Preclinical Pharmacokinetics and Biodistribution of LR004, a Novel Antiepidermal Growth Factor Receptor Monoclonal Antibody
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Published:2024-01-22
Issue:2
Volume:29
Page:545
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ISSN:1420-3049
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Container-title:Molecules
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language:en
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Short-container-title:Molecules
Author:
Zheng Ying12ORCID, Dou Guifang1ORCID, Liu Shuchen1, Meng Zhiyun1, Tsao Eric I.3, Yu Gang4, Zhu Xiaoxia1, Gu Ruolan1, Wu Zhuona1, Sun Yunbo1, Han Peng1, Gan Hui1
Affiliation:
1. Department of Pharmaceutical Sciences, Beijing Institute of Radiation Medicine, Beijing 100850, China 2. Artemisinin Research Center, China Academy of Chinese Medical Sciences, Beijing 100700, China 3. Synermore Biologics Co., Ltd., Suzhou 215000, China 4. State Key Laboratory of Toxicology and Medical Countermeasures, Beijing Institute of Pharmacology and Toxicology, Beijing 100850, China
Abstract
LR004 is a novel chimeric (human/mouse) monoclonal antibody developed for the treatment of advanced colorectal carcinoma with detectable epidermal growth factor receptor (EGFR) expression. We aimed to investigate the preclinical pharmacokinetics (PK) and in vivo biodistribution of LR004. The PK profiles of LR004 were initially established in rhesus monkeys. Subsequently, 125I radionuclide-labeled LR004 was developed and the biodistribution, autoradiography, and NanoSPECT/CT of 125I-LR004 in xenograft mice bearing A431 tumors were examined. The PK data revealed a prolonged half-life and nonlinear PK characteristics of LR004 within the dose range of 6–54 mg/kg. The radiochemical purity of 125I-LR004 was approximately 98.54%, and iodination of LR004 did not affect its specific binding activity to the EGFR antigen. In a classical biodistribution study, 125I-LR004 exhibited higher uptake in highly perfused organs than in poorly perfused organs. Prolonged retention properties of 125I-LR004 in tumors were observed at 4 and 10 days. Autoradiography and NanoSPECT/CT confirmed the sustained retention of 125I-LR004 at the tumor site in xenograft mice. These findings demonstrated the adequate tumor targeting capabilities of 125I-LR004 in EGFR-positive tumors, which may improve dosing strategies and future drug development.
Funder
Beijing Municipal Natural Science Foundation
Subject
Chemistry (miscellaneous),Analytical Chemistry,Organic Chemistry,Physical and Theoretical Chemistry,Molecular Medicine,Drug Discovery,Pharmaceutical Science
Reference32 articles.
1. Janani, B., Vijayakumar, M., Priya, K., Kim, J.H., Prabakaran, D.S., Shahid, M., Al-Ghamdi, S., Alsaidan, M., Othman Bahakim, N., and Hassan Abdelzaher, M. (2022). EGFR-Based Targeted Therapy for Colorectal Cancer-Promises and Challenges. Vaccines, 10. 2. Comprehensive review of targeted therapy for colorectal cancer;Xie;Signal Transduct. Target. Ther.,2020 3. Colorectal cancer;Kuipers;Nat. Rev. Dis. Primers,2015 4. Ohishi, T., Kaneko, M.K., Yoshida, Y., Takashima, A., Kato, Y., and Kawada, M. (2023). Current Targeted Therapy for Metastatic Colorectal Cancer. Int. J. Mol. Sci., 24. 5. Epidermal growth factor receptor signaling in colorectal cancer: Preclinical data and therapeutic perspectives;Spano;Ann. Oncol.,2005
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