Scaling function-first antibody discovery leveraging memory B cells

ABSTRACT Monoclonal antibody therapies represent a significant portion of blockbuster drugs, with their applications expected to expand dramatically in the coming decade. However, current antibody discovery methodologies often require trade-offs between performance and cost. Even state-of-the-art microfluidic approaches, despite their high capital costs, are limited in their ability to sample the full antibody repertoire. There is a critical need for advanced discovery tools that provide a comprehensive functional assessment of antibody performance during screening while remaining accessible to a wide range of users. Partillion Bioscience is addressing this need by developing workflows utilizing its specialized hydrogel microparticle reagent ("Nanovials") that enable ultra high-throughput sorting of single B cells and antibody- secreting cells (ASCs) based on secreted antibodies, using standard lab equipment and widely available flow cytometers. This Phase II proposal aims to significantly enhance antibody discovery workflows by increasing throughput by 10X. The proposed workflows will facilitate sophisticated functional antibody assays, such as binding to cell-surface-expressed targets and receptor activation assays, leveraging both ASCs and primary B cells. These innovations are expected to improve antibody discovery processes by expanding the antibody repertoire and reducing the occurrence of non-functional sequences, ultimately leading to more efficient and cost-effective therapeutic development. Specific aims include: (i) developing on-nanovial functional screening assays for binding to cell-surface- expressed targets and signaling pathway activation; (ii) discovering functional antibodies using a BCR-based two-cell assay; and (iii) benchmarking the antibody sequences discovered through these approaches against those recovered using standard hybridoma and BCR antigen baiting workflows. By making cutting-edge antibody discovery capabilities more accessible and cost-effective, this work has the potential to accelerate the development of therapeutic candidates and improve patient outcomes.