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Improved tumor imaging and therapy via i.v. IgG–mediated time-sequential modulation of neonatal Fc receptor
Jaspreet Singh Jaggi, … , Steven M. Larson, David A. Scheinberg
Jaspreet Singh Jaggi, … , Steven M. Larson, David A. Scheinberg
Published September 4, 2007
Citation Information: J Clin Invest. 2007;117(9):2422-2430. https://doi.org/10.1172/JCI32226.
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Research Article Oncology

Improved tumor imaging and therapy via i.v. IgG–mediated time-sequential modulation of neonatal Fc receptor

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Abstract

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.

Authors

Jaspreet Singh Jaggi, Jorge A. Carrasquillo, Surya V. Seshan, Pat Zanzonico, Erik Henke, Andrew Nagel, Jazmin Schwartz, Brad Beattie, Barry J. Kappel, Debjit Chattopadhyay, Jing Xiao, George Sgouros, Steven M. Larson, David A. Scheinberg

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Figure 1

FcRn blockade enhances the clearance of radiolabeled IgG antibody.

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FcRn blockade enhances the clearance of radiolabeled IgG antibody.
(A) W...
(A) Whole-body 111In activity at various time points after injection with 111In-HuM195 antibody (n = 4 per group). IgG-treated mice had faster whole-body clearance of radioactivity. (B) Organ distribution of 111In activity in the same mice after the last whole-body measurement (144 hours) revealed accelerated blood clearance after IgG treatment. %ID/g, percentage of injected dose per gram. (C–E) Whole-body and organ distribution of 111In activity in wild-type and FcRn knockout mice with or without IgG treatment. Genetic absence of a functional FcRn, or its pharmacological inhibition by high-dose IgG administration, resulted in accelerated whole-body elimination (C) and blood clearance of 111In-HuM195 antibody at 44 hours (D) and 160 hours (E) after injection. IgG treatment (1 g/kg i.p.; administered simultaneously with 111In-HuM195) did not alter whole-body clearance or organ distribution of 111In in FcRn knockout mice. Data are mean ± SEM. Scale of y axes varies in D and E.

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ISSN: 0021-9738 (print), 1558-8238 (online)

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