Abstract A149: Characterization of HER3 targeted radioligand therapy using molecular imaging

Abstract

Abstract Background: Radioligand therapy (RLT) is an emerging treatment modality that has shown potential to improve survival in cancer patients that often have limited or non-effective therapeutic options. We previously demonstrated that anti-HER3 antibody radioconjugate (HER3 ARC) has antitumor efficacy against HER3 expressing tumor xenograft models. One important step in the early development of RLT is to understand the targeting properties and the distribution of the RLT in vivo. Non-invasive molecular imaging such as single photon emission computed tomography (SPECT) and positron emission tomography (PET) offer unique opportunities to understand drug behavior in vivo, permitting real time drug targeting and distribution analysis. In this study, we assessed the targeting properties and distribution of our HER3 ARC in HER3 expressing preclinical xenograft tumor models using both SPECT and PET. Methods: HER3 monoclonal antibody was conjugated with p-SCN-Bn-deferoxamine (DFO) or p-SCN-Bn-DOTA (DOTA) then labeled with Zirconium-89 (89Zr) or Indium-111 (111In), respectively. Flow cytometry and gamma counting was used to characterize HER3 ARC biological activity in HER3-expressing tumor cell lines. Balb/c mice subcutaneously inoculated with HER3-expressing xenograft tumors (lung, ovarian and colorectal) were intravenously administered with 89Zr-DFO-HER3 or 111In-DOTA-HER3. PET or SPECT scans were acquired 72 and 120-144hrs post injection of the radiotracer. Separate cohorts of mice were simultaneously administered with 89Zr-DFO-HER3 or 111In-DOTA-HER3 and 20-fold excess of native HER3 antibody as control to block radiotracer binding. Tissue uptake was quantified by drawing 3D or 2D regions of interest (ROI) for PET or SPECT images, respectively. Results: HER3 ARC radiotracers were successfully prepared and demonstrated similar binding to HER3 expressing cells compared to native HER3 antibody. In tumor-bearing mice, 89Zr-DFO-HER3 and 111In-DOTA-HER3 specifically accumulated in HER3 expressing tumors and cleared throughout the reticuloendothelial system. High tumor uptake was observed 120hrs post radiotracer injection using both imaging modalities. In mice pre-treated with 20-fold excess of native antibody, tumor uptake was significantly lower, showing tumor binding specificity of ARC. PET and SPECT images showed similar tracer distribution profile in the HER3 tumors. As expected, radiotracer clearance organ signals were also visualized. Conclusions: In this study we show that PET or SPECT imaging using 89Zr or 111In, respectively, offers the potential to assess the distribution of HER3 targeted radioligand therapy during early stages of drug development. HER3 ARC showed highly specific HER3 tumor uptake that remained at least 120hrs post injection. Our findings warrant further investigation to support advancement of HER3 ARC as a therapeutic option. Citation Format: Sumit Mukherjee, Debbie Lewis, Jason Li, Le-Cun Xu, Amanda Chin, Mary Chen, Monideepa Roy, Patrik Brodin, William van der Touw, Helen Kotanides, Denis Beckford-Vera. Characterization of HER3 targeted radioligand therapy using molecular imaging [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2023 Oct 11-15; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2023;22(12 Suppl):Abstract nr A149.