Dual-labeled pertuzumab for multimodality image-guided ovarian tumor resection.

ABSTRACT

Pertuzumab is clinically employed in the treatment of cancers over-expressing human epidermal growth factor receptor 2 (HER2). Herein, we developed dual-labeled pertuzumab with a radionuclide (89Zr) and a near-infrared fluorophore (IRDye 800CW) to investigate the feasibility of utilizing dual-labeled monoclonal antibodies (mAbs) with numerous imaging modalities for preoperative imaging and image-guided surgery in ovarian cancer models. MAbs were dually-labeled with 89Zr and IRDye 800CW to generate 89Zr-Df-pertuzumab-800CW or 89Zr-Df-IgG-800CW. Serial positron emission tomography (PET) and near-infrared fluorescence (NIRF) images were acquired up to 72 hours after injection of dual-labeled mAbs to map the tracers' biodistributions. After the last time point, image-guided tumor resection was executed using different modalities (NIRF, Cerenkov luminescence [CL], and ß particle imaging) and ex vivo studies including biodistribution assays and histology analysis were performed to confirm the in vivo imaging data. SKOV3 ovarian cancer cells showed high expression of HER2 and pertuzumab conjugated with Df and IRDye 800CW maintained its binding affinity for these cells. For PET imaging in subcutaneous xenograft ovarian cancer models, 89Zr-Df-pertuzumab-800CW showed a significantly higher tumor-to-muscle ratio compared to the nonspecific 89Zr-Df-IgG-800CW from 24 hours after injection through the last time point (72 h 30.7 ± 7.4 vs. 7.5 ± 1.8, P < 0.01, n = 3-4). During image-guided surgery, three imaging modalities including NIRF, CL, and ß particle imaging could detect ovarian cancer in both subcutaneous and orthotopic models and each exhibited its own imaging characteristics. In addition, ex vivo imaging and biodistribution studies as well as histology analysis corroborated the in vivo imaging results. Therefore, we concluded that this single radiolabeled tracer can provide all-in-one contrast for multiple imaging modalities. The dual-labeled mAbs may hold promise to be employed for image-guided tumor surgery as well as diagnosis and staging through balancing out the strengths and weaknesses of various modalities such as PET/CT, NIRF, CL, and ß particle imaging.