ROTACs for transmembrane protein degradation; plus AntlerA’s lung regeneration therapy and more

German Cancer Research Center (DKFZ) scientists developed bispecific R-spondin chimeras, dubbed ROTACs, which use domains from secreted R-spondin proteins to engage the membrane-localized E3 ligases ZNRF3 and RNF43 for targeted lysosomal degradation of transmembrane proteins. The authors of the Cell Chemical Biology article developed a ROTAC that linked signaling-disabled domains of the R-spondin protein RSPO2 to a PD-L1-targeting domain, and showed it induced between 50-90% PD-L1 protein degradation and suppressed tumor cell growth in three melanoma cell lines.

The authors distinguished their strategy from AbTAC and PROTAB approaches, which also use bispecific proteins to degrade transmembrane targets via ZNRF3 and RNF43 ligases, by ROTACs’ use of natural R-spondin-derived, high-affinity ligase-binding domains. In March, Epibiologics Inc. emerged from stealth with a $50 million to develop AbTACs and KineTACs, another lysosomal protein degradation technology...