We developed a robust peptide therapeutics discovery platform based on ~500 venom peptide scaffolds, integrating phage and yeast surface display technologies. Libraries were designed using machine-learning (ML) models that predict key residues for peptide foldability. An ML-enabled, rapid, and cost-effective affinity maturation workflow accelerates lead optimization, enabling the efficient identification of potent and stable peptide candidates against diverse therapeutic targets.

Peptide-HLA (pHLA)-directed T cell engagers can target otherwise inaccessible intracellular viral and tumor-associated antigens, but require both high affinity and high specificity for safe and effective clinical use. We present an integrated high-throughput yeast-based platform to rapidly discover, engineer, and de-risk fully human soluble T cell receptors (TCRs) and TCR-mimetic (TCRm) antibodies with high affinity and high selectivity, enabling the development of potent and specific pHLA-targeting therapeutics.

Peripherally administered enzyme replacement therapies (ERTs) to address lysosomal storage disorders have been limited in their ability to target the CNS. Such ERTs are also limited by their instability in serum. To generate enzymes with sustained activity in serum, we developed a novel enzyme engineering strategy utilizing both yeast surface display and secretion technologies. We show durable activity with a POC enzyme in serum for many days. By fusing engineered enzymes to a TfR transport vehicle (TV) for delivery across the BBB, we also show improved substrate reduction in the brains of a relevant mouse disease model.

Bispecific proteins empower immune engagement, logical targeting, and pharmacokinetic modulation. Yet multi-domain antibody bispecifics require challenging engineering and limit delivery. We address this limitation by engineering a β-sheet in single-domain VHH antibodies as a second binding site. Dual-binding VHHs were engineered to multiple targets within multiple parental antibodies. Modularity is evidenced by grafting engineered β-sheets into other VHH, scFv, or IgG and incorporating a dual-binding VHH into a CAR.