# A cytokine receptor–targeting chimera toolbox for expanding extracellular targeted protein degradation

## TL;DR

Researchers expanded a toolbox for extracellular protein degradation using cytokine receptors to enable more specific and effective therapies.

## Contribution

The study expanded the kineTAC toolbox with 81 new chimeras targeting diverse cytokine receptors for cell-type-specific extracellular protein degradation.

## Key findings

- 55 out of 81 kineTACs expressed at suitable levels without optimization.
- Some kineTACs showed higher potency than the original CXCL12-based version against specific targets.
- kineTACs can enhance antibody drug conjugates by leveraging their internalizing capability.

## Abstract

The field of targeted protein degradation has been expanding rapidly into the extracellular space, providing several advantages over traditional inhibitors. Even with the emergence of new extracellular targeted protein degradation (eTPD) strategies seemingly every month, there is still a striking insufficiency in eTPD receptors that are expressed only in specific tissues. Here, we sought to address this problem by expanding our platform of cytokine receptor–targeting chimeras (kineTACs) to many other cytokine receptors, taking advantage of the natural tissue-restricted distribution of these receptors to achieve eTPD with therapeutic relevance, to deliver cytotoxic cargoes, and with cell type specificity. We anticipate that selective eTPD will greatly enhance therapeutic windows and reduce off-tissue adverse effects, allowing for an expansion of targetable antigens.

Extracellular targeted protein degradation (eTPD) is an important new modality for manipulating the extracellular proteome. However, most eTPD receptors are expressed broadly or are restricted to the liver, limiting specific degradation in other tissues. Cytokine receptor–targeting chimeras (kineTACs) are genetically encoded bispecifics for eTPD that fuse a natural ligand like CXCL12 to an antibody, directing soluble or membrane proteins for lysosomal degradation using the widely expressed chemokine receptor CXCR7 (K. Pance et al., Nat. Biotechnol.
41, 273–281 (2023)]. Here, we dramatically expand the kineTAC toolbox by constructing 81 different kineTACs based on an unbiased list of cytokines, chemokines, and growth factors. Remarkably, 55 of these expressed at suitable levels for analysis without any optimization. Many of these kineTACs bind receptors that have unique cell-type expression profiles, allowing for eTPD in specific cells and tissues, and some were more potent than the original CXCL12-based kineTAC against specific targets. We further show the internalizing capability of a kineTAC can enhance the performance of antibody drug conjugates. We believe these simple, genetically encoded tools will be useful for expanding the applications for optimized or cell type–selective eTPD.