Development of an optimal imaging strategy for selection of patients for affibody-based PNA-mediated radionuclide therapy

Anzhelika Vorobyeva,Anna Orlova,Mohamed Altai,Amelie Eriksson Karlström,Vladimir Tolmachev,Jens Sörensen,Sara Rinne,Kristina Westerlund,Bogdan Mitran

doi:10.1038/s41598-018-27886-0

Abstract

Affibody molecules are engineered scaffold proteins, which demonstrated excellent binding to selected tumor-associated molecular abnormalities in vivo and highly sensitive and specific radionuclide imaging of Her2-expressing tumors in clinics. Recently, we have shown that peptide nucleic acid (PNA)-mediated affibody-based pretargeted radionuclide therapy using beta-emitting radionuclide 177Lu extended significantly survival of mice bearing human Her2-expressing tumor xenografts. In this study, we evaluated two approaches to use positron emission tomography (PET) for stratification of patients for affibody-based pretargeting therapy. The primary targeting probe ZHER2:342-SR-HP1 and the secondary probe HP2 (both conjugated with DOTA chelator) were labeled with the positron-emitting radionuclide 68Ga. Biodistribution of both probes was measured in BALB/C nu/nu mice bearing either SKOV-3 xenografts with high Her2 expression or DU-145 xenografts with low Her2 expression. 68Ga-HP2 was evaluated in the pretargeting setting. Tumor uptake of both probes was compared with the uptake of pretargeted 177Lu-HP2. The uptake of both 68Ga-ZHER2:342-SR-HP1 and 68Ga-HP2 depended on Her2-expression level providing clear discrimination of between tumors with high and low Her2 expression. Tumor uptake of 68Ga-HP2 correlated better with the uptake of 177Lu-HP2 than the uptake of 68Ga-ZHER2:342-SR-HP1. The use of 68Ga-HP2 as a theranostics counterpart would be preferable approach for clinical translation.

Highlights

Affibody molecules are engineered scaffold proteins, which demonstrated excellent binding to selected tumor-associated molecular abnormalities in vivo and highly sensitive and specific radionuclide imaging of Human epidermal growth factor 2 (Her2)-expressing tumors in clinics
The primary targeting agent ZHER2:342-SR-HP1 bearing a DOTA chelator was labeled with 68Ga
We have recently demonstrated that affibody-mediated pretargeted radionuclide therapy using 177Lu successfully delayed tumor growth and doubled median survival of mice bearing SKOV3 xenografts

Summary

Introduction

Affibody molecules are engineered scaffold proteins, which demonstrated excellent binding to selected tumor-associated molecular abnormalities in vivo and highly sensitive and specific radionuclide imaging of Her2-expressing tumors in clinics. We have shown that peptide nucleic acid (PNA)-mediated affibody-based pretargeted radionuclide therapy using beta-emitting radionuclide 177Lu extended significantly survival of mice bearing human Her2-expressing tumor xenografts. Tumor uptake of both probes was compared with the uptake of pretargeted 177Lu-HP2 The uptake of both 68Ga-ZHER2:342-SR-HP1 and 68Ga-HP2 depended on Her2-expression level providing clear discrimination of between tumors with high and low Her[2] expression. Several Her2-targeted treatments have been shown to be effective in patients with Her2-positive breast and gastroesophageal cancer and provided significantly improved patient survival[3,4,5,6]. Her2-targeted immunotherapy using monoclonal antibody (mAb) trastuzumab together with chemotherapy has become a standard line of treatment for patients with Her2-positive breast cancer[7]. Radiolabeled mAbs provided clinical benefits for patients with lymphoma, but did not improve the survival of www.nature.com/scientificreports/

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