Main Conference Day 2Tuesday, 16 December 2025 - PT (Pacific Time, GMT-08:00)

We have commenced efforts to engineer knottins and cyclins as general-purpose binders for a variety of applications where their rugged durability would be enabling (e.g. oral delivery, cytoplasmic delivery, radioligand therapy). Occupying a parameter space intermediate between antibodies and small molecule drugs, these molecules present new challenges and opportunities for protein engineering.

We have discovered and characterized the first-ever Nanobodies that act as positive allosteric modulators (PAMs) of clinically relevant inhibitory immune checkpoint complexes (ICCs) that enhance receptor signaling with pathway-specific and spatio-temporal precision. Such ICC PAMs open up novel therapeutic modes of intervention that ensure patient safety, even in cases of overdose, and may outperform current inhibitor-based immunotherapies, which often cause significant side effects.

Immunogenicity is a major challenge in biologic drug development, compromising efficacy and safety. Our ADAx platform selectively suppresses B cell activation against therapeutics while preserving normal immune function and drug activity. It enables strong ADA suppression and improved pharmacokinetics in vivo, offering a versatile solution across protein and antibody formats.

Melanocortin receptor 4 (MC4R), a class A GPCR, suppresses appetite upon activation, but current peptide agonists lack receptor selectivity. Using Confo technology, we stabilized active-state MC4R with a conformation-selective ConfoBody to discover potent, MC4R-specific VHH agonists. We identified the most potent VHH and resolved its structure bound to the orthosteric pocket. This highly specific VHH offers a promising candidate for selective anti-obesity therapy via MC4R activation.