In this work, multispecific antibodies in a variety of formats are produced using intein-mediated protein splicing, thus enabling the high-throughput production of combinatorial libraries of complex antibody modalities. We show that conventionally produced and intein-spliced bispecific molecules exhibit indistinguishable biochemical and functional properties. Dual splicing reactions facilitate the generation of bivalent molecules, and building off the DuetMab platform enables the creation of trispecific formats with unexpected functional consequences.

Multispecific antibodies present unique engineering challenges driven by geometry, flexibility, and format diversity, often in data-limited settings. This talk describes practical and scalable structural modeling strategies to guide rational engineering multispecific antibodies across different formats. Automated workflows for structure modeling and conformational sampling are used to analyze avidity, binding geometry, and surface properties, enabling design decisions that improve functional performance while addressing developability considerations early in discovery. 

Despite rapid advances in AI-based protein design, predicting the function of multispecific antibodies remains a major challenge. This presentation will describe Aureka's closed-loop discovery platform, integrating AI-guided design with high-throughput single-cell functional screening to generate rich biological datasets that continuously improve predictive models. By learning the design principles underlying functional activity rather than binding alone, this approach aims to accelerate the discovery of best-in-class multispecific therapeutics.

We present an integrated nanobody discovery and engineering platform that combines serum proteomics, repertoire sequencing, AI-enabled structure prediction, and modular multivalent design. The workflow rapidly identifies high-affinity binders, maps complementary epitopes, and assembles compact multispecific biologics with exceptional potency, breadth, and developability. Using Staphylococcus aureus toxins as a model, we demonstrate how this platform can generate scalable countermeasures against antigenic diversity and support rapid translation across infectious disease and oncology.

Interleukin-10 possesses unique immunomodulatory activities with significant therapeutic potential, yet its clinical application has historically been limited by systemic toxicity and an unfavorable therapeutic window. This presentation will describe an engineered IL-10 mutant platform combined with antibody-directed delivery to selectively activate IL-10 biology at disease sites, illustrated by the PD-1×IL-10M immunocytokine FP008 for oncology and the TL1A×IL-10MM fusion protein FP012 for inflammatory diseases, highlighting a general strategy for designing safer and more effective multispecifics.

Next-generation bispecific ADCs overcome tumor heterogeneity and resistance by targeting dual antigens to accelerate endocytosis and combining dual-mechanism payloads. Utilizing OBI’s GlycOBIDUO site-specific conjugation and hydrophilic HYPrOBI linkers, the platform enables High DAR delivery without aggregation. Ultimately, enhanced linker stability minimizes off-target toxicity and expands the therapeutic window, offering a breakthrough for low-antigen-expressing tumors.