有機合成化学/糖質化学は抗体-薬物複合体開発にどのように貢献できるか：糖鎖連結均一抗体-薬物複合体合成とがん間質ターゲティング療法の開拓

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  • Contribution from Synthetic Organic Chemistry and Glycoscience to ADC Development: Homogeneous ADC Preparation and Development of Cancer Stromal Targeting Therapy
  • ユウキ ゴウセイ カガク/トウシツ カガク ワ コウタイ-ヤクブツ フクゴウタイ カイハツ ニ ドノ ヨウ ニ コウケン デキル カ : トウサ レンケツ キンイツ コウタイ-ヤクブツ フクゴウタイ ゴウセイ ト ガン カンシツ ターゲティング リョウホウ ノ カイタク

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<p>Antibody-drug conjugates (ADCs) have received considerable attention as next-generation antibody drug. ADCs bring cytotoxic agents to lesion site and release them. Traditional conjugation on Lys and Cys residues typically generates heterogeneous ADCs. In order to expand therapeutic index, homogeneous ADCs are highly desired. We achieved homogeneous ADC preparation via N-glycan in the Fc region using endo-β-N-acetylglucosaminidase (ENGase) and its mutant. The heterogenous original N-glycan was removed by ENGase, and azide carrying human-type glycan was attached by the ENGase mutant. Next, bio-orthogonal reaction between azide and strained alkyne in payload moiety afforded the homogeneous ADC. Moreover, we established reaction monitoring method using ultra-performance liquid chromatography with an amide-based wide-pore column and optimized the reaction conditions.</p><p>ADC treatment for solid-cancer has some limitation because abundant stroma hampers antibody access to the antigen on the cell surface. To overcome this limitation, we proposed the caner stromal targeting (CAST) therapy. We developed an antibody against insoluble fibrin and designed a plasmin-cleavable linker. The ADC showed potent antitumor effect in mice bearing stroma-rich tumor.</p>

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