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Leukemia & Lymphoma Volume 52, 2011 - Issue 11
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Research Article

Lethal iron deprivation induced by non-neutralizing antibodies targeting transferrin receptor 1 in malignant B cells

José A. RodríguezMolecular Biology Institute, University of California, Los Angeles, CA, USA;Division of Surgical Oncology, Department of Surgery, University of California, Los Angeles, CA, USA
,
Rosendo Luria-PérezDivision of Surgical Oncology, Department of Surgery, University of California, Los Angeles, CA, USA;Unit of Investigative Research on Oncological Disease, Children's Hospital of Mexico “Federico Gómez”, Mexico City, Mexico
,
Héctor E. López-ValdésDepartment of Neurology, University of California, Los Angeles, CA, USA
,
David CaseroDepartment of Molecular Cell and Developmental Biology, University of California, Los Angeles, CA, USA
,
Tracy R. DanielsDivision of Surgical Oncology, Department of Surgery, University of California, Los Angeles, CA, USA
,
Shabnum PatelDivision of Surgical Oncology, Department of Surgery, University of California, Los Angeles, CA, USA
,
David AvilaDivision of Surgical Oncology, Department of Surgery, University of California, Los Angeles, CA, USA
,
Richard LeuchterDivision of Surgical Oncology, Department of Surgery, University of California, Los Angeles, CA, USA
,
Sokuntheavy SoDivision of Surgical Oncology, Department of Surgery, University of California, Los Angeles, CA, USA
,
Elizabeth Ortiz-SánchezDivision of Surgical Oncology, Department of Surgery, University of California, Los Angeles, CA, USA
,
Benjamin BonavidaDepartment of Microbiology, Immunology and Molecular Genetics, University of California, Los Angeles, CA, USA;Jonsson Comprehensive Cancer Center, University of California, Los Angeles, CA, USA
,
Otoniel Martínez-MazaDepartment of Microbiology, Immunology and Molecular Genetics, University of California, Los Angeles, CA, USA;Jonsson Comprehensive Cancer Center, University of California, Los Angeles, CA, USA;Department of Obstetrics and Gynecology, University of California, Los Angeles, CA, USA;Department of Epidemiology, David Geffen School of Medicine, University of California, Los Angeles, CA, USA
,
Andrew C. CharlesDepartment of Neurology, University of California, Los Angeles, CA, USA
,
Matteo PellegriniDepartment of Molecular Cell and Developmental Biology, University of California, Los Angeles, CA, USA
,
Gustavo HelgueraDivision of Surgical Oncology, Department of Surgery, University of California, Los Angeles, CA, USA
&
Manuel L. PenichetMolecular Biology Institute, University of California, Los Angeles, CA, USA;Division of Surgical Oncology, Department of Surgery, University of California, Los Angeles, CA, USA;Department of Microbiology, Immunology and Molecular Genetics, University of California, Los Angeles, CA, USA;Jonsson Comprehensive Cancer Center, University of California, Los Angeles, CA, USACorrespondence[email protected]
 show all
Pages 2169-2178 | Received 12 Dec 2010, Accepted 05 Jun 2011, Published online: 28 Aug 2011
 
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Abstract

A number of antibodies have been developed that induce lethal iron deprivation (LID) by targeting the transferrin receptor 1 (TfR1/CD71) and either neutralizing transferrin (Tf) binding, blocking internalization of the receptor and/or inducing its degradation. We have developed recombinant antibodies targeting human TfR1 (ch128.1 and ch128.1Av), which induce receptor degradation and are cytotoxic to certain malignant B-cells. We now show that internalization of TfR1 bound to these antibodies can lead to its sequestration and degradation, as well as reduced Tf uptake, and the induction of a transcriptional response consistent with iron deprivation, which is mediated in part by downstream targets of p53. Cells resistant to these antibodies do not sequester and degrade TfR1 after internalization of the antibody/receptor complex, and accordingly maintain their ability to internalize Tf. These findings are expected to facilitate the rational design and clinical use of therapeutic agents targeting iron import via TfR1 in hematopoietic malignancies.

Acknowledgements

We thank Dr. Matthew Schibler (UCLA Advanced Light Microscopy Facility at the California NanoSystems Institute, CNSI), Rafaela Quintero (UCLA) and Giovanni Coppola (UCLA) for their technical assistance.

This work was supported in part by NIH/NCI grants R01CA107023, K01CA138559, R01CA57152, U54CA143931, R25GM0638, the training grant T32CA009120, NIH Fogarty AITRP-AIDS Malignancies Program D43TW000013S1, the UC MEXUS-CONACYT Fellowship Program, the Howard Hughes Medical Institute Gilliam Fellowship, the Whitcome Fellowship of the Molecular Biology Institute at UCLA and the Fletcher Jones Foundation. D. Casero was partially supported by a post-doctoral grant from the Spanish Foundation of Science and Technology (FECYT) and CNSI-UCLA. The UCLA JCCC Flow Cytometry Core Facility is supported by the NIH Awards CA16042 and AI28697, the Jonsson Cancer Center, the UCLA AIDS Institute and the UCLA School of Medicine.

Potential conflict of interest:

Disclosure forms provided by the authors are available with the full text of this article at www.informahealthcare.com/lal.

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