Radiolabeling and Preclinical Evaluation of Therapeutic Efficacy of 225 Ac-ch806 in Glioblastoma and Colorectal Cancer Xenograft Models
The epidermal growth factor receptor (EGFR) protein is highly expressed in a range of malignancies. Although therapeutic interventions directed toward EGFR have yielded therapeutic responses in cancer patients, side effects are common because of normal-tissue expression of wild-type EGFR. We develop...
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Published in | Journal of Nuclear Medicine Vol. 65; no. 9; pp. 1456 - 1462 |
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Main Authors | , , , , , , , , , , |
Format | Journal Article |
Language | English |
Published |
United States
01.09.2024
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Subjects | |
Online Access | Get full text |
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Summary: | The epidermal growth factor receptor (EGFR) protein is highly expressed in a range of malignancies. Although therapeutic interventions directed toward EGFR have yielded therapeutic responses in cancer patients, side effects are common because of normal-tissue expression of wild-type EGFR. We developed a novel tumor-specific anti-EGFR chimeric antibody ch806 labeled with
Ac and evaluated its in vitro properties and therapeutic efficacy in murine models of glioblastoma and colorectal cancer.
Ac-ch806 was prepared using different chelators, yielding [
Ac]Ac-macropa-tzPEG
Sq-ch806 and [
Ac]Ac-DOTA-dhPzPEG
-ch806. Radiochemical yield, purity, apparent specific activity, and serum stability of
Ac-ch806 were quantified. In vitro cell killing effect was examined. The biodistribution and therapeutic efficacy of
Ac-ch806 were investigated in mice with U87MG.de2-7 and DiFi tumors. Pharmacodynamic analysis of tumors after therapy was performed, including DNA double-strand break immunofluorescence of γH2AX, as well as immunohistochemistry for proliferation, cell cycle arrest, and apoptosis.
[
Ac]Ac-macropa-tzPEG
Sq-ch806 surpassed [
Ac]Ac-DOTA-dhPzPEG
-ch806 in radiochemical yield, purity, apparent specific activity, and serum stability. [
Ac]Ac-macropa-tzPEG
Sq-ch806 was therefore used for both in vitro and in vivo studies. It displayed a significant, specific, and dose-dependent in vitro cell-killing effect in U87MG.de2-7 cells.
Ac-ch806 also displayed high tumor uptake and minimal uptake in normal tissues.
Ac-ch806 significantly inhibited tumor growth and prolonged survival in both U87MG.de2-7 and DiFi models. Enhanced γH2AX staining was observed in
Ac-ch806-treated tumors compared with controls. Reduced Ki-67 expression was evident in all
Ac-ch806-treated tumors. Increased expression of p21 and cleaved caspase 3 was shown in U87MG.de2-7 and DiFi tumors treated with
Ac-ch806.
In glioblastoma and colorectal tumor models,
Ac-ch806 significantly inhibited tumor growth via induction of double-strand breaks, thereby constraining cancer cell proliferation while inducing cell cycle arrest and apoptosis. These findings underscore the potential clinical applicability of
Ac-ch806 as a potential therapy for EGFR-expressing solid tumors. |
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ISSN: | 0161-5505 1535-5667 2159-662X |
DOI: | 10.2967/jnumed.123.266894 |