Therapeutic Response Monitoring with 89Zr-DFO-Pertuzumab in HER2-Positive and Trastuzumab-Resistant Breast Cancer Models

Abstract

Immuno-positron emission tomography (PET) has great potential to evaluate the target expression level and therapeutic response for targeted cancer therapy. Immuno-PET imaging with pertuzumab, due to specific recognition in different binding sites of HER2, could be useful for the determination of the therapeutic efficacy of HER2-targeted therapy, trastuzumab, and heat shock protein 90 (HSP90) inhibitor, in HER2-expressing breast cancer. The aim of this study is to evaluate the feasibility of monitoring therapeutic response with 89Zr-DFO-pertuzumab for the treatment of HER2-targeted therapeutics, trastuzumab, or the HSP90 inhibitor 17-DMAG, in trastuzumab-resistant JIMT-1 breast cancer models. We prepared an immuno-PET imaging agent using desferoxamine (DFO)-pertuzumab labeled with 89Zr and performed the biodistribution and PET imaging in breast cancer xenograft models for monitoring therapeutic response to HER2-targeted therapy. 89Zr-DFO-pertuzumab was successfully prepared and showed specific binding to HER2 in vitro and clearly visualized HER2 expressing JIMT-1 tumors. 89Zr-DFO-pertuzumab had prominent tumor uptake in HER2 expressing JIMT-1 tumors. JIMT-1 tumors showed trastuzumab-resistant and HSP90 inhibitor sensitive characterization. In immuno-PET imaging, isotype antibody-treated JIMT-1 tumors had similar uptake in trastuzumab-treated JIMT-1 tumors, but 17-DMAG-treated JIMT-1 tumors showed greatly reduced uptake compared to vehicle-treated tumors. Additionally, HER2 downregulation evaluated by immuno-PET imaging was verified by western blot analysis and immunofluorescence staining which resulted in a significant reduction in the tumor’s HER2 level in 17-DMAG-treated JIMT-1 tumors. 89Zr-DFO-pertuzumab immuno-PET may be clinically translated to select pertinent patients for HER2-targeted therapy and to monitor the therapeutic response in HER2-positive cancer patients under various HER2-targeted therapeutics treatments.

Immuno-PET: Design options and clinical proof-of-concept

“…Another advantage of the immuno-PET in these clinical circumstances is that it allows a quantitative evaluation of the target expression to optimize the future therapeutic dose and allows a better evaluation of the in-vivo penetration (ability to cross the physiologic barrier) of mAbs in the tumor mass comparatively to the ex-vivo glass-slide immunohistochemistry (IHC) provided by cytology (73). A possible future for this dose finding may be clinically translated to predict and to monitor the HER2-targeted therapeutics treatments (74). The tumor uptake of 89 Zr-trastuzumab is related to the target concentration but there is still a pitfall due to the small range for distinguishing IHC classes 1 to 3 with relatively constant SUV.…”

A general approach to reduce off-target radioactivity in vivo via Tetrazine-Knock-Out (TKO)

“…5 While offering the promise of quantitative measurements of antigen density and greater specificity for tumor cells, 6 a substantial drawback emerges in the extended timeframe required to achieve optimal target-to-background signals. [7][8] When used as companion imaging and diagnostic tools, the high molecular weight of antibodies results in slow blood clearance, which can take weeks to clear from circulation. In both preclinical and clinical settings, the optimal imaging contrast typically becomes apparent 3-7 days after injection.…”