Single-domain antibodies (sdAbs) are compact, stable, single-chain biologics increasingly used in diagnostics, radio-immunoconjugates, and multispecifics. As a newer therapeutic format, the developability rules for sdAb containing Biologics are still emerging. We share lessons from the comprehensive biophysical profiling of >30 clinical-stage sdAbs in the VHH-Fc and VHH formats, spanning developability and manufacturability metrics, alongside preliminary in vivo PK results.

Enteric diseases are common human ailments. However, conventional biologics are not suited for enteric applications due to their susceptibility to degradation in the protease-rich hostile environment of the GI tract. Using click display, which directly links the protein library to the coding cDNA, and a language model to access "naturalness," we report the engineering of protein-stable DARPins for potent neutralization of C. difficile toxin TcdB as oral therapeutic candidates.

The modest ability of antibodies to penetrate the blood-brain barrier severely limits their use in therapeutic applications. We are developing antibody shuttles that target CNS proteins to mediate enhanced and selective CNS targeting and, in some cases, long-lived CNS retention. Here we will discuss our recent progress in engineering next-generation transferrin receptor and CD98hc-targeted CNS shuttles, as well as their application for delivering proteins and nucleic acids for therapeutic applications.

The blood-brain barrier presents a major obstacle to brain drug delivery. We have developed an enabling platform for the identification of blood-brain barrier targeting antibody-like molecules known as Variable Lymphocyte Receptors (VLRs). These VLRs could ultimately be used to ferry drug cargo into the brain. Here we will describe our recent efforts to identify and validate such blood-brain barrier targeting VLRs.

Targeting blood–brain barrier receptors enables brain delivery of biologics. We engineered an Fc-based dual transport vehicle (TV) that targets transferrin receptor (TfR) and CD98hc, combining rapid TfR-driven uptake with CD98hc-mediated retention. Dual TVs achieve higher brain concentrations than single-receptor formats. Adjusting TfR/CD98hc affinities tunes exposure kinetics and biodistribution. A mechanistic model links architectural designs to brain PK, guiding optimization of brain-penetrant biologics.

• Receptor selection & biology: What’s the most translatable biology across species?
• From uptake to pharmacology: Optimizing manufacturable LM brain-delivery architectures to achieve the right exposure, engagement, and efficacy 
• Moving beyond brain "uptake:" Taking a granular look at where the drug goes and how long it stays
• Emerging strategies to optimize CNS targeting and exposure: Next gen payloads and dual targeting​

• Why internalization varies across binders to the same antigen: epitope, receptor trafficking, avidity/format, and how to screen for “productive” uptake (vs surface binding only)
• Selection strategies for internalizing antibodies: functional display/selection concepts (e.g., uptake-coupled screens) and how they compare to conventional affinity-first discovery
• Assays and metrics that predict downstream performance: internalization kinetics, lysosomal routing vs recycling, payload delivery readouts, and what correlates best with in vivo activity
• Developability-by-design: how to incorporate stability, expression, aggregation, and sequence liabilities early so internalizing hits translate into drug-like leads
• Applications beyond ADCs: targeted protein downregulation, extracellular targeted protein degradation, and cargo delivery—what properties matter for each modality​

Accurately predicting developability characteristics is a pivotal yet challenging task in antibody therapeutic development. To overcome the limitations of small training datasets, we designed and implemented an integrative antibody feature engineering and machine learning framework called PROPERMAB. Using this framework, we developed predictive models for antibody hydrophobic interaction chromatography retention time and high-concentration viscosity. We also demonstrate the potential to scale our approach to repertoire-scale sequence datasets.

AbBiBench is a novel AI benchmarking framework designed to improve antibody binding affinity maturation by evaluating the entire antibody-antigen (Ab-Ag) complex as a single functional unit. By curating over 216,500 experimental measurements across diverse antigens like influenza and SARS-CoV-2, we created a rigorous system to assess 18 different computational models. The findings reveal that global structure-conditioned inverse folding models significantly outperform sequence-only or local-structure methods in predicting binding potential. Furthermore, the authors validated their pipeline through in vitro ELISA assays, successfully identifying new antibody variants with enhanced binding to the H1N1 influenza virus. Ultimately, AbBiBench provides a standardized, zero-leakage environment to guide the development of next-generation machine learning workflows for therapeutic antibody discovery.

Cytokines are vital for anti-tumor immunity but face several limitations as therapeutic molecules, including pleiotropic activity, poor stability and half-life, and dose-limiting toxicity. Different engineering approaches to modify the cytokine or turning to alternative formats such as antibody mimetics exist to address these limitations. In this talk, we describe engineering approaches undertaken to develop cytokine Fc fusion and mimetics for IL-27 agonism.

Internalizing antibodies underpin multiple targeted therapeutic modalities, including receptor-downregulating antagonists, antibody-drug conjugates (ADCs), extracellular targeted protein degraders (eTPDs), and targeted cargo delivery systems. Yet most antibody discovery platforms optimize binding rather than the ability to induce rapid, productive endocytosis, which is governed by epitope, binding geometry, and downstream trafficking. We present a lentiviral selection platform that couples receptor-mediated endocytosis to a genetic readout, enabling direct enrichment of internalizing, developable antibodies.

Voltage-gated sodium channels initiate action potentials in neurons and muscle. Dysfunction of these channels leads to sustained sodium influx that underlies various human diseases including cardiac arrhythmias and epilepsy. We used de novo protein design to engineer a peptide modulator that restores the proper function of these ion channels. These studies demonstrate the therapeutic potential of rationally designed biologic agents for correcting ion-channel dysfunction across cardiac and neurological disease settings.

G protein-coupled receptors (GPCRs) are among the most successful therapeutic targets, but their pharmacological landscape is dominated by small molecules. Antibodies have the potential to target GPCRs with enhanced specificity and differing pharmacokinetic properties, but few antibodies modulate GPCR function. We developed several strategies to discover functionally active, GPCR-targeting, synthetic antibody fragments. These antibodies exhibit rich and readily evolvable pharmacology, attesting to their potential as next-generation GPCR therapeutics.