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

• 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.

Ämnesord

MEDICIN OCH HÄLSOVETENSKAP  -- Medicinska och farmaceutiska grundvetenskaper -- Neurovetenskaper (hsv//swe)

MEDICAL AND HEALTH SCIENCES  -- Basic Medicine -- Neurosciences (hsv//eng)

MEDICIN OCH HÄLSOVETENSKAP  -- Klinisk medicin -- Neurologi (hsv//swe)

MEDICAL AND HEALTH SCIENCES  -- Clinical Medicine -- Neurology (hsv//eng)

Nyckelord

ImmunoPET

Transferrin receptor

Alzheimer's disease

Amyloid-beta

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