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Positron Emission Tomography Imaging of Cell Trafficking: A Method of Cell Radiolabeling
Published on: October 27, 2023
Detecting TRA-1-60 in Cancer via a Novel Zr-89 Labeled ImmunoPET Imaging Agent
Jordan M White1, Akhila N Kuda-Wedagedara1, Madison N Wicker2
1Department of Oncology, Karmanos Cancer Institute, Detroit, Michigan 48201, United States.
Abstract:
TRA-1-60 (TRA) is a cell-surface antigen implicated in drug resistance, relapse, and recurrence. Its expression has been reported in breast, prostate, pancreatic, ovarian tumors, and follicular lymphoma, which paved the development of the therapeutic antibody, Bstrongomab (Bsg), and its drug conjugates. Because patient selection is critical to achieve clinical benefit, a noninvasive imaging agent to select TRA+ lesions in patients is needed. Herein, we report the development of the immunopositron emission tomography (immunoPET) radiotracer 89Zr-radiolabeled Bsg and its potential to delineate TRA+ tumors. Bsg was conjugated to the bifunctional chelator desferrioxamine (DFO) and radiolabeled with [89Zr]Zr-oxalate. [89Zr]Zr-DFO-Bsg was characterized in vitro and evaluated in vivo for uptake and specificity in high and low TRA-expressing BxPC-3 pancreatic and PC-3 prostate cancer models, respectively. Uptake was compared against [89Zr]Zr-DFO-IgG, a nonspecific control radiotracer. Immunohistochemical (IHC) staining of patient cancer tissues using Bsg was performed to explore its clinical significance. A specific activity of 0.18 ± 0.01 GBq/mg (4.8 ± 0.3 mCi/mg) was obtained for [89Zr]Zr-DFO-Bsg. BxPC-3 xenografts exhibited three-fold higher radiotracer uptake compared to [89Zr]Zr-DFO-IgG. Competitive saturation studies using BxPC-3 xenografts further confirmed tracer specificity. The TRA-specific probe had lower accumulation in PC-3 xenografts. Ex vivo autoradiographs correlated with TRA expression from the histopathology of the resected tumor xenografts. Additionally, patient cancer tissues demonstrated positive staining with Bsg with metastatic lesions exhibiting the highest staining. This study demonstrates the potential of [89Zr]Zr-DFO-Bsg as an imaging agent for noninvasive detection of TRA+ tumors.
Insights
A novel imaging agent, 89Zr-labeled Bstrongomab (Bsg), can noninvasively detect TRA-1-60 (TRA) positive tumors. This radiotracer shows potential for patient selection in TRA-targeted therapies.
Area of Science:
- Nuclear Medicine
- Oncology
- Immunotherapy
Background:
- TRA-1-60 (TRA) is a cell-surface antigen associated with drug resistance and tumor recurrence in various cancers.
- Therapeutic antibodies like Bstrongomab (Bsg) targeting TRA are under development, necessitating patient selection tools.
- Noninvasive imaging is crucial for identifying TRA-positive lesions to guide treatment decisions.
Purpose of the Study:
- To develop and evaluate an immunoPET radiotracer for noninvasive imaging of TRA-expressing tumors.
- To assess the specificity and efficacy of 89Zr-labeled Bsg for delineating TRA+ lesions.
Main Methods:
- Bstrongomab (Bsg) was conjugated to desferrioxamine (DFO) and radiolabeled with 89Zr.
- The resulting radiotracer, 89Zr-DFO-Bsg, was characterized in vitro and evaluated in vivo using pancreatic (BxPC-3) and prostate (PC-3) cancer models.
- Uptake and specificity were compared against a nonspecific control (89Zr-DFO-IgG).
- Immunohistochemistry (IHC) was performed on patient tumor tissues.
Main Results:
- 89Zr-DFO-Bsg demonstrated high specific activity and selective uptake in TRA-high BxPC-3 xenografts compared to controls.
- Specificity was confirmed through competitive saturation studies and lower uptake in TRA-low PC-3 xenografts.
- Ex vivo autoradiography correlated with TRA expression, and patient tissues showed positive Bsg staining, particularly in metastatic sites.
Conclusions:
- 89Zr-DFO-Bsg is a promising immunoPET radiotracer for noninvasive detection of TRA-positive tumors.
- This agent has the potential to aid in patient selection for TRA-targeted therapies.
- The findings support the clinical significance of TRA expression in various cancers.
