Tumour targeting and radiation dose of radioimmunotherapy with 90Y-rituximab in CD20+ B-cell lymphoma as predicted by 89Zr-rituximab immuno-PET: impact of preloading with unlabelled rituximab

Abstract

PurposeTo compare using immuno-PET/CT the distribution of 89Zr-labelled rituximab without and with a preload of unlabelled rituximab to assess the impact of preloading with unlabelled rituximab on tumour targeting and radiation dose of subsequent radioimmunotherapy with 90Y-labelled rituximab in CD20+ B-cell lymphoma.MethodsFive patients with CD20+ B-cell lymphoma and progressive disease were prospectively enrolled. All patients underwent three study phases: initial dosimetric phase with baseline 89Zr-rituximab PET/CT imaging without a cold preload, followed 3 weeks later by a second dosimetric phase with administration of a standard preload (250 mg/m2) of unlabelled rituximab followed by injection of 89Zr-rituximab, and a therapeutic phase 1 week later with administration of unlabelled rituximab followed by 90Y-rituximab. PET/CT imaging and tracer uptake by organs and lesions were assessed.ResultsWith a cold rituximab preload, the calculated whole-body dose of 90Y-rituximab was similar (mean 0.87 mSv/MBq, range 0.82–0.99 mSv/MBq) in all patients. Without a preload, an increase in whole-body dose of 59 % and 87 % was noted in two patients with preserved circulating CD20+ B cells. This increase in radiation dose was primarily due to a 12.4-fold to 15-fold higher dose to the spleen without a preload. No significant change in whole-body dose was noted in the three other patients with B-cell depletion. Without a preload, consistently higher tumour uptake was noticed in patients with B-cell depletion.ConclusionAdministration of the standard preload of unlabelled rituximab impairs radioconjugate tumour targeting in the majority of patients eligible for radioimmunotherapy, that is patients previously treated with rituximab-containing therapeutic regimens. This common practice may need to be reconsidered and further evaluated as the rationale for this high preload has its origin in the “prerituximab era”.Clinical Trial Application: CTA 2011-005474-38Trial Registry: EudraCTElectronic supplementary materialThe online version of this article (doi:10.1007/s00259-015-3025-6) contains supplementary material, which is available to authorized users.

ImmunoPET of Malignant and Normal B Cells with 89Zr- and 124I-Labeled Obinutuzumab Antibody Fragments Reveals Differential CD20 Internalization In Vivo

“…(21) This study showed that tumor targeting is influenced by a variety of factors, e.g. B-cell depletion, spleen volume, tumor heterogeneity, the site of tumor involvement and preload of unlabeled antibody.…”

“…(20,21) However, the long plasma half-life of full length IgGs requires delays between tracer administration and image acquisition in order to achieve sufficient clearance of the radio-antibody and therefore high target-to-background ratios. In contrast, engineered antibody fragments such as diabodies (scFv dimer) and minibodies (scFv-C H 3) posses pharmacokinetics optimized for imaging.…”

B-cell imaging with zirconium-89 labelled rituximab PET-CT at baseline is associated with therapeutic response 24 weeks after initiation of rituximab treatment in rheumatoid arthritis patients

“…The 89 Zr-Rituximab was produced in a current Good Manufacturing Practice (cGMP) compliant way in a facility with a manufacturing license at the university campus (Amsterdam, The Netherlands) essentially the same as described before [13, 17]. …”

“…Zirconium-89 has a physical half-life of about 78.4 hours and can be stably coupled to mAbs. 89 Zr-labeled rituximab has been successfully applied for imaging and radioimmunotherapy of CD20-positive B-cell lymphomas [13]. In fact, this “immuno-PET” technique showed more tumor-positive lymph nodes than the standard fluorodeoxyglucose ( 18 F-FDG; glucose metabolism) PET scans [13].…”

“…89 Zr-labeled rituximab has been successfully applied for imaging and radioimmunotherapy of CD20-positive B-cell lymphomas [13]. In fact, this “immuno-PET” technique showed more tumor-positive lymph nodes than the standard fluorodeoxyglucose ( 18 F-FDG; glucose metabolism) PET scans [13]. 89 Zr-rituximab PET imaging may not only be interesting for visualization of B cells in B-cell lymphoma but also for other B-cell-related immune activity in the body.…”