Targeting emerging viruses with phage display-driven engineered antibodies: Bridging molecular design and clinical application

ABSTRACT

Phage display (PD) is a powerful platform that accelerates the discovery and engineering of therapeutic antibodies across diverse diseases, including emerging and re-emerging viral infections. The COVID-19 pandemic highlighted the urgency for rapid and adaptable antibody development against highly mutable pathogens, including severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). PD technology enables the rapid and high-throughput identification, optimization, and efficient reformatting of virus-neutralizing antibodies, yielding fully PD-derived antibodies and reformatted derivatives from PD fragments without requiring convalescent samples or animal immunization. This approach supports a proactive and scalable strategy for pandemic preparedness. This review provides a comprehensive overview of PD-derived therapeutic antibodies targeting infectious diseases, focusing on approved agents and candidates in clinical or preclinical development for SARS-CoV-2. We highlight recent case studies, including our own, showing the successful application of PD in generating potent neutralizing and multispecific antibody formats. These offer functional advantages such as enhanced breadth and affinity while also serving as versatile molecular tools for elucidating viral pathogenesis and immune evasion mechanisms. Despite PD's technological strengths, the clinical advancement of PD-derived candidates has been influenced by external circumstances associated with the evolving pandemic landscape, highlighting the need to strategically leverage PD's strengths to accelerate translational outcomes in future outbreaks. This review offers a well-rounded viewpoint on PD, outlining its applications, addressing its challenges, and incorporating emerging innovations into PD workflows. These advances position PD-derived candidates as a strategic, versatile, and rapid-response platform that bridges molecular insights with clinical translation, offering a robust framework for addressing current and future infectious disease challenges.