Radionuclide selection influences imaging outcomes in immunoPET with a brain-penetrant anti-Aβ antibody
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Background
Bispecific antibodies exploiting receptor-mediated transcytosis offer a promising strategy to overcome limited blood-brain barrier permeability in Alzheimer’s disease (AD) therapy and imaging. Lecanemab-Fab8D3 (Lec-Fab8D3), a bispecific anti-amyloid beta (Aβ) antibody engineered for enhanced brain delivery, holds potential as a companion immunoPET imaging diagnostic with the novel lecanemab immunotherapy. This study aimed to compare three radionuclides—zirconium-89 ( 89 Zr), copper-64 ( 64 Cu), and iodine-124 ( 124 I)—for PET imaging with Lec-Fab8D3 to study its in vivo brain distribution and evaluate its potential as an AD companion diagnostic.
Methods
Lec-Fab8D3 was conjugated to DFO* or NODAGA for 89 Zr and 64 Cu radiolabeling, respectively, or directly radioiodinated with 124 I. PET imaging was performed in the Tg-ArcSwe mouse model of Aβ pathology and wild-type (WT) littermates at multiple time points post administration of the radiolabeled antibody, followed by ex vivo biodistribution, autoradiography, and Aβ quantification to assess brain uptake, specificity, and distribution of the radiolabeled Lec-Fab8D3.
Results
Radiolabeled Lec-Fab8D3 variants showed retained binding properties with high radiochemical purity and yields. PET imaging demonstrated cortical brain uptake of all three tradiotracers in Tg-ArcSwe mice, with [ 89 Zr]Zr-DFO*-Lec-Fab8D3 and [ 124 I]I-Lec-Fab8D3 showing the best discrimination between Tg-ArcSwe and WT mice at 48–72 h post-injection. The highest absolute brain retention, combined with a lower brain-to-cerebellum ratio, was observed in both Tg-ArcSwe and WT mice that received the radiometal-labeled ( 89 Zr and 64 Cu) antibody, likely due to the residualizing nature of radiometals. Ex vivo analyses confirmed PET findings, and immunostaining demonstrated co-localization of Lec-Fab8D3 with Aβ deposits.
Conclusions
ImmunoPET imaging with bispecific Lec-Fab8D3 enables specific detection of brain Aβ pathology in an AD mouse model. 89 Zr was superior to 64 Cu due to a more compatible half-life, while 124 I displayed higher regional contrast than both radiometals, despite lower overall brain signal. The combined findings from radiometal- and iodine-based immunoPET will enhance our understanding of intra-brain distribution of bispecific antibodies. Furthermore, this highlights the importance of the choice of radiolabeling strategy and how it will impact the outcome of immunoPET with bispecific Aβ antibodies.
