JNM: 89Zr-7E11 for immuno-PET can monitor tumor therapy response
89Zr-desferrioxamine B (DFO)-7E11 displays high tumor-to-background tissue contrast in immuno-PET and can be used as a tool to monitor and quantify with high specificity tumor response in prostate-specific membrane antigen (PSMA)-positive prostate cancer, according to research published in the October issue of the Journal of Nuclear Medicine.
The potential of the positron-emitting 89Zr has been recently investigated for the design of radioimmunoconjugates for immuno-PET. In this study, Alessandro Ruggiero, MD, from the department of radiology at Memorial Sloan-Kettering Cancer Center in New York City, and colleagues reported the preparation and in vivo evaluation of 89Zr-DFO-7E11, a novel 89Zr-labeled monoclonal antibody (mAb) construct for targeted imaging of PSMA, a prototypical cell surface marker highly overexpressed in prostate cancer. The ability of 89Zr-DFO-7E11 to delineate tumor response to therapy was also investigated, because it binds to the intracellular epitope of PSMA, which becomes available only on membrane disruption in dead or dying cells.
The researchers studied 7E11 as a marker of dying cells by flow cytometry and microscopy of cells after antiandrogen-, radio- and chemotherapy in LNCaP and PC3 PSMA–positive cells. The in vivo behavior of 89Zr-DFO-7E11 was characterized in mice bearing subcutaneous LNCaP (PSMA-positive) tumors by biodistribution studies and immuno-PET. They evaluated the potential of assessing tumor response in vivo after radiotherapy.
In vitro studies correlated 7E11 binding with markers of apoptosis (7-amino-actinomycin-D and caspase-3), Ruggerio and colleagues wrote. In vivo biodistribution experiments revealed high, target-specific uptake of 89Zr-DFO-7E11 in LNCaP tumors after 24 hours (20.35 percentage injected dose per gram [ID/g]), 48 hours (22.82 percentage ID/g), 96 hours (36.94 percentage ID/g) and 120 hours (25.23 percentage ID/g).
They reported “excellent image contrast” with immuno-PET, and the 7E11 uptake was statistically increased in irradiated versus control tumor as measured by immuno-PET and biodistribution studies. Binding specificity was assessed by effective blocking studies at 48 hours.
The researchers selectively administered radiation therapy to LNCaP xenografts, using contralateral (untreated) tumors as a control in the same animal. They observed that uptake of 89Zr-7E11 was “significantly higher in the selectively treated tumors than in the control tumors. These data suggested a tumor response to therapy resulting in higher availability of the internal epitope of PSMA.”
Autoradiography showed an intratumoral distribution of 89Zr-7E11 corresponding to necrotic or apoptotic areas (by caspase-3 and H/E staining).
“Overall, our studies demonstrate that 89Zr-7E11 for immuno-PET of changing PSMA levels has the potential to be used in monitoring patient response to therapies, including various chemotherapies and radiation therapy,” the study authors concluded. “We anticipate that as with 7E11 for PC, the concept of targeting an intracellular epitope of a molecular protein target may find application in various other pathologies, particularly those responding to cytotoxic treatment.”
The potential of the positron-emitting 89Zr has been recently investigated for the design of radioimmunoconjugates for immuno-PET. In this study, Alessandro Ruggiero, MD, from the department of radiology at Memorial Sloan-Kettering Cancer Center in New York City, and colleagues reported the preparation and in vivo evaluation of 89Zr-DFO-7E11, a novel 89Zr-labeled monoclonal antibody (mAb) construct for targeted imaging of PSMA, a prototypical cell surface marker highly overexpressed in prostate cancer. The ability of 89Zr-DFO-7E11 to delineate tumor response to therapy was also investigated, because it binds to the intracellular epitope of PSMA, which becomes available only on membrane disruption in dead or dying cells.
The researchers studied 7E11 as a marker of dying cells by flow cytometry and microscopy of cells after antiandrogen-, radio- and chemotherapy in LNCaP and PC3 PSMA–positive cells. The in vivo behavior of 89Zr-DFO-7E11 was characterized in mice bearing subcutaneous LNCaP (PSMA-positive) tumors by biodistribution studies and immuno-PET. They evaluated the potential of assessing tumor response in vivo after radiotherapy.
In vitro studies correlated 7E11 binding with markers of apoptosis (7-amino-actinomycin-D and caspase-3), Ruggerio and colleagues wrote. In vivo biodistribution experiments revealed high, target-specific uptake of 89Zr-DFO-7E11 in LNCaP tumors after 24 hours (20.35 percentage injected dose per gram [ID/g]), 48 hours (22.82 percentage ID/g), 96 hours (36.94 percentage ID/g) and 120 hours (25.23 percentage ID/g).
They reported “excellent image contrast” with immuno-PET, and the 7E11 uptake was statistically increased in irradiated versus control tumor as measured by immuno-PET and biodistribution studies. Binding specificity was assessed by effective blocking studies at 48 hours.
The researchers selectively administered radiation therapy to LNCaP xenografts, using contralateral (untreated) tumors as a control in the same animal. They observed that uptake of 89Zr-7E11 was “significantly higher in the selectively treated tumors than in the control tumors. These data suggested a tumor response to therapy resulting in higher availability of the internal epitope of PSMA.”
Autoradiography showed an intratumoral distribution of 89Zr-7E11 corresponding to necrotic or apoptotic areas (by caspase-3 and H/E staining).
“Overall, our studies demonstrate that 89Zr-7E11 for immuno-PET of changing PSMA levels has the potential to be used in monitoring patient response to therapies, including various chemotherapies and radiation therapy,” the study authors concluded. “We anticipate that as with 7E11 for PC, the concept of targeting an intracellular epitope of a molecular protein target may find application in various other pathologies, particularly those responding to cytotoxic treatment.”