ArticleThe AAPS journal2025
Implementing Synthetic Multi-Transmembrane Receptor Protein in a Duplex Immunoassay for Assessment of Neutralizing Antibody to a Bispecific Biotherapeutic.
Article in The AAPS journal, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Not yet cited in PubMed.
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Abstract
The development of multi-specific biotherapeutics has revolutionized targeted therapy by simultaneously engaging multiple receptors or pathways, thereby enhancing therapeutic efficacy and specificity. However, evaluating the immunogenic potential of these complex molecules remains a significant challenge, particularly in the reliable detection of neutralizing antibodies (NAbs). To support the development of a bispecific biotherapeutic, we initially established a cell-based bioassay utilizing a cytotoxicity assay platform for NAb assessment. This traditional approach faced significant limitations due to severely limited drug tolerance which prevented accurate NAb classification. To address this hurdle, we developed a non-cell based competitive ligand binding (CLB) assay. The primary obstacle was the multi-transmembrane receptor target, which lacks a soluble form suitable for conventional immunoassays. We successfully addressed this challenge by leveraging a novel synthetic version of the multi-transmembrane receptor as the surrogate target. This enabled the development of a duplex competitive ligand binding assay utilizing a homogeneous bead-based AlphaLISA™ assay platform. This innovative duplex NAb assay significantly increased drug tolerance by at least 170-fold when compared to the cell-based assay, enabling sensitive and specific detection of NAb against each drug target binding domain. The AlphaLISA™ based CLB NAb exhibited negligible matrix interference and generated excellent intra-assay and inter-assay precision, with data concordant across different reagent lots and plate readers. Our results demonstrate that the AlphaLISA™ assay platform offers a robust, sensitive, and drug-tolerant alternative to traditional cell-based NAb assays. This approach provides a superior solution for assessment of NAb against multi-specific biotherapeutics targeting multi-transmembrane receptors.
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