Long-Lived Positron Emitters Zirconium-89 and Iodine-124 for Scouting of Therapeutic Radioimmunoconjugates with PET

Abstract

Antibody-PET imaging might be of value for the selection of radioimmunotherapy (RIT) candidates to confirm tumor targeting and to estimate radiation doses to tumor and normal tissues. One of the requirements to be set for such a scouting procedure is that the biodistributions of the diagnostic and therapeutic radioimmunoconjugates should be similar. In the present study we evaluated the potential of the positron emitters zirconium-89 ((89)Zr) and iodine-124 ((124)I) for this approach, as these radionuclides have a relatively long half-life that matches with the kinetics of MAbs in vivo (t(1/2) 3.27 and 4.18 days, respectively). After radiolabeling of the head and neck squamous cell carcinoma (HNSCC)-selective chimeric antibody (cMAb) U36, the biodistribution of two diagnostic (cMAb U36-N-sucDf-(89)Zr and cMAb U36-(124)I) and three therapeutic radioimmunoconjugates (cMAb U36-p-SCN-Bz-DOTA-(88)Y-with (88)Y being substitute for (90)Y, cMAb U36-(131)I, and cMAb U36-MAG3-(186)Re) was assessed in mice with HNSCC-xenografts, at 24, 48, and 72 hours after injection. Two patterns of biodistribution were observed, one pattern matching for (89)Zr- and (88)Y-labeled cMAb U36 and one pattern matching for (124)I-, (131)I-, and (186)Re-cMAb U36. The most remarkable differences between both patterns were observed for uptake in tumor and liver. Tumor uptake levels were 23.2 +/- 0.5 and 24.1 +/- 0.7%ID/g for the (89)Zr- and (88)Y-cMAb U36 and 16.0 +/- 0.8, 15.7 +/- 0.79 and 17.1 +/- 1.6%ID/g for (124)I-, (131)I-, and (186)Re-cMAb U36-conjugates, respectively, at 72 hours after injection. For liver these values were 6.9 +/- 0.8 ((89)Zr), 6.2 +/- 0.8 ((88)Y), 1.7 +/- 0.1 ((124)I), 1.6 +/- 0.1 ((131)I), and 2.3 +/- 0.1 ((186)Re), respectively. These preliminary data justify the further development of antibody-PET with (89)Zr-labeled MAbs for scouting of therapeutic doses of (90)Y-labeled MAbs. In such approach (124)I-labeled MAbs are most suitable for scouting of (131)I- and (186)Re-labeled MAbs.

Tissue Distribution Studies of Protein Therapeutics Using Molecular Probes: Molecular Imaging

“…This property of residualizing in the cell after catabolism is possessed by most radiometal labels, which are usually lysine-or cysteine-linked to the protein of interest through chelating groups such as diethylenetriaminepentaacetic acid (DTPA), 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid, or desferrioxamine B (DFO) (27). Upon catabolism, they tend to remain cell-trapped as charged lysine adducts (28,29).…”

Routine Production of 89Zr Using an Automated Module

“…Fortunately, high radionuclidic purity can still be achieved using ~15 MeV protons because 89m Zr has a short half-life (t 1/2 = 4.2 m) and a high degree of isomeric transition (IT = 93.8%) and because the (p,2n) and (p,pn) reactions require greater proton beam energies, so they have low cross-sections at E p~1 5 MeV-less than 0.2 and 0.02 b, respectively [19]. The important characteristics of 89 Zr production in general are summarized in Table 2, and the parameters and results from eight publications [20][21][22][23][24][25][26][27] about 89 Zr production are shown in the ESI. 88 Zr contaminant, while still producing 89 Zr [19,[28][29][30][31][32][33][34][35][36].…”

“…Out of eight papers that used the (p,n) reaction for 89 Zr production, five used Y foil targets [20,21,23,26,27], two used sputtered Y onto Cu [24,25], and one used Y 2 O 3 pellets [22]. Although the sputtered targets provided superior heat transfer and therefore allowed for higher beam currents, we chose to use Y foil for ease of use.…”

Positive Progress in ImmunoPET—Not Just a Coincidence

“…On the radiolabeling side, Perk et al 18 have accomplished easier and faster 89 Zr labeling by using a novel chelate. In a previous study, Verel et al 19 modified desferrioxamine B (Df ) to produce tetrafluorophenol-Nsuccinyldesferal (TFP-N-sucDf ). TFP-N-sucDf was used to successfully couple 89 Zr to the monoclonal antibody U36, but the multistep process required for production of TFP-N-sucDf precludes it from being a practical bifunctional chelate.…”

“…As mentioned in the preceding section, the first clinical study involving zirconium-89 was conducted in 2006. In this study, Bö rjesson et al 19 evaluated the safety and imaging capability of 89 Zr-labeled chimeric U36 (cmAb U36), an anti-CD44v6 intact antibody that had previously been shown to detect small squamous cell carcinoma of the head and neck (HNSCC) in mice. 33 89 Zr-cmAb U36 immunoPET (up to 6 days postinjection) as well as computed tomography (CT) and/or magnetic resonance imaging (MRI) scans were acquired for the 20 enrolled HNSCC patients prior to surgery.…”