End-To-End Automated Intact Protein Mass Spectrometry for High-Throughput Screening and Characterization of Bispecific and Multispecific Antibodies

化学 质谱法 双特异性抗体 表征(材料科学) 吞吐量 抗体 色谱法 单克隆抗体 纳米技术 免疫学 计算机科学 电信 生物 材料科学 无线
作者
Ben Niu,Benjamin C. Lee,Wen Chen,Cristian Alberto,Karen Betancourt Moreira,Philip D. Compton,Kristoff T. Homan,Jason Pinckney,Yaxing Zhu,Michelle C. Vendel,Karl M. Wetterhorn,Shana C. Walrond,Esrath Santha,Amanda Horowitz,Nicole Zaubi,Jeffrey D. Johnson
出处
期刊:Analytical Chemistry [American Chemical Society]
标识
DOI:10.1021/acs.analchem.4c04833
摘要

Bispecific antibodies (bsAbs) and multispecific antibodies (msAbs) represent a promising frontier in therapeutic antibody development, offering unique capabilities not achievable with traditional monoclonal antibodies. Despite their potential, significant challenges remain due to their increased molecular complexity. One prominent challenge is the correct assembly of light and heavy chains, as improper pairing leads to mispaired or incompletely assembled species that lack therapeutic efficacy and possess undesired properties, impairing the developability, manufacturability, and safety. There is a critical need for rapid, sensitive analytical tools to monitor and control these undesired species and ensure the quality assessment of bsAbs and msAbs. To address this need, we present a novel high-throughput, format-agnostic intact mass workflow that significantly enhances the efficiency of detecting and quantifying biotherapeutic products and related impurities. This workflow integrates automated sample preparation, novel high-resolution rapid mass detection powered by SampleStream-MS, and an advanced data analysis pipeline. It offers increased throughput and data quality while substantially reducing analysis turnover time and labor. This was demonstrated in a pilot program where ∼800 multispecific antibodies were processed in 10 working days. The article details the evaluation and validation of our method, demonstrating its repeatability and intermediate precision in terms of measurement accuracy and relative quantification of various product-related species. We underscore the transformative potential of this end-to-end high-throughput workflow in expediting bispecific and multispecific antibody discovery, optimizing production processes, and ensuring high-quality development and manufacturing for therapeutic antibodies.
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