Abstract
Monoclonal antibodies (mAbs) have not been used as positron emission tomography (PET) ligands for in vivo imaging of the brain because of their limited passage across the blood-brain barrier (BBB). However, due to their high affinity and specificity, mAbs may be an attractive option for brain PET if their brain distribution can be facilitated. In the present study, a F(ab’)2 fragment of the amyloid-beta (Aβ) protofibril selective mAb158 was chemically conjugated to the transferrin receptor (TfR) antibody 8D3 to enable TfR mediated transcytosis across the BBB. The generated bispecific protein, 8D3-F(ab’)2-h158, was subsequently radiolabeled and used for microPET imaging of Aβ pathology in two mouse models of AD. [124I]8D3-F(ab’)2-h158 was distributed across the BBB several fold more than unmodified mAbs in general and its accumulation in the brain reflected disease progression, while its concentration in blood and other organs remained stable across all age groups studied. Cerebellum was largely devoid of 8D3-F(ab’)2-h158 in young and middle aged mice, while mice older than 18 months also showed some accumulation in cerebellum. In a longer perspective, the use of bispecific antibodies as PET ligands may enable in vivo ‘immunohistochemistry’ also of other proteins in the brain for which PET radioligands are lacking.
Highlights
Alzheimer’s disease (AD) is characterized by deposition of amyloid-beta (Aβ) in the brain
We have previously described the use of this mechanism to increase the brain concentrations of the monoclonal antibody mAb158, which binds selectively to soluble Aβ protofibrils, with only moderate binding to fibrillar Aβ, low binding to Aβ monomers and no binding the Aβ
There was no difference in radioligand half-life between transgenic and wt mice at any age
Summary
Alzheimer’s disease (AD) is characterized by deposition of amyloid-beta (Aβ) in the brain. The exact fraction is unknown, some AD patients lack dense core plaques and may be falsely diagnosed as Aβ negative with [11C]PIB and analogues[11] This highlights the need for a PET radioligand that can visualize other than insoluble forms of Aβ aggregates. In the present study the aim was to investigate the brain accumulation of the novel bispecific mAb-based radioligand [124I]8D3-F(ab’)2-h158 (Fig. 1c) in wild-type (wt) and two transgenic models of Aβ pathology displaying different disease progression patterns: tg-ArcSwe mice, harboring both the Arctic and the Swedish AβPP mutations, display an early onset of Aβ pathology with dense Aβ deposits, resembling human amyloid plaques; tg-Swe mice overexpress AβPP with only the Swedish mutation and has a late onset of Aβ pathology but with a rapid progression and less dense deposits[19,20]. Systemic pharmacokinetics and distribution to major peripheral organs were investigated
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