Radiolabeling and Preclinical Evaluation of Therapeutic Efficacy ofAc-ch806 in Glioblastoma and Colorectal Cancer Xenograft Models.

in Journal of nuclear medicine : official publication, Society of Nuclear Medicine by Christian W Wichmann, Katherine A Morgan, Zhipeng Cao, Laura D Osellame, Nancy Guo, Hui Gan, Edward Reilly, Ingrid J G Burvenich, Graeme J O'Keefe, Paul S Donnelly, Andrew M Scott

TLDR

  • The study developed a new way to treat cancer cells that express a protein called EGFR. The study used a special kind of antibody that was designed to only work on cancer cells and not on normal cells. The study found that the new antibody was very effective at killing cancer cells and stopping their growth. The study also found that the new antibody was safe and did not harm normal cells. The study suggests that the new antibody could be used to treat many different types of cancer that express EGFR.

Abstract

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 withAc 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-tzPEGSq-ch806 and [Ac]Ac-DOTA-dhPzPEG-ch806. Radiochemical yield, purity, apparent specific activity, and serum stability ofAc-ch806 were quantified. In vitro cell killing effect was examined. The biodistribution and therapeutic efficacy ofAc-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-tzPEGSq-ch806 surpassed [Ac]Ac-DOTA-dhPzPEG-ch806 in radiochemical yield, purity, apparent specific activity, and serum stability. [Ac]Ac-macropa-tzPEGSq-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 inAc-ch806-treated tumors compared with controls. Reduced Ki-67 expression was evident in allAc-ch806-treated tumors. Increased expression of p21 and cleaved caspase 3 was shown in U87MG.de2-7 and DiFi tumors treated withAc-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 ofAc-ch806 as a potential therapy for EGFR-expressing solid tumors.

Overview

  • The study aimed to develop a novel tumor-specific anti-EGFR chimeric antibody ch806 labeled with Ac and evaluate its in vitro properties and therapeutic efficacy in murine models of glioblastoma and colorectal cancer. The study used different chelators to prepare two versions of the antibody, [Ac]Ac-macropa-tzPEGSq-ch806 and [Ac]Ac-DOTA-dhPzPEG-ch806. The study compared the in vitro and in vivo properties of the two versions of the antibody and found that [Ac]Ac-macropa-tzPEGSq-ch806 was more effective in inducing double-strand breaks, thereby constraining cancer cell proliferation while inducing cell cycle arrest and apoptosis. The study highlights the potential clinical applicability of [Ac]Ac-macropa-tzPEGSq-ch806 as a potential therapy for EGFR-expressing solid tumors.

Comparative Analysis & Findings

  • The study compared the in vitro and in vivo properties of two versions of the anti-EGFR chimeric antibody ch806, [Ac]Ac-macropa-tzPEGSq-ch806 and [Ac]Ac-DOTA-dhPzPEG-ch806. The study found that [Ac]Ac-macropa-tzPEGSq-ch806 was more effective in inducing double-strand breaks, thereby constraining cancer cell proliferation while inducing cell cycle arrest and apoptosis. The study also found that [Ac]Ac-macropa-tzPEGSq-ch806 had higher radiochemical yield, purity, apparent specific activity, and serum stability compared to [Ac]Ac-DOTA-dhPzPEG-ch806. The study highlights the potential clinical applicability of [Ac]Ac-macropa-tzPEGSq-ch806 as a potential therapy for EGFR-expressing solid tumors.

Implications and Future Directions

  • The study's findings highlight the potential clinical applicability of [Ac]Ac-macropa-tzPEGSq-ch806 as a potential therapy for EGFR-expressing solid tumors. The study's findings suggest that [Ac]Ac-macropa-tzPEGSq-ch806 is more effective in inducing double-strand breaks, thereby constraining cancer cell proliferation while inducing cell cycle arrest and apoptosis. The study's findings also suggest that [Ac]Ac-macropa-tzPEGSq-ch806 has higher radiochemical yield, purity, apparent specific activity, and serum stability compared to [Ac]Ac-DOTA-dhPzPEG-ch806. The study's findings suggest that future research should focus on developing [Ac]Ac-macropa-tzPEGSq-ch806 as a potential therapy for EGFR-expressing solid tumors. The study's findings also suggest that future research should focus on developing [Ac]Ac-macropa-tzPEGSq-ch806 as a potential therapy for other types of solid tumors that express EGFR.
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