Reduced neonatal Fc receptor binding increases clearance and brain-to-blood ratio of a brain penetrating amyloid-β antibody

• Recent advances in the development of amyloid-β (Aβ) targeted immunotherapies for Alzheimer’s disease (AD) has highlighted the need for accurate diagnostic methods. Antibody-based positron emission tomography (PET) ligands are well suited for this purpose as they can be directed towards the same target as the therapeutic antibody. Bispecific brain penetrating antibodies are interesting for this purpose, but the slow clearance of antibodies remains a challenge for their use PET radioligands since antibody in the circulation as well as unbound antibody in the brain contribute to a non-specific background signal. Thus, a substantial time between the injection and the time of PET scanning is required to achieve an acceptable specific-to-nonspecific signal in PET. In this study, two antibody pairs were designed based on the Aβ antibody Bapineuzumab (Bapi), one regular IgG (Bapi) and one bispecific antibody with a Fab fragment of the transferrin receptor (TfR) antibody 8D3 fused to one of the heavy chains (Bapi-Fab8D3), for active TfR-mediated transport into the brain. One of the pairs was engineered to harbor a mutation in the Fc domain which reduced its binding to the neonatal Fc receptor (FcRn) and thereby increased the clearance of the antibody. Blood and brain pharmacokinetics of the antibody pairs were studied in WT mice and in the AD mouse model AppNL-G-F. The FcRn mutation substantially reduced blood half-life of both Bapi and Bapi-Fab8D3. With the high brain uptake of Bapi-Fab8D3, the brain-to-blood ratio of its FcRn mutated form was significantly higher in AppNL-G-F than WT mice already 12 h after injection and this difference increased further up to 24 h after antibody injection. Ex vivo autoradiography, used to visualize antibody distribution in the brain, showed specific antibody retention in areas with high amounts of Aβ pathology. Taken together, these results suggest that reducing FcRn binding of a full-sized bispecific antibody could drastically reduce the time from injection to 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

Alzheimer’s disease (AD)

bispecific antibody

Amyloid-β (Aβ)

Receptor mediated transcytosis (RMT)

Neonatal Fc receptor (FcRn)

Blood-brain barrier (BBB)

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vet (ämneskategori)

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