Antibody-based
therapy has shown great success in the treatment of many diseases, including
cancers. While
antibodies and
antibody-drug conjugates (ADCs) have also been evaluated for central nervous system (CNS) disorders as well as
brain tumors, their therapeutic efficacy can be substantially limited due to low permeability across the blood-brain barrier (BBB). Thus, improving BBB permeability of therapeutic
antibodies is critical in establishing this
drug class as a reliable clinical option for
CNS diseases. Here, we report that, compared with a conventional heterogeneous conjugation, homogeneous conjugation of the synthetic BBB shuttle
peptide angiopep-2 (Ang2) to a
monoclonal antibody (mAb) provides improved binding affinity for brain microvascular endothelial cells in vitro and accumulation into normal brain tissues in vivo. In a mouse model, we also demonstrate that the homogeneous anti-EGFR mAb-Ang2 conjugate administered intravenously efficiently accumulates in intracranial
tumors. These findings suggest that homogeneous conjugation of BBB shuttle
peptides such as Ang2 is a promising approach to enhancing the therapeutic efficacy of antibody agents for
CNS diseases.