Aβ targeting ImmunoPET : Brain pharmacokinetics comparison between a brain penetrating and a regular antibody

• Bispecific antibodies utilizing the transferrin receptor (TfR) for transport into the brain are being developed for both therapeutic and diagnostic applications. Compared with regular monospecific antibodies, the brain uptake of TfR-binding bispecific antibodies is rapid and efficient. However, due to differences in pharmacokinetic properties, it has been challenging to directly compare their brain uptake in vivo. In this study, we have studied the amyloid-β (Aβ) antibody Bapineuzumab (Bapi) and its bispecific variant Bapi-Fab8D3, which contains a fragment of the TfR-binding antibody 8D3. Both antibodies were recombinantly engineered to harbour a mutation that reduces binding to the neonatal Fc receptor (FcRn) and thus contributes to an increased clearance rate from blood.The antibodies were labelled with fluorine-18 (18F) and administered to wildtype (WT) mice, which were PET scanned for 2 h in an alternating manner to cover a period of 9 h, followed by ex vivo analyses. Next, the bispecific antibody [18F]Bapi-Fab8D3 was used for PET imaging if Aβ pathology in the AD mouse model AppNL-G-F compared with WT mice at 12 h after antibody administration. [18F]Bapi and [18F]Bapi-Fab8D3 had identical blood elimination curves in WT mice and PET data quantification demonstrated that [18F]Bapi brain concentration declined from the start and throughout the 9 h time period, while [18F]Bapi-Fab8D3 displayed a higher brain concentration, indicative of its active transport into the brain.[18F]Bapi-Fab PET imaging discriminated AppNL-G-F from WT mice already at 12 h after administration, suggesting that this novel antibody-based ligand could be used for same-day PET imaging.

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

Positron emission tomography (PET)

bispecific antibody

receptor mediated transcytosis (RMT)

Blood-brain barrier (BBB)

Alzheimer’s disease (AD)

Amyloid-β (Aβ)

Publikations- och innehållstyp

vet (ämneskategori)

ovr (ämneskategori)