Mitigation of Anti‐Drug Antibody Production for Augmenting Anticancer Efficacy of Therapeutic Protein via Co‐Injection of Nano‐Rapamycin

Abstract The induction of anti‐drug antibody (ADA) is a formidable challenge for protein‐based therapy. Trichosanthin (TCS) as a class of ribosome‐inactivating proteins is widely studied in tumor treatment. However, the immunogenicity can induce the formation of ADA, which can cause hypersensitivity reactions and neutralize the efficacy of TCS, thus limiting its clinical application in cancer therapy. Here, a promising solution to this issue is presented by co‐administration of the rapamycin nanoparticles and TCS. PEGylated rapamycin amphiphilic molecule is designed and synthesized as a prodrug and a delivery carrier, which can self‐assemble into a nanoparticle system with encapsulation of free rapamycin, a hydrophobic drug. It is found that co‐injection of the PEGylated rapamycin nanoparticles and TCS could mitigate the formation of anti‐TCS antibody via inducing durable immunological tolerance. Importantly, the combination of TCS and the rapamycin nanoparticles has an enhanced effect on inhibit the growth of breast cancer. This work provides a promising approach for protein toxin‐based anticancer therapy and for promoting the clinical translation.