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HER3 PET Imaging: 68Ga-Labeled Affibody Molecules Provide Superior HER3 contrast to 89Zr-Labeled Antibody and Antibody-Fragment-Based Tracers

2021.09.24.

Sara S. Rinne et al., Cancers, 2021

Summary                         

The human epidermal growth factor receptor type 3 (HER3) is known to be a marker of several cancers, for example, breast and prostate cancer, but it is a challenging target for diagnostic radionuclide molecular imaging due to the relatively modest overexpression in tumors and substantial expression in healthy organs.

Radiolabeled monoclonal antibodies were among the first tracers to be evaluated for molecular imaging of the HER-receptor family. However, the slow extravasation and long residence time in blood are potential disadvantages for antibody-based imaging agents, because they result in an elevated background signal from blood-borne activity and increase the unspecific accumulation in non-targeted tissue. Sufficient imaging contrast with antibody-based tracers is generally not achieved until several days after injection. Variety of smaller tracers based on different classes of targeting molecules have emerged as alternatives to antibody-based tracers like antibody-fragments (e.g. F(ab’)2-fragments) and engineered scaffold proteins (ESPs). In the present study, PET tracers were comapred: the 89Zr-labeled therapeutic antibody seribantumab, a seribantumab-derived F(ab)2-fragment labeled with both 89Zr and 68Ga and the 68Ga-labeled affibody molecule ZHER3. The novel conjugates were radiolabeled and characterized in vitro using HER3-expressing BxPC-3 and DU145 human cancer cells. Biodistribution was studied using Balb/c nu/nu mice bearing BxPC-3 xenografts scanned with nanoScan PET/CT. Results show that 68Ga-DFO-seribantumab-F(ab’)2 is unsuitable for imaging due to the low stability and high uptake in normal organs. The highest tumor-to-non-tumor contrast with 89Zr-DFO-seribantumab and 89Zr-DFO-seribantumab-F(ab’)2 was achieved at 96h and 48h pi, respectively. Despite lower tumor uptake, 68Ga-ZHER3 provided the best imaging contrast due to the fastest clearance from blood and normal organs. The results suggest that affibody-based tracers are more suitable for PET imaging of HER3 expression than antibody- and antibody-fragment-based tracers.

Results from nanoScan PET/CT

BxPC-3 xenograft-bearing female mice were intravenously injected with 89Zr-DFO-seribantumab-F(ab’)2 (1.18 MBq), 89Zr-DFO-seribantumab (1.38 MBq) and 68Ga-ZHER3 (7.05 MBq).

Whole-body PET images were acquired using a nanoScan PET/MRI. Scan times were 45–60 min for 89Zr-DFO-seribantumab-F(ab’)2 and 89Zr-DFO-seribantumab, and 30 min for 68Ga-ZHER3. A CT scan was performed immediately after the PET scan, using a nanoScan SPECT/CT with the same bed. The parameters for the CT scans were a 5 min acquisition time, an X-ray energy peak of 50 keV/670µA, and 480 projections. Reconstruction of the PET scans was conducted using the Tera-Tomo™ 3D reconstruction engine with decay correction at the injection administration time. CT data were reconstructed using filter back projection in Nucline Software. PET and CT scans were fused using InterViewFusion software.

The PET images of 89Zr-DFO-seribantumab-F(ab’)2, 89Zr-DFO-seribantumab, and 68Ga-ZHER3 were acquired at the respective time points selected for biodistribution and are displayed on the Figure below. No images were acquired for 68Ga-DFO-seribantumab-F(ab’)2 due to the unfavorable biodistribution.

  • 89Zr-DFO-seribantumab-F(ab’)2, 89Zr-DFO-seribantumab, and 68Ga-ZHER3 were able to visualize the HER3-expressing BxPC-3 xenografts. Images were in good agreement with the biodistribution results.
  • High background signal from blood was observed for 89Zr-DFO-seribantumab-F(ab’)2 and 89Zr-DFOseribantumab at early time points.
  • Additionally, high activity uptake for 89Zr-DFO-seribantumab-F(ab’)2 and 89Zr-DFO-seribantumab was visible in the liver and GI tract as well as uptake in the bones and joints.

Full article on mdpi.com

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