Background:Hijacking the transferrin receptor(TfR)is an effective strategy to transport amyloid-beta(Aβ)immuno-positron emission tomography(immunoPET)ligands across the blood-brain barrier(BBB).Such ligands are more ...Background:Hijacking the transferrin receptor(TfR)is an effective strategy to transport amyloid-beta(Aβ)immuno-positron emission tomography(immunoPET)ligands across the blood-brain barrier(BBB).Such ligands are more sensitive and specific than small-molecule ligands at detecting Aβpathology in mouse models of Alzheimer’s disease(AD).This study aimed to determine if this strategy would be as sensitive in rats and to assess how TfR affinity affects BBB transport of bispecific immunoPET radioligands.Methods:Two affinity variants of the rat TfR antibody,OX26,were chemically conjugated to a F(ab′)2 fragment of the anti-Aβantibody,bapineuzumab(Bapi),to generate two bispecific fusion proteins:OX265-F(ab′)2-Bapi and OX2676-F(ab′)2-Bapi.Pharmacokinetic analyses were performed 4 h and 70 h post-injection of radioiodinated fusion proteins in wild-type(WT)rats.[124I]I-OX265-F(ab′)2-Bapi was administered to TgF344-AD and WT rats for in vivo PET imaging.Ex vivo distribution of injected[124I]I-OX265-F(ab′)2-Bapi and Aβpathology were assessed.Results:More[125I]I-OX265-F(ab′)2-Bapi was taken up into the brain 4 h post-administration than[124I]I-OX2676-F(ab′)2-Bapi.[124I]I-OX265-F(ab′)2-Bapi PET visualized Aβpathology with significantly higher signals in the TgF344-AD rats than in the WT littermates without Aβpathology.The PET signals significantly correlated with Aβlevels in AD animals.Conclusion:Affinity to TfR affects how efficiently a TfR-targeting bispecific fusion protein will cross the BBB,such that the higher-affinity bispecific fusion protein crossed the BBB more efficiently.Furthermore,bispecific immunoPET imaging of brain Aβpathology using TfR-mediated transport provides good imaging contrast between TgF344-AD and WT rats,suggesting that this immunoPET strategy has the potential to be translated to higher species.展开更多
基金the European Union’s Horizon 2020 research and innovation programme under the Marie Skłodowska-Curie Grant Agreement No.813528,the Swedish Research Council(2017-02413,2018-02715,2021-1083 and 2021-03524),the Swedish Innovation Agency(2019-00106)Alzheimerfonden,Hjärnfonden,Hedlunds stiftelse,Torsten Söderbergs stiftelse,Åhlenstiftelsen,Stiftelsen för gamla tjänarinnor,Stohnes stiftelse,Magnus Bergvalls stiftelse,Konug Gustaf V:s och Drottning Victorias frimuarestiftelse,Åke Wibergs stiftelse and Turku University Hospital.The funding organizations did not take part in designing the study,in collecting,analysing,or interpreting the data,or in writing the manuscript.
文摘Background:Hijacking the transferrin receptor(TfR)is an effective strategy to transport amyloid-beta(Aβ)immuno-positron emission tomography(immunoPET)ligands across the blood-brain barrier(BBB).Such ligands are more sensitive and specific than small-molecule ligands at detecting Aβpathology in mouse models of Alzheimer’s disease(AD).This study aimed to determine if this strategy would be as sensitive in rats and to assess how TfR affinity affects BBB transport of bispecific immunoPET radioligands.Methods:Two affinity variants of the rat TfR antibody,OX26,were chemically conjugated to a F(ab′)2 fragment of the anti-Aβantibody,bapineuzumab(Bapi),to generate two bispecific fusion proteins:OX265-F(ab′)2-Bapi and OX2676-F(ab′)2-Bapi.Pharmacokinetic analyses were performed 4 h and 70 h post-injection of radioiodinated fusion proteins in wild-type(WT)rats.[124I]I-OX265-F(ab′)2-Bapi was administered to TgF344-AD and WT rats for in vivo PET imaging.Ex vivo distribution of injected[124I]I-OX265-F(ab′)2-Bapi and Aβpathology were assessed.Results:More[125I]I-OX265-F(ab′)2-Bapi was taken up into the brain 4 h post-administration than[124I]I-OX2676-F(ab′)2-Bapi.[124I]I-OX265-F(ab′)2-Bapi PET visualized Aβpathology with significantly higher signals in the TgF344-AD rats than in the WT littermates without Aβpathology.The PET signals significantly correlated with Aβlevels in AD animals.Conclusion:Affinity to TfR affects how efficiently a TfR-targeting bispecific fusion protein will cross the BBB,such that the higher-affinity bispecific fusion protein crossed the BBB more efficiently.Furthermore,bispecific immunoPET imaging of brain Aβpathology using TfR-mediated transport provides good imaging contrast between TgF344-AD and WT rats,suggesting that this immunoPET strategy has the potential to be translated to higher species.
