Main Conference Day 1Monday, 15 December 2025 - PT (Pacific Time, GMT-08:00)

I will discuss SureTACs technology that we developed for targeted degradation of transmembrane proteins, utilizing heterobifunctional antibodies that mediate induced proximity of a transmembrane E3 ubiquitin ligase and the target. Upon tethering E3 to target, the target protein undergoes ubiquitination, endocytosis and lysosomal degradation. I will discuss how we identify optimal E3-target combinations and share proof-of-principle and in vivo efficacy data for PD-L1-targeting SureTACs.

ADCs and eTPD specifically depend on efficient lysosomal trafficking for activity. Here we leveraged the well-characterized low-density lipoprotein receptor (LDLR), and engineered bispecific LDLR-targeting chimeras (LIPTACs), for efficient degradation of extracellular membrane proteins. We further developed degrader–drug conjugates that intentionally hybridize eTPD with ADCs for greater efficiency of drug payload delivery. This platform broadens the therapeutic potential of antibody-based modalities.

Current extracellular targeted protein degradation (eTPD) strategies primarily rely on recycling receptors and lysosomal trafficking for internalization and degradation. Here, we developed bispecific antibodies that recruit membrane-bound proteases to proteins of interest, enabling their “degradation” them via enzymatic shedding. Additionally, the induced proteolysis releases soluble ligands that may influence downstream cellular processes. This approach provides a new mechanism of eTPD and broadens the scope of antibody-based therapeutics.

EpiTACs are bispecific antibodies in which one arm binds a pathogenic target, and the other arm leverage tissue-enriched degrading receptors to selectively degrade a wide range of extracellular targets including membrane, soluble, and multi-span proteins. EpiTACs to multiple oncology and autoimmune targets demonstrate that target degradation drives compelling in vivo activity. EpiTACs can also deliver ADC payloads creating novel therapeutics that combines target degradation with ADC cytotoxicity. The dual mechanism of EpiTAC ADCs leads to anti-tumor activity that outpaces current standard of care molecules.