Transcriptome comparison of monocytes, activated CD4 T cells, and activated CD8 T cells in healthy human peripheral blood

Molecular tether-mediated extracellular targeted protein degradation (ePTD) emerges as a promising drug modality. The existing strategies for ePTD have exploited several membrane degrader proteins. However, the current panel of ePTD degraders clearly needs to be expanded, as a given degrader may present tissue-dependent expression and activity. Based on screening of >50 receptors on endocytic rates and on their tissue distribution, we established a resource of potential endocytic carriers that may mediate effective ePTD. We subsequently introduced an adaptable design to assemble “Selected endocytic carrier-targeting chimera (SecTAC)” based on bispecific antibody constructs. The resultant modular chimeras, by co-opting newly identified degraders, directed efficient internalization of extracellular protein cargoes (or nucleic acids). Importantly, shaped by the availability of the corresponding endocytic carrier, the output of a SecTAC could present cell subset selectivity. We also validated the therapeutic potential of SecTAC agents for targeting several cell membrane proteins in tumor cells and primary T cells. Furthermore, we adapted the platform to establish multi-cargo tethers that triggered simultaneous degradation of two cell surface proteins in primary T cells. Taken together, our SecTAC platform has laid the foundation for development of preclinical drug candidates capable of inducing extracellular and membrane target degradation in desirable population of cells.