SPECT imaging of distribution and retention of a brain-penetrating bispecific amyloid-β antibody in a mouse model of Alzheimer’s disease

BACKGROUND: Alzheimer’s disease (AD) immunotherapy with antibodies targeting amyloid-β (Aβ) has been extensively explored in clinical trials. The aim of this study was to study the long-term brain distribution of two radiolabeled monoclonal Aβ 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 ((125)I)-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 Aβ and CD31 immunostaining to investigate the intrabrain distribution of the antibodies and their interactions with Aβ. RESULTS: Despite faster blood clearance, [(125)I]RmAb158-scFv8D3 displayed higher brain exposure than [(125)I]RmAb158 throughout the study. The brain distribution of [(125)I]RmAb158-scFv8D3 was more uniform and coincided with parenchymal Aβ pathology, while [(125)I]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 Aβ interactions for [(125)I]RmAb158-scFv8D3, whereas [(125)I]RmAb158 displayed retention and Aβ 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.