The extracellular proteome plays central roles in health and disease. Harnessing TfR1, a constitutive, rapidly internalizing receptor, we developed Transferrin Receptor Targeting Chimeras (TransTACs) for targeted degradation of membrane and extracellular proteins. In two applications, TransTACs enabled the targeting of drug-resistant EGFR-driven lung cancer and reversible control of CAR-T cells. TransTACs represent a promising new family of bifunctional antibodies for precise manipulation of extracellular proteins and for targeted cancer therapy.

Utilizing the ability of antibodies as delivery vehicles has resulted in a therapeutic modality known as antibody-drug conjugates or ADCs. As the field advances, new opportunities for antibody-mediated delivery are being explored. This talk will focus on our efforts to link chimeric protein degraders (aka PROTACs) to antibodies, their efficacy and safety, and how this general approach can expand the utility of directed protein degradation as both a biological tool and a therapeutic possibility.

Degrader antibody conjugates (DACs) combine the unique strengths of ADCs with selective protein degraders. Our state-of-the-art platform enables DACs broadly. Degraders with different mechanisms of action and diverse structures can be delivered in antigen-dependent manner opening exciting opportunities for this novel therapeutic modality.

Elimination of extracellular proteins is a compelling therapeutic modality. EpiTACs are bispecific antibodies in which one arm binds a target and the other arm leverages an EpiAtlas of tissue-enriched degrading receptors comprised of transmembrane ligases, cytokine/chemokine receptors, and internalizing receptors resulting in selective degradation of membrane and soluble proteins. EpiTACs elicit robust in-vitro and in-vivo activity in a target-, tissue- and disease-specific manner for a broad range of indications. Compelling data across multiple targets demonstrates that EpiTACs can degrade a target independent of mutational status, are better than neutralizing antibodies in preclinical models, and drive a survival benefit in preclinical tumor models.

Single domain antibodies (sdAbs) are about one-tenth the size of standard antibodies and have several advantages for therapeutic development. We have generated numerous sdAbs from llamas immunized with tau or α-synuclein proteins. The presentation will highlight our key findings to date and ongoing studies.

The Lysosome Targeting Chimera (LYTAC) is a targeted protein degradation modality that utilizes receptor-mediated endocytosis to drive internalization and lysosome-mediated degradation of extracellular target proteins. In this presentation, we will disclose application of Lycia’s platform to design and generate small molecule conjugate and fully biologic LYTACs that promote strong in vitro and in vivo depletion of protein targets of interest.