ImmunoPET imaging of amyloid-beta in a rat model of Alzheimer's disease with a bispecific, brain-penetrating fusion protein

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Fältnamn	Indikatorer	Metadata
000		04401naa a2200445 4500
001		oai:DiVA.org:uu-497066
003		SwePub
008		230223s2022 \| \|\|\|\|\|\|\|\|\|\|\|000 \|\|eng\|
024	7	a https://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-4970662 URI
024	7	a https://doi.org/10.1186/s40035-022-00324-y2 DOI
040		a (SwePub)uu
041		a engb eng
042		9 SwePub
072	7	a ref2 swepub-contenttype
072	7	a art2 swepub-publicationtype
100	1	a Bonvicini, Gillianu Uppsala universitet,Geriatrik,BioArctic AB, S-11251 Stockholm, Sweden.4 aut0 (Swepub:uu)gilbo136
245	1 0	a ImmunoPET imaging of amyloid-beta in a rat model of Alzheimer's disease with a bispecific, brain-penetrating fusion protein
264		c 2022-12-26
264	1	b BioMed Central (BMC),c 2022
338		a electronic2 rdacarrier
520		a Background: Hijacking the transferrin receptor (TfR) is an effective strategy to transport amyloid-beta (A beta) 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 A beta pathology 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-A beta antibody, bapineuzumab (Bapi), to generate two bispecific fusion proteins: OX26(5)-F(ab')(2)-Bapi and OX26(76)-F(ab')(2)-Bapi. Pharmacokinetic analyses were performed 4 h and 70 h post-injection of radioiodinated fusion proteins in wild-type (WT) rats. [I-124]I-OX26(5)-F(ab')(2)-Bapi was administered to TgF344-AD and WT rats for in vivo PET imaging. Ex vivo distribution of injected [I-124]I-OX26(5)-F(ab')(2)-Bapi and A beta pathology were assessed.Results: More [I-125]I-OX26(5)-F(ab')(2)-Bapi was taken up into the brain 4 h post-administration than [I-124]I-OX26(76)-F(ab')(2)-Bapi. [I-124]I-OX26(5)-F(ab')(2)-Bapi PET visualized A beta pathology with significantly higher signals in the TgF344-AD rats than in the WT littermates without A beta pathology. The PET signals significantly correlated with A beta levels 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 A beta pathology 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.
650	7	a MEDICIN OCH HÄLSOVETENSKAPx Medicinska och farmaceutiska grundvetenskaperx Neurovetenskaper0 (SwePub)301052 hsv//swe
650	7	a MEDICAL AND HEALTH SCIENCESx Basic Medicinex Neurosciences0 (SwePub)301052 hsv//eng
650	7	a MEDICIN OCH HÄLSOVETENSKAPx Klinisk medicinx Neurologi0 (SwePub)302072 hsv//swe
650	7	a MEDICAL AND HEALTH SCIENCESx Clinical Medicinex Neurology0 (SwePub)302072 hsv//eng
653		a ImmunoPET
653		a Transferrin receptor
653		a Alzheimer's disease
653		a Amyloid-beta
700	1	a Syvänen, Stinau Uppsala universitet,Geriatrik4 aut0 (Swepub:uu)stsyv838
700	1	a Andersson, Ken G. G.u BioArctic AB, S-11251 Stockholm, Sweden.4 aut
700	1	a Haaparanta-Solin, Merjau Univ Turku, Turku PET Ctr, Preclin Imaging Lab, Turku 20520, Finland.;Univ Turku, MediCity Res Lab, Turku 20520, Finland.4 aut
700	1	a Lopez-Picon, Franciscou Univ Turku, Turku PET Ctr, Preclin Imaging Lab, Turku 20520, Finland.;Univ Turku, MediCity Res Lab, Turku 20520, Finland.4 aut
700	1	a Sehlin, Dag,d 1976-u Uppsala universitet,Geriatrik4 aut0 (Swepub:uu)daseh499
710	2	a Uppsala universitetb Geriatrik4 org
773	0	t Translational Neurodegenerationd : BioMed Central (BMC)g 11q 11x 2047-9158
856	4	u https://doi.org/10.1186/s40035-022-00324-yy Fulltext
856	4	u https://uu.diva-portal.org/smash/get/diva2:1739084/FULLTEXT01.pdfx primaryx Raw objecty fulltext:print
856	4 8	u https://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-497066
856	4 8	u https://doi.org/10.1186/s40035-022-00324-y

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