Discovery of mutation-independent cKit degrading bispecific antibodies that suppress tumor growth in preclinical models of GIST

Extracellular targeted protein degradation (eTPD) has emerged as a promising drug modality focused on the selective elimination of extracellular and transmembrane proteins. Unlike intracellular protein degraders, such as proteolysis targeting chimeras (PROTACs) and molecular glues, which rely on ubiquitin-proteasome pathways, extracellular degraders can harness a variety of internalizing receptors that can be tailored to specific targets and tumor types. EpiTACs are a novel type of extracellular targeted protein degrader (eTPD) defined as bispecific antibodies designed to bind a protein of interest (POI) with one arm and a degrading cell-surface receptor with the other. When the receptor is engaged, it carries the POI target into the cell, leading to selective degradation of the POI on receptor-expressing cells. EpiTACs combine favorable pharmacological and manufacturing properties of antibodies with the ability to engineer tissue specificity aiming to enhance efficacy while reducing off-target toxicity. To demonstrate the potential of this platform, we developed EpiTACs to the canonical receptor tyrosine kinase c-KIT. c-KIT is a critical driver of gastrointestinal stromal tumor (GIST) pathogenesis, with activating mutations representing the primary oncogenic event. Current kinase inhibitors are limited by the inevitable emergence of secondary resistance mutations. EpiTACs offer a compelling alternative by eliminating c-KIT itself, rather than merely inhibiting its activity, thereby overcoming mutation-dependent resistance and providing a potentially more durable therapeutic strategy. Importantly, c-KIT is also expressed on healthy cells, including hematopoietic stem cells (HSCs), highlighting the need for approaches that selectively target tumor cells while sparing normal tissue. We generated over 50 c-KIT-targeting EpiTACs spanning 10 degrading receptors expressed on GIST cells but absent from HSCs. These constructs were screened in tumor cell-based assays for c-KIT internalization and degradation. One such construct preserved degrading receptor expression, allowing for sustained catalytic degradation of the POI, which resulted in markedly reduced c-KIT levels and strong efficacy in vitro and in CDX and PDX mouse models. This EpiTAC demonstrates limited toxicity to HSCs, and could be used as a complementary approach as well as a front line combination opportunity with standard of care. In conclusion, eTPD of c-KIT using EpiTACs represents a promising new therapeutic modality and expands the toolbox of extracellular targeted degraders that can be applied in a target-, tissue-, and disease-specific manner.