作者: Kumar, Bijender ; Rosenthal, Joseph ; Yazaki, Paul J. ; Vallera, Daniel A. ; Vishwasrao, Paresh ; Miller, Aaron ; Echavarria Parra, Liliana ; Poku, Kofi ; Nair, Indu ; Sanchez, James ; Bowles, Nicole ; Hui, Susanta K. ; Ebner, Todd ; Brooks, Jamison ; Chea, Junie ; Shively, John E. ; Wong, Jeffrey Y.C. ; Zuro, Darren ; Colcher, David ; Molnar, Justin ; Srideshikan, Sargur Madabushi ; Orellana, Marvin ; Stein, Anthony S.

AbstractPurpose:Acute myeloid leukemia (AML) is a highly aggressive form of leukemia, which results in poor survival outcomes. Currently, diagnosis and prognosis are based on invasive single-point bone marrow biopsies (iliac crest). There is currently no AML-specific noninvasive imaging method to detect disease, including in extramedullary organs, representing an unmet clinical need. About 85% to 90% of human myeloid leukemia cells express CD33 cell surface receptors, highlighting CD33 as an ideal candidate for AML immunoPET.Experimental Design:We evaluated whether [64Cu]Cu-DOTA-anti-CD33 murine mAb can be used for immunoPET imaging of AML in a preclinical model. MicroCT was adjusted to detect spatial/anatomical details of PET activity. For translational purposes, a humanized anti-CD33 antibody was produced; we confirmed its ability to detect disease and its distribution. We reconfirmed/validated CD33 antibody-specific targeting with an antibody–drug conjugate (ADC) and radioimmunotherapy (RIT).Results:[64Cu]Cu-DOTA-anti-CD33–based PET-CT imaging detected CD33+ AML in mice with high sensitivity (95.65%) and specificity (100%). The CD33+ PET activity was significantly higher in specific skeletal niches [femur (P < 0.00001), tibia (P = 0.0001), humerus (P = 0.0014), and lumber spine (P < 0.00001)] in AML-bearing mice (over nonleukemic control mice). Interestingly, the hybrid PET-CT imaging showed high disease activity in the epiphysis/metaphysis of the femur, indicating regional spatial heterogeneity. Anti-CD33 therapy using newly developed humanized anti-CD33 mAb as an ADC (P = 0.02) and [225Ac]Ac-anti-CD33-RIT (P < 0.00001) significantly reduced disease burden over that of respective controls.Conclusions:We have successfully developed a novel anti-CD33 immunoPET-CT–based noninvasive modality for AML and its spatial distribution, indicating a preferential skeletal niche.

2019-06-01·Journal of Nuclear Medicine1区 · 医学

⁶⁴Cu-SARTATE PET Imaging of Patients with Neuroendocrine Tumors Demonstrates High Tumor Uptake and Retention, Potentially Allowing Prospective Dosimetry for Peptide Receptor Radionuclide Therapy

1区 · 医学

Article

作者: Akhurst, Timothy A ; Donnelly, Paul S ; Paterson, Brett M ; Jeffery, Charmaine M ; Roselt, Peter ; Ware, Robert E ; Pattison, David A ; Kong, Grace ; Jackson, Price ; Noonan, Wayne ; Harris, Matthew ; Hicks, Rodney J ; Hedt, Amos ; Hofman, Michael S ; Herschtal, Alan ; Drummond, Elizabeth ; Callahan, Jason ; Hicks, Lauren J ; Hong, Emily ; Price, Roger

Imaging of somatostatin receptor expression is an established technique for staging of neuroendocrine neoplasia and determining the suitability of patients for peptide receptor radionuclide therapy. PET/CT using ⁶⁸Ga-labeled somatostatin analogs is superior to earlier agents, but the rapid physical decay of the radionuclide poses logistic and regulatory challenges. ⁶⁴Cu has attractive physical characteristics for imaging and provides a diagnostic partner for the therapeutic radionuclide ⁶⁷Cu. Based on promising preclinical studies, we have performed a first-time-in-humans trial of ⁶⁴Cu-MeCOSar-Tyr³-octreotate (⁶⁴Cu-SARTATE) to assess its safety and ability to localize disease at early and late imaging time-points. Methods: In a prospective trial, 10 patients with known neuroendocrine neoplasia and positive for uptake on ⁶⁸Ga-DOTA-octreotate (⁶⁸Ga-DOTATATE) PET/CT underwent serial PET/CT imaging at 30 min, 1 h, 4 h, and 24 h after injection of ⁶⁴Cu-SARTATE. Adverse reactions were recorded, and laboratory testing was performed during infusion and at 1 and 7 d after imaging. Images were analyzed for lesion and normal-organ uptake and clearance to assess lesion contrast and perform dosimetry estimates. Results:⁶⁴Cu-SARTATE was well tolerated during infusion and throughout the study, with 3 patients experiencing mild infusion-related events. High lesion uptake and retention were observed at all imaging time-points. There was progressive hepatic clearance over time, providing the highest lesion-to-liver contrast at 24 h. Image quality remained high at this time. Comparison of ⁶⁴Cu-SARTATE PET/CT obtained at 4 h to ⁶⁸Ga-DOTATATE PET/CT obtained at 1 h indicated comparable or superior lesion detection in all patients, especially in the liver. As expected, the highest early physiologic organ uptake was in the kidneys, liver, and spleen. Conclusion:⁶⁴Cu-SARTATE is safe and has excellent imaging characteristics. High late-retention in tumor and clearance from the liver suggest suitability for diagnostic studies and for prospective dosimetry for ⁶⁷Cu-SARTATE peptide receptor radionuclide therapy, and the half-life of ⁶⁴Cu would also facilitate good-manufacturing-practice production and distribution to sites without access to ⁶⁸Ga.

2018-12-01·Molecular Imaging and Biology3区 · 医学

Optimization of a Labeling and Kit Preparation Method for Ga-68 Labeled DOTATATE, Using Cation Exchange Resin Purified Ga-68 Eluates Obtained from a Tin Dioxide 68Ge/68Ga Generator

3区 · 医学

Article

作者: Prince, Deidré ; Rossouw, Daniel ; Rubow, Sietske

PURPOSEThe aim of this study was to optimize a radiolabeling method using cationic processed Ga-68 eluates from a SnO₂-based ⁶⁸Ge/⁶⁸Ga generator, followed by the development of DOTA-Tyr³-Thre⁸-octreotide (DOTATATE) kits.PROCEDURESDiluted generator eluates were adsorbed on a SCX resin and desorbed with acidified 5 M NaCl solution. Optimized labeling conditions were determined by variation of pH, using 35 μg DOTATATE and sodium acetate buffer. DOTATATE kits were developed based on optimized radiolabeling conditions, were labeled, and evaluated.RESULTSOptimized labeling conditions resulted in a radiolabeling efficiency of around 99 % and radiochemical yield of almost 85 %. Different kit preparation methods did not significantly influence the radiolabeling results. Kits were found to be stable over 3 months.CONCLUSIONA labeling method using SCX-processed Ga-68 eluates was optimized. DOTATATE kits specifically for these SCX-processed Ga-68 eluates were successfully formulated. A post-labeling Sep-Pak C18 purification should be optional.

100 项与 64Cu-DOTA-[3-Tyr]-octreotate 相关的药物交易

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