177Lu-labeled antibodies for EGFR-targeted SPECT/CT imaging and radioimmunotherapy in a preclinical head and neck carcinoma model.
Epidermal growth factor receptor (EGFR) has been well characterized as an important target for cancer therapy. Immunotherapy based on EGFR-specific antibodies (e.g., panitumumab and cetuximab) has shown great clinical promise. However, increasing evidence has indicated that only a subgroup of patients receiving these antibodies will benefit from them, and even patients who do initially experience a major response may eventually develop therapeutic resistance. In this study, we investigated whether panitumumab and cetuximab can serve as delivery vehicles for tumor-targeted radionuclide therapy in a preclinical tumor model that did not respond to immunotherapy. The in vitro toxicity and cell binding properties of panitumumab and cetuximab were characterized. Both antibodies were conjugated with 1,4,7,10-tetraazadodecane-N,N',N",N"'-tetraacetic acid (DOTA) and radiolabeled with (177)Lu. Small-animal SPECT/CT, biodistribution, and radioimmunotherapy (RIT) studies of (177)Lu-DOTA-panitumumab ((177)Lu-Pan) and (177)Lu-DOTA-cetuximab ((177)Lu-Cet) were performed in the UM-SCC-22B tumor model. Both (177)Lu-Pan and (177)Lu-Cet exhibited favorable tumor targeting efficacy. The tumor uptake was 20.92 ± 4.45, 26.10 ± 5.18, and 13.27 ± 1.94% ID/g for (177)Lu-Pan, and 15.67 ± 3.84, 15.72 ± 3.49, and 7.82 ± 2.36% ID/g for (177)Lu-Cet at 24, 72, and 120 h p.i., respectively. RIT with a single dose of 14.8 MBq of (177)Lu-Pan or (177)Lu-Cet significantly delayed tumor growth. (177)Lu-Pan induced more effective tumor growth inhibition due to a higher tumor uptake. Our results suggest that panitumumab and cetuximab can function as effective carriers for tumor-targeted delivery of radiation, and that RIT is promising for targeted therapy of EGFR-positive tumors, especially for those tumors that are resistant to antibody-based immunotherapy.
Medical Isotopes Research Center and ‡Department of Radiation Medicine, School of Basic Medical Sciences, Peking University , Beijing 100191, China.
Zhaofei
Z
Liu
Teng
T
Ma
Hao
H
Liu
Zhongxia
Z
Jin
Xianlei
X
Sun
Huiyun
H
Zhao
Jiyun
J
Shi
Bing
B
Jia
Fang
F
Li
Fan
F
Wang
D000818:Animals; D000911:Antibodies, Monoclonal / Q000493:pharmacokinetics / Q000627:therapeutic use*; D061067:Antibodies, Monoclonal, Humanized / Q000627:therapeutic use; D000970:Antineoplastic Agents / Q000627:therapeutic use; D002294:Carcinoma, Squamous Cell / Q000000981:diagnostic imaging / Q000276:immunology / Q000378:metabolism / Q000532:radiotherapy*; D049109:Cell Proliferation / Q000187:drug effects / Q000528:radiation effects*; D000068818:Cetuximab; D066246:ErbB Receptors / Q000037:antagonists & inhibitors* / Q000276:immunology; D005260:Female; D006258:Head and Neck Neoplasms / Q000000981:diagnostic imaging / Q000276:immunology / Q000378:metabolism / Q000532:radiotherapy*; D008187:Lutetium / Q000493:pharmacokinetics / Q000627:therapeutic use*; D051379:Mice; D008807:Mice, Inbred BALB C; D000077544:Panitumumab; D016499:Radioimmunotherapy; D014018:Tissue Distribution; D015899:Tomography, Emission-Computed, Single-Photon; D023041:Xenograft Model Antitumor Assays
D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents; D008187:Lutetium; D000077544:Panitumumab; C512478:EGFR protein, human; D066246:ErbB Receptors; D000068818:Cetuximab
antibody; epidermal growth factor receptor; small-animal imaging; targeted therapy