VLRB antibodies: advances in screening, molecular engineering, and application

Variable lymphocyte receptor B (VLRB) antibodies from jawless vertebrates represent a structurally distinct and highly versatile class of adaptive immune receptors. Unlike conventional immunoglobulins, VLRBs achieve antigen specificity through leucine-rich repeat (LRR) modules and form multimeric assemblies that enhance binding avidity. These features have sparked growing interest in their biomedical and biotechnological applications. This review outlines recent advances in VLRB antibody discovery and selection, with a focus on high-throughput screening platforms such as yeast surface display, phage display, and long-read sequencing. We then explore the unique glycan-binding capabilities of VLRBs and their emerging utility in glycomics research and glycan-targeted probe development. Next, we discuss engineering strategies-including Fc fusion, multimerization, and rational design-to enhance stability, affinity, and expression. Building on their inherent multivalency, VLRBs have been employed to boost vaccine immunogenicity through antigen multimerization. In disease diagnostics, VLRBs have shown high specificity toward tumor-associated carbohydrate antigens, as well as glycosylated microbial epitopes, enabling precise detection of cancer and infectious agents. Finally, we examine their application in targeted drug delivery, particularly across the blood-brain barrier and into tumor microenvironments. Together, these developments position VLRBs as promising next-generation tools for diagnostics, therapeutics, and biomolecular engineering.