Article

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

Molecular Biology Institute, David Geff en School of Medicine, University of California, Los Angeles, CA 90095-1782, USA.
Leukemia & lymphoma (Impact Factor: 2.89). 08/2011; 52(11):2169-78. DOI: 10.3109/10428194.2011.596964
Source: PubMed

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.

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    • "Importantly, both antibodies exhibit direct anti-proliferative/proapoptotic activity against a variety of malignant hematopoietic cells, including malignant B cells, in vitro through the induction of TfR1 degradation and subsequent lethal iron deprivation (Ng et al., 2006; Ortiz-Sanchez et al., 2009; Rodriguez et al., 2011). Interestingly , fusion of avidin to the antibody ch128.1 results in enhanced TfR1 degradation and cytotoxicity in vitro (Daniels et al., 2011; Ng et al., 2002, 2006; Rodriguez et al., 2011). However, the levels of sensitivity to ch128.1 and ch128.1Av "

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    • "Importantly, both antibodies exhibit direct anti-proliferative/proapoptotic activity against a variety of malignant hematopoietic cells, including malignant B cells, in vitro through the induction of TfR1 degradation and subsequent lethal iron deprivation (Ng et al., 2006; Ortiz-Sanchez et al., 2009; Rodriguez et al., 2011). Interestingly , fusion of avidin to the antibody ch128.1 results in enhanced TfR1 degradation and cytotoxicity in vitro (Daniels et al., 2011; Ng et al., 2002, 2006; Rodriguez et al., 2011). However, the levels of sensitivity to ch128.1 and ch128.1Av "
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    ABSTRACT: The transferrin receptor 1 (TfR1) is involved in cellular iron uptake and regulation of cell proliferation. The increased expression of TfR1 observed in malignant cells, compared to normal cells, together with its extracellular accessibility, make this receptor an attractive target for antibody-mediated cancer therapy. We have developed a mouse/human chimeric IgG3 specific for human TfR1 (ch128.1), which shows anti-tumor activity against certain malignant B cells in vitro through TfR1 degradation and iron deprivation, and in vivo through a mechanism yet to be defined. To further explore potential mechanisms of action of ch128.1, we examined its ability to induce antibody-dependent cell-mediated cytotoxicity (ADCC) and complement-mediated cytotoxicity (CDC). We now report that ch128.1 is capable of mediating ADCC and CDC against malignant B cells, which is consistent with its ability to bind FcγRI, FcγRIIIa, and the complement component C1q. To delineate the residues involved in these effector functions, we developed a panel of three constructs with mutations in the lower hinge region and CH2 domain: 1) L234A/L235A, 2) P331S, and 3) L234A/L235A/P331S. The triple mutant consistently displayed a significant reduction in ADCC, while the L234A/L235A mutant exhibited less reduction in ADCC, and the P331S mutant did not show reduced ADCC. However, all three mutants exhibited impaired binding to FcγRI and FcγRIIIa. These results suggest that all three residues contribute to ADCC, although to different degrees. The P331S mutant showed drastically decreased C1q binding and abolished CDC, confirming the critical role of this residue in complement activation, while the other residues play a less important role in CDC. Our study provides insights into the effector functions of human IgG3 in the context of an antibody targeting TfR1. Copyright © 2015 Elsevier Ltd. All rights reserved.
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    • "The former, binding TfR1, inhibit the function of the receptor by inducing its sequestration and subsequently degradation in sensitive cells. It has been shown that TfR1 level reduction on the cell surface results in decreased transferrin uptake and induction of lethal iron deprivation (LID) in hematopoietic malignancies [105, 106]. "
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    ABSTRACT: Anaplastic thyroid carcinoma (ATC) is one of the most aggressive human cancers. Actually, ATC is refractory to conventional therapies, including surgery, chemotherapy, radiotherapy, and radioiodine ( 131 I) therapy. Accordingly, genetic and molecular characterizations of ATC have been frequently and periodically reviewed in order to identify potential biological markers exploitable for target therapy. This review briefly focuses on main molecular events that characterize ATC and provides an update about preclinical studies. In addition, the overexpression of transferrin receptor 1 (TfR1/CD71) by neoplastic cells of ATC is emphasized in that it could represent a potential therapeutic target. In this regard, new therapeutic approaches based on the use of monoclonal or recombinant antibodies, or transferrin-gallium-TfR1/CD71 molecular complexes, or lastly small interfering RNAs (siRNAs) are proposed.
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