Natriuretic peptide receptor 1 targeting chimeras for cardiovascular selective degradation of extracellular proteins
L Dai, K Y Zhang, H J WangAbstract
Aims
Targeted protein degradation, particularly extracellular TPD (eTPD), represents a promising therapeutic strategy for traditionally undruggable targets. However, its application in cardiovascular disease remains limited. This study aimed to develop CardioTAC, a novel heart-targeting bispecific antibody platform using Natriuretic Peptide Receptor 1 (NPR1) to degrade extracellular proteins in myocardial tissue.
Methods and Results
Combining Human Protein Atlas database with multi-organ immunofluorescence staining, we observed that NPR1 is highly expressed in cardiac tissue. Screening with EVOLVEpro directed evolution technology, we designed NPR1 Targeting Chimeras (CardioTAC), a heterobispecific antibody modality for disease-relevant targets depletion through NPR1-dependent lysosomal in cardiomyocytes. Biological experiments demonstrate that CardioTAC can achieve high degradation efficacy for three extracellular soluble proteins (S100 calcium-binding protein A8/A9, growth differentiation factor-15, and human epididymis protein 4) in myocardial infarction and ischemia/reperfusion mice models, which highlighting the generalizability and modularity of our approach. Multi-organ immunohistochemistry and cardiac proteomics demonstrated the specific targeted degradation of CardioTAC in cardiac tissue. Comprehensive assessment of hepatic/renal function parameters and multi-organ histopathology demonstrated an excellent safety profile for CardioTAC. Integrated spatial transcriptomic and proteomic analyses indicate that CardioTAC ameliorates cardiomyocyte injury, reduces fibrosis, and attenuates infiltration of inflammatory cells in cardiac tissue.
Conclusion
Our findings establish CardioTAC as a novel and versatile eTPD platform technology. By harnessing the internalization function of NPR1, CardioTAC enables the efficient degradation of specific extracellular targets, offering a powerful new approach for modulating pathogenic factors in cardiovascular diseases.Graphical abstract