medium, EBC-1/high). 177Lu-mAb1 efficacy and radiosensitization were evaluated in subcutaneous models.
Results: CDCP1 was significantly upregulated in A549-R cells and tumors. 89Zr/177Lu-mAb1 showed high radiochemical yield (~80%), purity (>98%), and stability in vitro and in vivo. DFO-mAb1 bound CDCP1 with Kd=33.8 nM; DOTA conjugation preserved affinity. PET/CT demonstrated CDCP1-expression-dependent tumor uptake (EBC-1>H1975>A549), validated by blocking studies. 177Lu-mAb1 achieved >80% tumor inhibition in EBC-1 models, ~70% in H1975 models, and no effect in A549 models, confirming expression-dependent efficacy. In A549-R models, 177Lu-mAb1 combined with external beam radiotherapy (EBRT) showed superior tumor control compared to EBRT alone, indicating radiosensitization. No significant weight loss or organ toxicity was observed.
Conclusion: CDCP1-directed 89Zr/177Lu-mAb1 enables CDCP1-expression-dependent imaging, targeted radionuclide therapy, and radiosensitization in radioresistant NSCLC, supporting clinical development for theranostic management of radioresistant NSCLC.