Improved tumor imaging and therapy via i.v. IgG-mediated time-sequential modulation of neonatal Fc receptor.
The long plasma half-life of IgG, while allowing for enhanced tumor uptake of tumor-targeted IgG conjugates, also results in increased background activity and normal-tissue toxicity. Therefore, successful therapeutic uses of conjugated antibodies have been limited to the highly sensitive and readily accessible hematopoietic tumors. We report a therapeutic strategy to beneficially alter the pharmacokinetics of IgG antibodies via pharmacological inhibition of the neonatal Fc receptor (FcRn) using high-dose IgG therapy. IgG-treated mice displayed enhanced blood and whole-body clearance of radioactivity, resulting in better tumor-to-blood image contrast and protection of normal tissue from radiation. Tumor uptake and the resultant therapeutic response was unaltered. Furthermore, we demonstrated the use of this approach for imaging of tumors in humans and discuss its potential applications in cancer imaging and therapy. The ability to reduce the serum persistence of conjugated IgG antibodies after their infusion can enhance their therapeutic index, resulting in improved therapeutic and diagnostic efficacy.
Jaggi
Jaspreet Singh
JS
Molecular Pharmacology, Memorial Sloan-Kettering Cancer Center, New York, New York 10021, USA.
Carrasquillo
Jorge A
JA
Seshan
Surya V
SV
Zanzonico
Pat
P
Henke
Erik
E
Nagel
Andrew
A
Schwartz
Jazmin
J
Beattie
Brad
B
Kappel
Barry J
BJ
Chattopadhyay
Debjit
D
Xiao
Jing
J
Sgouros
George
G
Larson
Steven M
SM
Scheinberg
David A
DA
D000186:Actinium / Q000737:chemistry; D000818:Animals; D005260:Female; D015395:Histocompatibility Antigens Class I / Q000378:metabolism*; D006801:Humans; D007074:Immunoglobulin G / Q000008:administration & dosage / Q000009:adverse effects / Q000276:immunology* / Q000627:therapeutic use*; D007167:Immunotherapy; D007205:Indium Radioisotopes / Q000737:chemistry; D007275:Injections, Intravenous; D007457:Iodine Radioisotopes; D051379:Mice; D009369:Neoplasms / Q000276:immunology / Q000378:metabolism / Q000473:pathology* / Q000628:therapy*; D049268:Positron-Emission Tomography; D011961:Receptors, Fc / Q000378:metabolism*; D013997:Time Factors
D015395:Histocompatibility Antigens Class I; D007074:Immunoglobulin G; D007205:Indium Radioisotopes; D007457:Iodine Radioisotopes; D011961:Receptors, Fc; D000186:Actinium; C100688:Fc receptor, neonatal
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