A Fusion Protein of RGD4C and β-Lactamase Has a Favorable Targeting Effect in Its Use in Antibody Directed Enzyme Prodrug Therapy.
Antibody directed enzyme prodrug therapy (ADEPT) utilizing β-lactamase is a promising treatment strategy to enhance the therapeutic effect and safety of cytotoxic agents. In this method, a conjugate (antibody-β-lactamase fusion protein) is employed to precisely activate nontoxic cephalosporin prodrugs at the tumor site. A major obstacle to the clinical translation of this method, however, is the low catalytic activity and high immunogenicity of the wild-type enzymes. To overcome this challenge, we fused a cyclic decapeptide (RGD4C) targeting to the integrin with a β-lactamase variant with reduced immunogenicity which retains acceptable catalytic activity for prodrug hydrolysis. Here, we made a further investigation on its targeting effect and pharmacokinetic properties, the results demonstrated that the fusion protein retains a targeting effect on integrin positive cells and has acceptable pharmacokinetic characteristics, which benefits its use in ADEPT.
Tianjin Key Lab of Molecular Nuclear Medicine, Institute of Radiation Medicine, Chinese Academy of Medical Sciences and Peking Union Medical College, Tianjin 300192, China. wanghao@irm-cams.ac.cn.
Hao
H
Wang
Tianjin Key Lab of Molecular Nuclear Medicine, Institute of Radiation Medicine, Chinese Academy of Medical Sciences and Peking Union Medical College, Tianjin 300192, China. zhouxiaoliang@irm-cams.ac.cn.
Xiao-Liang
XL
Zhou
Tianjin Key Lab of Molecular Nuclear Medicine, Institute of Radiation Medicine, Chinese Academy of Medical Sciences and Peking Union Medical College, Tianjin 300192, China. longway@irm-cams.ac.cn.
Wei
W
Long
Tianjin Key Lab of Molecular Nuclear Medicine, Institute of Radiation Medicine, Chinese Academy of Medical Sciences and Peking Union Medical College, Tianjin 300192, China. liujinjian@irm-cams.ac.cn.
Jin-Jian
JJ
Liu
Tianjin Key Lab of Molecular Nuclear Medicine, Institute of Radiation Medicine, Chinese Academy of Medical Sciences and Peking Union Medical College, Tianjin 300192, China. fanfeiyue10@126.com.
Fei-Yue
FY
Fan
D000818:Animals; D000906:Antibodies / Q000378:metabolism*; D045744:Cell Line, Tumor; D005455:Fluorescent Antibody Technique; D008856:Microscopy, Fluorescence; D009842:Oligopeptides / Q000627:therapeutic use*; D011355:Prodrugs / Q000627:therapeutic use*; D017208:Rats, Wistar; D011993:Recombinant Fusion Proteins / Q000097:blood / Q000493:pharmacokinetics / Q000627:therapeutic use*; D013667:Technetium; D014018:Tissue Distribution; D023041:Xenograft Model Antitumor Assays; D001618:beta-Lactamases / Q000627:therapeutic use*
D000906:Antibodies; D009842:Oligopeptides; D011355:Prodrugs; D011993:Recombinant Fusion Proteins; D013667:Technetium; D001618:beta-Lactamases