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次世代型・多重特異性抗体医薬の高速エンジニアリングのための全工程自動化プラットフォームの確立

mAbs Journal
August 12, 2021

Norbert Furtmann1, Marion Schneider1, Nadja Spindler1, Bjoern Steinmann1, Ziyu Li1, Ingo Focken1, Joachim Meyer1,  Dilyana Dimova1, Katja Kroll1, Wulf Dirk Leuschner1, Audrey Debeaumont1, Magali Mathieu2, Christian Lange1, Werner Dittrich1, Jochen Kruip1, Thorsten Schmidt1, Joerg Birkenfeld1 | 1Sanofi-Aventis Deutschland GmbH | 2Sanofi Vitry sur Seine Cedex

日本語アブストラクト

次世代型抗体医薬として開発された多重特異性抗体は、一つの抗体分子が複数の標的に結合することで、単一の標的にのみ結合する従来型の抗体よりも高い薬効をもたらす。しかしながら高機能化された多重特異性抗体は収量の低さや物性の問題に直面することが多く、開発に時間を要する。そのため、創薬初期段階からハイスループットスクリーニングにより大量のバリアント分子の中から薬効、収量、物性の全てにおいて優れた候補を選抜することが重要である。今回、サノフィ社はGenedata Biologics®を用いて多重特異性抗体のデザイン・評価・選抜の全工程を強力にサポートするプラットフォームを構築した。このプラットフォームを用いて25,000以上の候補の中から、薬効が1000倍以上に向上し収量も良い二重特異性抗体のバリアントを短期間のうちに同定する事に成功し、有用性が確認された。 

Next-generation multi-specific antibody therapeutics (MSATs) are engineered to combine several functional activities into one molecule to provide higher efficacy compared to conventional, mono-specific antibody therapeutics. However, highly engineered MSATs frequently display poor yields and less favorable drug-like properties (DLPs), which can adversely affect their development. Systematic screening of a large panel of MSAT variants in very high throughput (HT) is thus critical to identify potent molecule candidates with good yield and DLPs early in the discovery process. Here we report on the establishment of a novel, format-agnostic platform process for the fast generation and multiparametric screening of tens of thousands of MSAT variants. To this end, we have introduced full automation across the entire value chain for MSAT engineering. Specifically, we have automated the in-silico design of very large MSAT panels such that it reflects precisely the wet-lab processes for MSAT DNA library generation. This includes mass saturation mutagenesis or bulk modular cloning technologies while, concomitantly, enabling library deconvolution approaches using HT Sanger DNA sequencing. These DNA workflows are tightly linked to fully automated downstream processes for compartmentalized mammalian cell transfection expression, and screening of multiple parameters. All sub-processes are seamlessly integrated with tailored workflow supporting bioinformatics. As described here, we used this platform to perform multifactor optimization of a next-generation bispecific, cross-over dual variable domain-Ig (CODV-Ig). Screening of more than 25,000 individual protein variants in mono- and bispecific format led to the identification of CODV-Ig variants with over 1,000-fold increased potency and significantly optimized production titers, demonstrating the power and versatility of the platform.

Genedata Biologics® was used to support all individual work steps along the MSAT engineering value chain.