6 research outputs found
Cerebral rituximab uptake in multiple sclerosis: A 89Zr-immunoPET pilot study
Previous studies have demonstrated that the chimeric monoclonal antibody rituximab significantly reduces clinical and radiological disease activity in relapsing-remitting multiple sclerosis as early as 4 weeks after the first administration. The exact mechanisms leading to this rapid effect have not yet been clarified. The aim of this positron emission tomography study was to assess central nervous system penetration as a possible explanation, using zirconium-89-labelled rituximab. No evidence was found for cerebral penetration of [89Zr]rituximab
Synthesis of phosphine and antibody-azide probes for in vivo staudinger ligation in a pretargeted imaging and therapy approach
\u3cp\u3eThe application of intact monoclonal antibodies (mAbs) as targeting agents in nuclear imaging and radioimmunotherapy is hampered by the slow pharmacokinetics of these molecules. Pretargeting with mAbs could be beneficial to reduce the radiation burden to the patient, while using the excellent targeting capacity of the mAbs. In this study, we evaluated the applicability of the Staudinger ligation as pretargeting strategy using an antibody-azide conjugate as tumor-targeting molecule in combination with a small phosphine-containing imaging/therapeutic probe. Up to 8 triazide molecules were attached to the antibody without seriously affecting its immunoreactivity, pharmacokinetics, and tumor uptake in tumor bearing nude mice. In addition, two \u3csup\u3e89\u3c/sup\u3eZr- and \u3csup\u3e67/68\u3c/sup\u3eGa-labeled desferrioxamine (DFO)-phosphines, a \u3csup\u3e177\u3c/sup\u3eLu-1,4,7,10-tetraazacyclododecane-1,4,7,10- tetraacetic acid (DOTA)-phosphine and a \u3csup\u3e123\u3c/sup\u3eI-cubyl phosphine probe were synthesized and characterized for their pharmacokinetic behavior in nude mice. With respect to the phosphine probes, blood levels at 30 min after injection were <5% injected dose per gram tissue, indicating rapid blood clearance. In vitro Staudinger ligation of 3.33 μM antibody-azide conjugate with 1 equiv of radiolabeled phosphine, relative to the azide, in aqueous solution resulted in 20-25% efficiency after 2 h. The presence of 37% human serum resulted in a reduced ligation efficiency (reduction max. 30% at 2 h), while the phosphines were still >80% intact. No in vivo Staudinger ligation was observed in a mouse model after injection of 500 μg antibody-azide, followed by 68 μg DFO-phosphine at t = 2 h, and evaluation in blood at t = 7 h. To explain negative results in mice, Staudinger ligation was performed in vitro in mouse serum. Under these conditions, a side product with the phosphine was formed and ligation efficiency was severely reduced. It is concluded that in vivo application of the Staudinger ligation in a pretargeting approach in mice is not feasible, since this ligation reaction is not bioorthogonal and efficient enough. Slow reaction kinetics will also severely restrict the applicability of Staudinger ligation in humans.\u3c/p\u3
[89Zr]Zr-rituximab PET/CT activity in patients with therapy refractory interstitial pneumonitis : a feasibility study
Recent studies on immune-mediated inflammatory lung diseases show encouraging treatment results with rituximab, a monoclonal antibody (mAb) against CD20-expressing B lymphocytes. The present pilot study aimed to explore the possibility to image CD20-expression in the lungs as future early predictor of treatment response. We describe a series of 10 patients with therapy refractory interstitial pneumonitis who were treated with rituximab (1000 mg at day 0 and day 14) and underwent PET/CT after the administration of [89Zr]Zr-N-suc-DFO-rituximab abbreviated as [89Zr]Zr-rituximab. [89Zr]-rituximab PET/CT of the chest was performed on day 3 and 6. [89Zr]Zr-rituximab PET/CT showed visual and quantifiable increased pulmonary activity in four patients. Other patients demonstrated no increased activity in the lungs. One patient developed a severe allergic reaction during infusion of the first 10% unlabeled rituximab after which rituximab infusion was ceased. Subsequent administration of [89Zr]Zr-rituximab, however, did not result in any adverse reaction. This patient demonstrated the highest uptake of [89Zr]Zr-rituximab in mediastinal lymph nodes and lung parenchyma compared to the other 9 patients who did receive the full dose rituximab before [89Zr]Zr-rituximab. This pilot study demonstrates that [89Zr]Zr-rituximab PET/CT imaging in patients with therapy refractory interstitial pneumonitis is feasible and shows lung-specific uptake in some patients. Further research with larger sample size should establish if the [89Zr]Zr-rituximab uptake correlates with treatment response to rituximab. The higher uptake in the absence of a full 1000 mg rituximab preload may suggest that future studies should consider [89Zr]Zr-rituximab imaging at low mAb dose before treatment with rituximab
Performance of nanoScan PET/CT and PET/MR for quantitative imaging of 18F and 89Zr as compared with ex vivo biodistribution in tumor-bearing mice
Abstract Introduction The assessment of ex vivo biodistribution is the preferred method for quantification of radiotracers biodistribution in preclinical models, but is not in line with current ethics on animal research. PET imaging allows for noninvasive longitudinal evaluation of tracer distribution in the same animals, but systemic comparison with ex vivo biodistribution is lacking. Our aim was to evaluate the potential of preclinical PET imaging for accurate tracer quantification, especially in tumor models. Methods NEMA NU 4-2008 phantoms were filled with 11C, 68Ga, 18F, or 89Zr solutions and scanned in Mediso nanoPET/CT and PET/MR scanners until decay. N87 tumor-bearing mice were i.v. injected with either [18F]FDG (~ 14 MBq), kept 50 min under anesthesia followed by imaging for 20 min, or with [89Zr]Zr-DFO-NCS-trastuzumab (~ 5 MBq) and imaged 3 days post-injection for 45 min. After PET acquisition, animals were killed and organs of interest were collected and measured in a γ-counter to determine tracer uptake levels. PET data were reconstructed using TeraTomo reconstruction algorithm with attenuation and scatter correction and regions of interest were drawn using Vivoquant software. PET imaging and ex vivo biodistribution were compared using Bland–Altman plots. Results In phantoms, the highest recovery coefficient, thus the smallest partial volume effect, was obtained with 18F for both PET/CT and PET/MR. Recovery was slightly lower for 11C and 89Zr, while the lowest recovery was obtained with 68Ga in both scanners. In vivo, tumor uptake of the 18F- or 89Zr-labeled tracer proved to be similar irrespective whether quantified by either PET/CT and PET/MR or ex vivo biodistribution with average PET/ex vivo ratios of 0.8–0.9 and a deviation of 10% or less. Both methods appeared less congruent in the quantification of tracer uptake in healthy organs such as brain, kidney, and liver, and depended on the organ evaluated and the radionuclide used. Conclusions Our study suggests that PET quantification of 18F- and 89Zr-labeled tracers is reliable for the evaluation of tumor uptake in preclinical models and a valuable alternative technique for ex vivo biodistribution. However, PET and ex vivo quantification require fully described experimental and analytical procedures for reliability and reproducibility