Exo-Linker: Unlocking Enhanced Stability and Therapeutic Efficacy in Antibody-Drug Conjugates

Drug Delivery System 40-5, 2025 385 る有望な戦略として注目されている 1) 。現在、米国 食品医薬品局 (FDA) により13 種類以上の ADC が 承認されており、さらに100 を超える候補品が臨床 開発段階にある。FDA に承認を受けている ADC に用いられているリンカーは、Val-Cit リンカーや Val-Ala リンカーといった従来型のリンカーが最も 多く、これらの従来型リンカーは安全性および有効 性の課題を抱えている。主な課題として、疎水性の 高さと一部の酵素に対する脆弱性が挙げられる。疎 1. はじめに 抗 体 薬 物 複 合 体 (Antibody-drug conjugates： ADCs) は、標的志向性の高いモノクローナル抗体 と強力な細胞毒性を有する低分子薬剤 (payload) を 適切なリンカーを介して結合させたバイオ医薬品で あり、治療の有効性向上および毒性低減に寄与す S D D Exo-Linker：抗体薬物複合体の 安定性と有効性の向上 Exo-Linker: Unlocking Enhanced Stability and Therapeutic Efficacy in Antibody-Drug Conjugates Antibody-drug conjugates (ADCs) combine cytotoxic payloads with monoclonal antibodies via chemical linkers.While the number of ADCs approved by the FDA continues to increase, the conventional Val-Cit linker still presents several challenges, including increased aggregation due to hydrophobicity, limitations in drug-to-antibody ratio (DAR) , and instability of the linker moiety during blood circulation.In this study, we incorporated hydrophilic amino acid residues into the cathepsin-cleavable Val-Cit linker and introduced the cleavable linker at the "Exo" position -i.e., the branch position of the linear connection between the antibody and payloadto enhance the masking effect by shortening the distance between the antibody and payload.This design addresses the limitations of the Val-Cit platform and improves the ADC in vivo profiles.In vitro and in vivo evaluations showed that Exo-linker ADCs reduced premature payload release, increased DAR, and avoided significant aggregation, even with hydrophobic payloads.Furthermore, the payload remained stably attached to the ADC even in the presence of enzymes like carboxylesterases and human neutrophil elastase, indicating the potential for a favorable safety profile.