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2025.12.25.
At the 2024 American Society of Clinical Oncology (ASCO) Annual Meeting, preliminary clinical data from a phase I/II study of JST-TFR09, a fully human monoclonal antibody targeting transferrin receptor 1 (TFR1), was presented. The antibody showed a manageable safety profile and preliminary anti-tumor activity in patients with relapsed/refractory acute myeloid leukemia (AML) and diffuse large B-cell lymphoma (DLBCL), achieving an objective response rate (ORR) of 35%.
As a key molecular link between cellular metabolism and proliferation, let's explore the TFR1 target.
What is TFR1?
Transferrin receptor 1 (TFR1 or CD71), encoded by the TFRCgene, is a 90 kDa type II transmembrane glycoprotein. It serves as the primary receptor for cellular iron uptake, playing a central role in regulating iron metabolism and maintaining iron homeostasis. Each monomer consists of 760 amino acids with a C-terminal extracellular domain, a transmembrane region, and an N-terminal intracellular domain. The extracellular domain binds iron-carrying transferrin (TF). Functional TFR1 exists as a homodimer on the cell membrane, linked by disulfide bonds.
A marker of ferroptosis, TFR1 is highly expressed on rapidly proliferating cells (e.g., hematopoietic, epithelial) and is frequently upregulated in many malignancies. After binding iron-loaded TF, the complex undergoes clathrin-mediated endocytosis. Within acidic endosomes, iron is released and transported into the cytosol via the divalent metal transporter (DMT1) to support critical processes like DNA synthesis and energy metabolism, fueling rapid cell growth.
Image Source: Antibodies Targeting the Transferrin Receptor 1 (TfR1) as Direct Anti-cancer Agents
I. TFR1 in Cancer: A Dual Driver of Malignant Proliferation and Immune Evasion
Due to their high iron dependency, fast-growing cancer cells often overexpress TFR1. Elevated TFR1 levels correlate with poor prognosis in various solid tumors (e.g., esophageal squamous cell carcinoma, breast cancer, ovarian cancer) and hematological malignancies. Its pro-tumor mechanisms are twofold:
1. Metabolic Reprogramming & Proliferative Signaling: Oncogenes (e.g., c-MYC) and hypoxic microenvironments directly enhance TFRCgene transcription. Iron, as a cofactor for ribonucleotide reductase M2 (RRM2), drives deoxyribonucleotide synthesis. It also activates MAPK/ERK and PI3K/AKT pathways to promote cell cycle progression. While iron-dependent Fenton reactions generate reactive oxygen species (ROS), cancer cells counteract ferroptosis by upregulating glutathione peroxidase 4 (GPX4) and the cystine/glutamate antiporter (System Xc-).
2. Metabolic Competition in the Immune Microenvironment: Tumor cells overexpressing TFR1 scavenge iron, creating a relative iron deficiency in the microenvironment. Activated T cells also rely on TFR1 for iron to support clonal expansion. This metabolic competition leads to intracellular iron insufficiency in T cells, impairing mitochondrial function and the production of key cytokines like interleukin-2 (IL-2), ultimately promoting T cell exhaustion and facilitating tumor immune escape. TFR1-targeting monoclonal antibodies (e.g., JST-TFR09) bind specifically to TFR1 on tumor cells via their Fab region. Their Fc domain can then recruit and activate natural killer (NK) cells and macrophages, triggering potent antibody-dependent cellular cytotoxicity (ADCC) and phagocytosis (ADCP) to eliminate cancer cells.
Image Source: Antibodies Targeting the Transferrin Receptor 1 (TfR1) as Direct Anti-cancer Agents
II. TFR1 in Anemia: Systemic Iron Homeostasis Disruption
TFR1 is central to iron regulation in anemia. The IRP-IRE system upregulates DMT1 and ferroportin (FPN) expression in duodenal enterocytes, enhancing dietary iron absorption and release into circulation. Erythroid precursor cells significantly increase membrane TFR1 expression to maximize uptake of transferrin-bound iron. However, interleukin-6 (IL-6) induces hepcidin production in hepatocytes via the JAK-STAT pathway. Hepcidin binds to macrophage FPN, triggering its ubiquitination and degradation, thereby blocking iron recycling. Consequently, even compensatory TFR1 upregulation in erythroid progenitors cannot support effective hemoglobin synthesis.
III. TFR1 in Neurodegenerative Diseases: Brain Iron Dysregulation
Disrupted brain iron homeostasis is a hallmark of neurodegenerative disorders. In Alzheimer's disease, β-amyloid (Aβ) oligomers and hyperphosphorylated tau protein may interfere with TFR1 endocytic recycling, leading to abnormal neuronal iron accumulation, oxidative stress, and mitochondrial dysfunction. In Parkinson's disease, aberrant TFR1 expression in dopaminergic neurons of the substantia nigra contributes to iron deposition, forming a vicious cycle with α-synuclein aggregation that exacerbates lipid peroxidation and neuronal death.
Image Source: The role of iron in brain ageing and neurodegenerative disorders
Mouse Models for TFR1 Research
● TFRC Knockout Mice: Complete loss of TFRCfunction is embryonic lethal (around E12.5-E14.5), with homozygous embryos exhibiting severe hematopoietic defects and neurological developmental abnormalities.
● Neuron-Specific TFRC Knockout Mice: TFRCis conditionally knocked out in specific neurons, making this model ideal for studying brain iron metabolism and neurodegeneration.
● Humanized TFRC Mice: These mice carry and endogenously express the human TFRCgene sequence, maintaining basic iron homeostasis. They are excellent tools for evaluating the in vivoefficacy of therapeutics targeting human TFR1, such as antibodies or antibody-drug conjugates (ADCs).
Mingceler Biotech Facilitates Mechanistic Research and Drug Development
While gene therapies offer hope for various diseases, their development and validation rely heavily on animal models. Mingceler Biotech, leveraging its proprietary TurboMice™ technology, has developed numerous disease mouse models. The TurboMice™ platform overcomes traditional challenges like long modeling cycles and low success rates for complex models. It enables precise editing at virtually any target genomic locus, allowing for the generation of complete homozygous gene-edited mouse models directly from embryonic stem cells in as little as two months.
Mingceler Biotech offers custom generation of various TFRC-related mouse models, including TFRC knockout, neuron-specific TFRC knockout, and humanized TFRC mice. We welcome inquiries.
References：
[1]Torti SV, Torti FM. Iron and cancer: more ore to be mined. Nat Rev Cancer. 2013 May;13(5):342-55. doi: 10.1038/nrc3495. Epub 2013 Apr 18. PMID: 23594855; PMCID: PMC4036554.
[2]Candelaria, P. V., Leoh, L. S., & Daniels-Wells, T. R. (2021). Antibodies targeting the transferrin receptor 1 (TfR1) as direct anti-cancer agents. Frontiers in Immunology, 12, 607692. https://doi.org/10.3389/fimmu.2021.607692
[3]Ward RJ, Zucca FA, Duyn JH, Crichton RR, Zecca L. The role of iron in brain ageing and neurodegenerative disorders. Lancet Neurol. 2014 Oct;13(10):1045-60. doi: 10.1016/S1474-4422(14)70117-6. PMID: 25231526; PMCID: PMC5672917.
[4]Shimosaki S, Nakahata S, Ichikawa T, Kitanaka A, Kameda T, Hidaka T, Kubuki Y, Kurosawa G, Zhang L, Sudo Y, Shimoda K, Morishita K. Development of a complete human IgG monoclonal antibody to transferrin receptor 1 targeted for adult T-cell leukemia/lymphoma. Biochem Biophys Res Commun. 2017 Mar 25;485(1):144-151. doi: 10.1016/j.bbrc.2017.02.039. Epub 2017 Feb 8. Erratum in: Biochem Biophys Res Commun. 2020 Sep 17;530(2):486. doi: 10.1016/j.bbrc.2020.05.147. PMID: 28189691.
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