The transferrin receptor part I: Biology and targeting with cytotoxic antibodies for the treatment of cancer

doi:10.1016/j.clim.2006.06.010

Clinical Immunology

Volume 121, Issue 2, November 2006, Pages 144-158

https://doi.org/10.1016/j.clim.2006.06.010 Get rights and content

Abstract

The transferrin receptor (TfR) is a cell membrane-associated glycoprotein involved in the cellular uptake of iron and in the regulation of cell growth. Iron uptake occurs via the internalization of iron-loaded transferrin (Tf) mediated by the interaction with the TfR. In addition, the TfR may also contain other growth regulatory properties in certain normal and malignant cells. The elevated levels of TfR in malignancies, its relevance in cancer, and the extracellular accessibility of this molecule make it an excellent antigen for the treatment of cancer using antibodies. The TfR can be targeted by monoclonal antibodies specific for the extracellular domain of the receptor. In this review, we summarize advancements in the basic physiology of the TfR including structure, function, and expression. We also discuss the efficacy of targeting the TfR using cytotoxic antibodies that inhibit cell growth and/or induce apoptosis in targeted malignant cells.

Section snippets

Transferrin

Iron is a required cofactor of heme and nonheme proteins involved in a variety of cellular processes including metabolism, respiration, and DNA synthesis [1], [2]. Dietary iron is absorbed by the intestine [3]. Iron in the ferric state (Fe³⁺) is reduced to the ferrous state (Fe²⁺) in the intestinal lumen and Fe²⁺ is transported across the duodenal epithelium by the divalent metal transporter 1. Ferroportin then exports Fe²⁺ into the portal circulation where it is oxidized to Fe³⁺. At

Conclusion

Recent studies on the structural interaction between Tf and the TfR have refined our knowledge on how these two molecules interact and mediate the uptake of iron. Other studies have demonstrated that the TfR not only binds Tf but may interact with other proteins as well and thus may have additional functions besides its role in iron homeostasis. The TfR is an attractive targeting molecule that could potentially be used to treat a variety of malignancies. Targeting the TfR through the use of

Acknowledgments

This work was supported in part by grants K01 CA86915 and R01 CA107023 from NCI/NIH, the 2004 Brian D. Novis International Myeloma Foundation Senior Grant Award, and the 2003 Jonsson Cancer Center Foundation Interdisciplinary Grant “Targeted Therapy of Multiple Myeloma.”

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ReviewThe transferrin receptor part I: Biology and targeting with cytotoxic antibodies for the treatment of cancer

Abstract

Section snippets

Transferrin

Conclusion

Acknowledgments

Int. J. Biochem. Cell Biol.

Biochim. Biophys. Acta

Drug Discovery Today

Int. J. Biochem. Cell Biol.

Trends Pharmacol. Sci.

Clin. Immunol. Immunopathol.

Cell. Immunol.

Blood

Lancet

Chest

Crit. Rev. Oncol./Hematol.

Adv. Drug Delivery Rev.

Cell

J. Biol. Chem.

J. Biol. Chem.

J. Mol. Biol.

Blood

Int. J. Biochem. Cell Biol.

J. Biol. Chem.

Blood

Blood

J. Biol. Chem.

Blood

Blood

Blood

Blood

Exp. Cell Res.

Iron metabolism and the IRE/IRP regulatory system: an update

Ann. N. Y. Acad. Sci.

Targeted drug delivery via the transferrin receptor-mediated endocytosis pathway

Pharmacol. Rev.

The effect of the iron saturation of transferrin on its binding and uptake by rabbit reticulocytes

Biochem. J.

Transferrin receptor expression and the control of cell growth

Cancer Invest.

Transferrin receptor is necessary for development of erythrocytes and the nervous system

Nat. Genet.

Transferrin/transferrin receptor-mediated drug delivery

Med. Res. Rev.

Identification of the intermolecular disulfide bonds of the human transferrin receptor and its lipid-attachment site

EMBO J.

Human cell-surface glycoprotein with unusual properties

Nature

Ubiquitous cell-surface glycoprotein on tumor cells is proliferation-associated receptor for transferrin

Proc. Natl. Acad. Sci. U. S. A.

Demonstration of the transferrin receptor in human breast cancer tissue. Potential marker for identifying dividing cells

Int. J. Cancer

Characterization of a monoclonal antibody (5E9) that defines a human cell surface antigen of cell activation

J. Immunol.

Monoclonal antibody OKT-9 recognizes the receptor for transferrin on human acute lymphocytic leukemia cells

J. Immunol.

Transferrin receptor as a potential therapeutic target

Prog. Allergy

Transferrin receptors in human tissues: their distribution and possible clinical relevance

J. Clin. Pathol.

Analysis of lymphopoietic stem cells with a monoclonal antibody to the rat transferrin receptor

Immunology

Heterogeneity of the human transferrin receptor and use of anti-transferrin receptor antibodies to detect tumours in vivo

Immunol. Cell. Biol.

Characterization and phenotypic analysis of differentiating CD34+ human bone marrow cells in liquid culture

Eur. J. Haematol.

The role of transferrin receptors in hemopoietic cell growth

Exp. Hematol.

Altered iron metabolism, transferrin receptor 1 and ferritin in patients with colon cancer

Cancer Lett.

Serum transferrin receptor level is not altered in invasive adenocarcinoma of the breast

Am. J. Clin. Pathol.

Potent cytotoxicity of an antihuman transferrin receptor-ricin A-chain immunotoxin on human glioma cells in vitro

Cancer Res.

Soluble CD23 and other receptors (CD4, CD8, CD25, CD71) in serum of patients with chronic lymphocytic leukemia

Leukemia

Transferrin receptor is inversely correlated with estrogen receptor in breast cancer

Breast Cancer Res. Treat.

Review
The transferrin receptor part I: Biology and targeting with cytotoxic antibodies for the treatment of cancer