Triggering apoptosis of tumor cells has been in focus of cancer‐inspired research since decades. As clustering of death receptor 5 (DR5), which is overexpressed on various cancer cells, leads to formation of the death‐inducing signaling cascade (DISC), DR5 has recently become a promising target for tumor treatment. Herein, we demonstrate that covalent multimerization of a death receptor targeting peptide (DR5TP) on a dextran scaffold generates potent apoptosis‐inducing conjugates (EC50=2–20 nm). A higher conformational flexibility compared to reported DR5TP multimerization approaches, introduced by the polysaccharide framework compensates the reported need for the defined ligand orientation that was considered as essential prerequisite for effective receptor clustering and apoptosis induction. Enzyme‐catalyzed ligation of a hydrophilic dextran conjugate bearing multiple DR5‐targeting sites to a human fragment crystallizable (Fc) receptor did not affect the potency (EC50=2–7 nm), providing an option for improved in vivo half‐life and prospective conjugation to an antibody of interest in view of bispecific tumor targeting.

No abstract