Development of ⁶⁴Cu-NOTA-Trastuzumab for HER2 Targeting: A Radiopharmaceutical with Improved Pharmacokinetics for Human Studies

Abstract

The purpose of this study was to develop Cu-labeled trastuzumab with improved pharmacokinetics for human epidermal growth factor receptor 2. Trastuzumab was conjugated with SCN-Bn-NOTA and radiolabeled with Cu. Serum stability and immunoreactivity ofCu-NOTA-trastuzumab were tested. Small animal PET imaging and biodistribution study were performed in HER2-positive breast cancer xenograft model (BT-474). Internal dosimetry of experimental animals was performed using the image-based approach with the Monte Carlo N-Particle Code. Cu-NOTA-trastuzumab was prepared with high radiolabel yield and radiochemical purity (>98%) and showed high stability in serum and good immunoreactivity. Uptake of Cu-NOTA-trastuzumab was highest at 48 h after injection determined by PET imaging and biodistribution results in BT-474 tumors. The blood radioactivity concentrations ofCu-NOTA-trastuzumab decreased bi-exponentially with time in both mice with and without BT-474 tumor xenografts. The calculated absorbed dose of Cu-NOTA-trastuzumab was 0.048 mGy/MBq for the heart, 0.079 for the liver and 0.047 for the spleen.Cu-NOTA-trastuzumab was effectively targeted to the HER2-expressing tumor and, and it exhibited relatively low absorbed dose due to short residence time. Therefore, Cu-NOTA-trastuzumab could be applied to select the right patients/right timing for HER2 therapy, to monitor the treatment response after HER2-targeted therapy, and to detect distal or metastatic spread.

Synthesize of a novel 89Zr labeled HER2 affibody and its application study in tumor PET imaging

“…[13][14][15] Radiolabeled antibodies have shown promise in identifying the presence of HER2 in the tumor. [16][17][18] For example, 89 Zr-trastuzumab PET/CT detected unsuspected HER2-positive metastases in patients with HER2-negative primary breast cancer. [19] It also found lesions in patients with metastatic HER2-positive esophagogastric cancer [20] .…”

A Microdose Clinical Trial to Evaluate 64Cu-NOTA-Trastuzumab as a Positron Emission Tomography Imaging Agent in Patients with Breast Cancer

“…The speci c receptors that are expressed in cancer cells have been studied as targets for the treatment of tumors, resulting in the improved therapeutic performance of cancer patients [1]. Among them, human epidermal growth factor receptor (HER), which is involved in the growth of cancer cells, is a target of a representative molecular therapeutic agent [1,2]. It is known that the overexpression of HER, an intrinsic protein tyrosine kinase, is closely related to rapidprogress tumors [3].…”

“…The expression of HER2 is evaluated with tumor tissue and to obtain tumor tissue is inevitably invasive [2,5,6]. It has been reported that the discordance rate of HER2 expression between primary tumors and distant metastatic lesions is 4.9-17.7% [7].…”

“…However, repeated biopsies are di cult for the patient as it causes discomfort. In order to overcome this limitation, the need for a non-invasive evaluation of HER2 expression is growing, and one of the proposed methods is the non-invasive evaluation of the expression of HER2 using radioisotopes [2,5,6,9].…”

Al18F labeled sulfonamide‐conjugated positron emission tomography tracer in vivo tumor‐targeted imaging

“…2,3 A positron-emitting radiopharmaceutical (PET tracer) is a unique imaging biomarker that gives an enhanced image of diseased tissues where the agent accumulates and is distinguished from the normal tissue. [4][5][6] However, the widely used clinical PET tracers, for example, 18 F-fluorodeoxyglucose ( 18 F-FDG) and F-Al-1,4,7-triazacyclononane-1,4,7-triacetic acid (NOTA), are the markers of cellular metabolism, which can undergo cellular uptake via the same mechanisms as a glucose and excrete easily. Their biodistributions usually depend on the excretion of some biological molecules in vivo, such as glucose and amino acids, and then possess no tumortargeting property.…”