Homogeneous antibody-angiopep 2 conjugates for effective brain targeting.

Yasuaki Anami,Chisato M Yamazaki,Aiko Yamaguchi,Wei Xiong,Kyoji Tsuchikama,Zhiqiang An,Ningyan Zhang

doi:10.1039/d1ra08131d

Abstract

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.

Highlights

Antibody-based therapy has shown great success in the treatment of many diseases, including cancers.[1]
These findings suggest that homogeneous conjugation of blood–brain barrier (BBB) shuttle peptides such as Ang[2] is a promising approach to enhancing the therapeutic efficacy of antibody agents for central nervous system (CNS) diseases
A recent successful example in this eld is the amyloid beta-targeting monoclonal antibody aducanumab (Aduhelm®) approved for treating Alzheimer's disease by the Food and Drug Administration (FDA) in 2021.3 many studies have led to a consensus that the therapeutic efficacy of most mAbs for CNS diseases is substantially limited due to their extremely low permeability to the brain

Summary

Introduction

A plethora of molecular design and administration methods have been investigated to improve mAb delivery to the brain parenchyma.[6] Modi cation with BBB shuttle peptides is a common approach for promoting transcytosis mediated by transporters or receptors on brain endothelial cells.[7] Angiopep-2 (Ang2), a 19-mer synthetic BBB shuttle peptide,[8] has been shown to promote brain uptake of small molecules,[9,10] liposomes,[11,12,13] and nanoparticles[14,15,16] via transcytosis mediated by the low-density lipoprotein receptorrelated protein 1 (LRP-1).[17,18] Further, Regina et al reported that an anti-HER2 mAb–Ang[2] conjugate showed enhanced BBB penetrability and therapeutic efficacy in an intracranial tumor mouse model.[19] While promising, they used a heterogeneous conjugate that differs in conjugation sites and the number of Ang[2] installed. We demonstrate that the homogeneous Ang[2] conjugate administered intravenously efficiently targets intracranially implanted GBM tumors. Our ndings could lay the foundation for developing better antibody-based therapeutics for CNS disorders

Results and discussion

Conclusions

Conflicts of interest