Clinical-stage human anti-transferrin receptor antibodies suppress colorectal cancer metastasis

Abstract

Editor Advanced colorectal cancer (CRC) is a leading cause of cancer-related mortality worldwide, with distant metastasis and therapeutic resistance representing critical clinical hurdles. 1 Transferrin receptor (TFRC), a key iron transporter that is frequently over-expressed in tumors, plays a vital role in tumor progression and is correlated with poor prognosis. 2 While TFRC inhibition has been shown to suppress growth in various cancers, 3 its therapeutic effect on the CRC metastatic cascade remains unexplored. While the safety of PPMX-T003 (a clinical-stage, fully human anti-TFRC monoclonal antibody) has been con fi rmed in phase 1 trials for hematological conditions and a phase 1/2 trial is currently ongoing for aggressive natural killer-cell leukemia, 4,5 its ef fi cacy against solid tumors remains unknown. To our knowledge, this is the fi rst study to evaluate the ef fi cacy of PPMX-T003 against CRC, providing novel preclinical evidence that direct TFRC inhibition effectively suppresses both primary tumor growth and metastatic spread.Toinvestigate this, we evaluated the in vivo ef fi cacy of PPMX-T003 using a patient-derived xenograft (PDX) model of CRC liver metastasis. Immunohistochemical analysis demonstrated that TFRC was expressed in both the primary rectal tumor and the corresponding metastasized liver from a patient with CRC whose sample was used to establish the PDX. In addition, histological examination con fi rmed that the PDX tumors retained the morphological features of colorectal adenocarcinoma and closely recapitulated those of the original patient tumors. These fi ndings support the clinical relevance of our PDX model for evaluating the therapeutic ef fi cacy of PPMX-T003 against CRC liver metastasis. Following subcutaneous implantation, the established tumors were treated with PPMX-T003