2024-06-03 スイス連邦工科大学ローザンヌ校(EPFL)
◆現在、EPFL の Elisa Oricchio 氏と Bruno Correia 氏が率いる科学者チームは、これらの限界を克服する新しいアプローチを開発しました。彼らは、非天然ペプチド阻害剤 (NNPI) を抗体と結合させて抗体ペプチド阻害剤複合体 (APIC) を作成するモジュール式薬物プラットフォームを作成しました。この方法により、阻害剤ががん細胞に特異的に送達され、全身の副作用が軽減され、治療効果が高まります。
<関連情報>
- https://actu.epfl.ch/news/antibody-peptide-inhibitor-conjugates-a-new-path-f/
- https://www.nature.com/articles/s41589-024-01627-z
抗体-ペプチドコンジュゲートは、発癌性カテプシンをブロックする共有結合阻害剤を提供する Antibody–peptide conjugates deliver covalent inhibitors blocking oncogenic cathepsins
Aaron Petruzzella,Marine Bruand,Albert Santamaria-Martínez,Natalya Katanayeva,Luc Reymond,Sarah Wehrle,Sandrine Georgeon,Damla Inel,Floris J. van Dalen,David Viertl,Kelvin Lau,Florence Pojer,Margret Schottelius,Vincent Zoete,Martijn Verdoes,Caroline Arber,Bruno E. Correia & Elisa Oricchio
Nature Chemical Biology Published:29 May 2024
DOI:https://doi.org/10.1038/s41589-024-01627-z
Abstract
Cysteine cathepsins are a family of proteases that are relevant therapeutic targets for the treatment of different cancers and other diseases. However, no clinically approved drugs for these proteins exist, as their systemic inhibition can induce deleterious side effects. To address this problem, we developed a modular antibody-based platform for targeted drug delivery by conjugating non-natural peptide inhibitors (NNPIs) to antibodies. NNPIs were functionalized with reactive warheads for covalent inhibition, optimized with deep saturation mutagenesis and conjugated to antibodies to enable cell-type-specific delivery. Our antibody–peptide inhibitor conjugates specifically blocked the activity of cathepsins in different cancer cells, as well as osteoclasts, and showed therapeutic efficacy in vitro and in vivo. Overall, our approach allows for the rapid design of selective cathepsin inhibitors and can be generalized to inhibit a broad class of proteases in cancer and other diseases.
