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In vivo trafficking of a tumor-targeting IgE antibody: molecular imaging demonstrates rapid hepatobiliary clearance compared to IgG counterpart

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Original languageEnglish
Article number1966970
JournalOncoImmunology
Volume10
Issue number1
DOIs
Published6 Sep 2021

Bibliographical note

Funding Information: This work was supported by the Wellcome EPSRC Centre for Medical Engineering at KCL [grant number WT 203148/Z/16/Z], the KCL/UCL Comprehensive Cancer Imaging Centre funded by CRUK and EPSRC in association with the MRC and DoH (England), the Medical Research Council Confidence in Concepts scheme, CRUK/NIHR in England/DoH for Scotland, Wales and Northern Ireland Experimental Cancer Medicine Centre (C10355/A15587), the Cancer Research UK King?s Health Partners Centre at King?s College London (C604/A25135), Cancer Research UK (C30122/A11527; C30122/A15774); the Academy of Medical Sciences, The Guy?s and St Thomas?s Foundation Trust Charity Melanoma Special Fund (573), the Medical Research Council (MR/L023091/1), Breast Cancer Now (147; KCL-BCN-Q3), the National Institute for Health Research (NIHR) Biomedical Research Centre based at Guy?s and St Thomas? NHS Foundation Trust and KCL [grant number IS-BRC-1215-20006], the Research England Confidence in Collaboration scheme and the CRUK City of London Centre. The views expressed are those of the authors and not necessarily those of the NHS, the NIHR or the Department of Health Publisher Copyright: © 2021 The Author(s). Published with license by Taylor & Francis Group, LLC. Copyright: Copyright 2021 Elsevier B.V., All rights reserved.

King's Authors

Abstract

IgE antibodies elicit powerful immune responses, recruiting effector cells to tumors more efficiently and with greater cytotoxicity than IgG antibodies. Consequently, IgE antibodies are a promising alternative to conventional IgG-based therapies in oncology (AllergoOncology). As the pharmacokinetics of IgE antibodies are less well understood, we used molecular imaging in mice to compare the distribution and elimination of IgE and IgG antibodies targeting the human tumor-associated antigen chondroitin sulfate proteoglycan 4 (CSPG4). Anti-CSPG4 IgE and IgG1 antibodies with human Fc domains were radiolabeled with 111In. CSPG4-expressing A375 human melanoma xenografts implanted in NOD-scid IL2rg-/- mice were also engrafted with human immune cells by intravenous administration. 111In-anti-CSPG4 antibodies were administered intravenously. Their distribution was determined by single-photon emission computed tomography (SPECT) and ex vivo gamma-counting over 120 h. SPECT imaging was conducted from 0 to 60 min after antibody administration to precisely measure the early phase of IgE distribution. 111In-labeled anti-CSPG4 IgG and IgE showed serum stability in vitro of >92% after 5 days. In A375 xenograft-bearing mice, anti-CSPG4 IgE showed much faster blood clearance and higher accumulation in the liver compared to anti-CSPG4 IgG. However, tumor-to-blood and tumor-to-muscle ratios were similar between the antibody isotypes and higher compared with a non-tumor-targeting isotype control IgE. IgE excretion was much faster than IgG. In non-tumor-bearing animals, early SPECT imaging revealed a blood clearance half-life of 10 min for IgE. Using image-based quantification, we demonstrated that the blood clearance of IgE is much faster than that of IgG while the two isotypes showed comparable tumor-to-blood ratios.

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