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SPECT imaging of di...
Abstract
Ämnesord
Stäng
- Background Alzheimer's disease (AD) immunotherapy with antibodies targeting amyloid-beta (A beta) has been extensively explored in clinical trials. The aim of this study was to study the long-term brain distribution of two radiolabeled monoclonal A beta antibody variants - RmAb158, the recombinant murine version of BAN2401, which has recently demonstrated amyloid removal and reduced cognitive decline in AD patients, and the bispecific RmAb158-scFv8D3, which has been engineered for enhanced brain uptake via transferrin receptor-mediated transcytosis. Methods A single intravenous injection of iodine-125 (I-125)-labeled RmAb158-scFv8D3 or RmAb158 was administered to AD transgenic mice (tg-ArcSwe). In vivo single-photon emission computed tomography was used to investigate brain retention and intrabrain distribution of the antibodies over a period of 4 weeks. Activity in blood and brain tissue was measured ex vivo and autoradiography was performed in combination with A beta and CD31 immunostaining to investigate the intrabrain distribution of the antibodies and their interactions with A beta. Results Despite faster blood clearance, [I-125]RmAb158-scFv8D3 displayed higher brain exposure than [I-125]RmAb158 throughout the study. The brain distribution of [I-125]RmAb158-scFv8D3 was more uniform and coincided with parenchymal A beta pathology, while [I-125]RmAb158 displayed a more scattered distribution pattern and accumulated in central parts of the brain at later times. Ex vivo autoradiography indicated greater vascular escape and parenchymal A beta interactions for [I-125]RmAb158-scFv8D3, whereas [I-125]RmAb158 displayed retention and A beta interactions in lateral ventricles. Conclusions The high brain uptake and uniform intrabrain distribution of RmAb158-scFv8D3 highlight the benefits of receptor-mediated transcytosis for antibody-based brain imaging. Moreover, it suggests that the alternative transport route of the bispecific antibody contributes to improved efficacy of brain-directed immunotherapy.
Ämnesord
- MEDICIN OCH HÄLSOVETENSKAP -- Klinisk medicin -- Radiologi och bildbehandling (hsv//swe)
- MEDICAL AND HEALTH SCIENCES -- Clinical Medicine -- Radiology, Nuclear Medicine and Medical Imaging (hsv//eng)
Nyckelord
- Alzheimer's disease
- Amyloid beta
- SPECT
- Immunotherapy
- Bispecific antibody
- Transferrin receptor
Publikations- och innehållstyp
- ref (ämneskategori)
- art (ämneskategori)
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