Influence of Residualizing Properties of the Radiolabel on Radionuclide Molecular Imaging of HER3 Using Affibody Molecules.

Sara S Rinne,John Löfblom,Charles Dahlsson Leitao,Anna Orlova,Anzhelika Vorobyeva,Stefan Ståhl,Vladimir Tolmachev,Tianqi Xu

doi:10.3390/ijms21041312

Abstract

Human epidermal growth factor receptor type 3 (HER3) is an emerging therapeutic target in several malignancies. To select potential responders to HER3-targeted therapy, radionuclide molecular imaging of HER3 expression using affibody molecules could be performed. Due to physiological expression of HER3 in normal organs, high imaging contrast remains challenging. Due to slow internalization of affibody molecules by cancer cells, we hypothesized that labeling (HE)3-ZHER3:08698-DOTAGA affibody molecule with non-residualizing [125I]-N-succinimidyl-4-iodobenzoate (PIB) label would improve the tumor-to-normal organs ratios compared to previously reported residualizing radiometal labels. The [125I]I-PIB-(HE)3-ZHER3:08698-DOTAGA was compared side-by-side with [111In]In-(HE)3-ZHER3:08698-DOTAGA. Both conjugates demonstrated specific high-affinity binding to HER3-expressing BxPC-3 and DU145 cancer cells. Biodistribution in mice bearing BxPC-3 xenografts at 4 and 24 h pi showed faster clearance of the [125I]I-PIB label compared to the indium-111 label from most tissues, except blood. This resulted in higher tumor-to-organ ratios in HER3-expressing organs for [125I]I-PIB-(HE)3-ZHER3:08698-DOTAGA at 4 h, providing the tumor-to-liver ratio of 2.4 ± 0.3. The tumor uptake of both conjugates was specific, however, it was lower for the [125I]I-PIB label. In conclusion, the use of non-residualizing [125I]I-PIB label for HER3-targeting affibody molecule provided higher tumor-to-liver ratio than the indium-111 label, however, further improvement in tumor uptake and retention is needed.

Highlights

Human epidermal growth factor receptor type 3 (HER3) is a transmembrane protein belonging to the human epidermal growth factor receptor (HER) family, which is involved in the regulation of cellular proliferation, motility, and apoptosis [1]
These results suggest that the use of predictive biomarkers is necessary to select a sub-cohort of patients who would most likely benefit from HER3-targeted therapeutics [13,16]
While this study demonstrated feasibility of the use of non-residualizing labels for enhancing the tumor-to-liver ratio of anti-HER3 affibody molecule, the low tumor uptake is of concern

Summary

Introduction

Human epidermal growth factor receptor type 3 (HER3) is a transmembrane protein belonging to the human epidermal growth factor receptor (HER) family, which is involved in the regulation of cellular proliferation, motility, and apoptosis [1]. Monoclonal antibody seribantumab was studied in several clinical trials but did not prolong progression-free survival, no biomarkers were used for selection of patients enrolled for these trials [20] These results suggest that the use of predictive biomarkers is necessary to select a sub-cohort of patients who would most likely benefit from HER3-targeted therapeutics [13,16]. Upregulation of HER3 in response to therapy suggests that biopsy sampling has to be performed repeatedly to detect onset of resistance. Such a repetitive and invasive procedure is hardly feasible in the clinics

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