Abstract Transferrin receptor1 (TfR1) is a type II transmembrane glycoprotein that involves intracellular uptake of iron. TfR1 is ubiquitously expressed at low levels in normal cells except erythroblasts and placental trophoblasts, which express high levels of TfR1 due to the need of up taking a large amount of iron. Accumulating studies have shown elevated levels of TfR1 in both solid tumor cells, as well as hematologic malignant cells when compared to their normal counterparts. Since TfR1 is implicated in growth and survival in various cancer cells, targeting TfR1 could be attractive strategy for cancer therapeutics. To this end, we have developed a fully human antibody against TfR1, PPMX-T003, which displayed potent anti-tumor activity in vitro and in vivo. PPMX-T003 induced apoptosis or cell cycle arrest with EC50s of 3~200ng/ml in various tumor cell lines. Mechanistically, PPMX-T003 triggers apoptosis or cell growth arrest by inhibiting binding of TfR1 to its ligand transferrin and blocking iron uptake. In addition, PPMX-T003 elicits antibody dependent cellular cytotoxicity (ADCC) activity in cancer cells. Importantly, PPMX-T003 showed potent efficacy against several blood cancer xenograft models. PPMX-T003 completely eradicated established subcutaneous tumors in two acute myeloid leukemia (AML) models generated by Kasumi-1 and HL-60, at a dose of 10 mg/kg when administrated (I.V.) once a week for 4 weeks. Moreover, PPMX-T003 completely eradicated established tumors in a lymphoma xenograft model (SU-DHL-2) at a dose of 3 mg/kg. Furthermore, PPMX-T003 greatly prolonged mice survival in a disseminated leukemia model (CCRF-CEM: acute lymphoblastic leukemia cell line). The control mice engrafted with CCRF-CEM cells (n=10) developed leukemia and died within 42 days, whereas 8 of the 10 mice treated with PPMX-T003 survived 179 days until the experiment was terminated. A preliminary toxicology study in Cynomolgus monkeys with multiple doses was also carried out. Although moderate anemia was observed at the dose of 30 mg/kg, no other abnormalities were observed, indicating a tolerable safety profile. Taken together, these results indicate that PPMX-T003 could be a potent therapeutic antibody for the treatment of hematologic malignancies. Citation Format: Lilin Zhang, Fumiko Nomura, Yoichi Aikawa, Yoshikazu Kurosawa, Kazuhiro Morishita, Yukio Sudo. PPMX-T003, a fully human anti-TfR1 antibody with potent efficacy against hematologic malignancies [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 5586. doi:10.1158/1538-7445.AM2017-5586