Abstract Recent advances in antibody discovery technologies have profoundly reshaped in vitro diagnostics (IVD). Over the past century, diagnostic antibody development has evolved from serum‐derived polyclonal and hybridoma‐derived monoclonal antibodies to phage display, single‐B‐cell screening, reverse sequencing, and now AI‐assisted design, firmly establishing antibodies as indispensable components of modern IVD systems. Yet as antibody generation grows increasingly scalable, reproducible, and standardized, conventional metrics like affinity and specificity can no longer fully account for assay‐level diagnostic performance, widening the critical gap between binder acquisition and assay‐ready functionality. This review reveals a clear paradigm shift in diagnostic antibody research: from discovery‐centered strategies to assay‐aware, design‐oriented engineering. We organize current progress around four core themes: inherent tradeoffs among major discovery routes; context‐dependent affinity interpretation; key advances in functional antibody engineering; and AI's emerging role linking sequence optimization with structure, developability, and assay translation. A consistent trend emerges: diagnostic antibodies are evolving from passive molecular recognition reagents into engineered, structurally programmable, system‐integrated analytical units. Future IVD advances will thus depend not only on improved molecular recognition, but also on rational design of antibody behavior within complex diagnostic systems.
Song et al. (Tue,) studied this question.
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