title: Lethal iron deprivation induced by non-neutralizing antibodies targeting transferrin receptor 1 in malignant B cells.
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.
authors.affiliation: Molecular Biology Institute, David Geff en School of Medicine, University of California, Los Angeles, CA 90095-1782, USA.
authors.forename: José A
authors.initials: JA
authors.lastname: Rodríguez
authors.forename: Rosendo
authors.initials: R
authors.lastname: Luria-Pérez
authors.forename: Héctor E
authors.initials: HE
authors.lastname: López-Valdés
authors.forename: David
authors.initials: D
authors.lastname: Casero
authors.forename: Tracy R
authors.initials: TR
authors.lastname: Daniels
authors.forename: Shabnum
authors.initials: S
authors.lastname: Patel
authors.forename: David
authors.initials: D
authors.lastname: Avila
authors.forename: Richard
authors.initials: R
authors.lastname: Leuchter
authors.forename: Sokuntheavy
authors.initials: S
authors.lastname: So
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Ortiz-Sánchez
authors.forename: Benjamin
authors.initials: B
authors.lastname: Bonavida
authors.forename: Otoniel
authors.initials: O
authors.lastname: Martínez-Maza
authors.forename: Andrew C
authors.initials: AC
authors.lastname: Charles
authors.forename: Matteo
authors.initials: M
authors.lastname: Pellegrini
authors.forename: Gustavo
authors.initials: G
authors.lastname: Helguera
authors.forename: Manuel L
authors.initials: ML
authors.lastname: Penichet
mesh_terms: D000818:Animals; D000906:Antibodies / Q000276:immunology / Q000378:metabolism* / Q000494:pharmacology; D015703:Antigens, CD / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D001402:B-Lymphocytes / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D002460:Cell Line; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D003676:Deferoxamine / Q000494:pharmacology; D004705:Endocytosis / Q000187:drug effects; D020869:Gene Expression Profiling; D006801:Humans; D015151:Immunoblotting; D007501:Iron / Q000378:metabolism*; D051379:Mice; D016513:Mice, SCID; D009101:Multiple Myeloma / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D020411:Oligonucleotide Array Sequence Analysis; D011485:Protein Binding; D011990:Receptors, Transferrin / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D017262:Siderophores / Q000494:pharmacology; D014168:Transferrin / Q000378:metabolism; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays
chemical_list: D000906:Antibodies; D015703:Antigens, CD; C068126:CD71 antigen; D011990:Receptors, Transferrin; D017262:Siderophores; D014168:Transferrin; D016159:Tumor Suppressor Protein p53; D007501:Iron; D003676:Deferoxamine