Abstract 377: Evaluating delivery of TFR1-targeting therapies to the CNS in a novel humanized TFR1 mouse model

Abstract Transferrin receptor protein 1 (TFR1), also known as CD71, is a cell surface receptor that plays a major role in cellular iron uptake via receptor-mediated endocytosis. In mammalian species, this receptor is required for erythropoiesis and neural development. The efficient cellular uptake properties of TFR1 have been exploited for site-specific delivery of anti-cancer drugs and biologics, as well as targeted delivery of therapeutic genes to malignant cells overexpressing TFR1. Such delivery is achieved by several methods, including chemical conjugation of transferrin with therapeutic agents, genetic fusion of transferrin with peptides, and anti-TFR1 antibodies. Delivery of therapeutics cross the blood-brain barrier to the central nervous system (CNS) is also greatly facilitated by targeting the TFR1. At Biocytogen, we have successfully generated a humanized B-hTFR1 mouse model for evaluating TFR1-targeted therapeutics in preclinical studies. In this model, the exons 4-19 of mouse Tfr1 gene that encode the extracellular domain of the receptor were replaced by its human counterparts. As the result of this engineering, the ectodomain of the TFR1 is humanized while intracellular domain remains unchanged, maintaining the receptor’s signaling function in mice. Surface staining of erythroid cells from B-hTFR1 mice showed high levels of expression of humanized TFR1. In addition, we were able to detect anti-human TFR1 bispecific antibodies in brain tissues of the B-hTFR1 mouse after intravenous administration of the antibodies, suggesting a robust uptake of the antibodies via the hTFR1 receptor. These results indicate that the B-hTFR1 mouse model is a powerful preclinical tool to evaluate the delivery of therapeutics to the CNS in vivo. Citation Format: Chang Liu, Chengzhang Shang, Limei Ma, Xiaofei Zhou, Chaoshe Guo. Evaluating delivery of TFR1-targeting therapies to the CNS in a novel humanized TFR1 mouse model [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 377.