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

• Autores: Rodríguez, José A.; Luria Pérez, Rosendo; López Valdés, Héctor E.; Casero, David; Daniels, Tracy R.; Patel, Shabnum; Avila, David; Leuchter, Richard; So, Sokuntheavy; Ortiz Sánchez, Elizabeth; Bonavida, Benjamin; Martínez Maza, Otoniel; Charles, Andrew C.; Pellegrini, Matteo; Helguera, Gustavo Fernando; Penichet, Manuel L.
• Año de publicación: 2011
• Idioma: inglés
• Tipo de recurso: artículo
• Materia: Transferrin,; Monoclonal Antibody; iron deprivation; Cancer
• Institución: Consejo Nacional de Investigaciones Científicas y Técnicas

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.
Fil: Rodríguez, José A.. University of California at Los Angeles; Estados Unidos
Fil: Luria Pérez, Rosendo. University of California at Los Angeles; Estados Unidos. Hospital infantil de México “Federico Gómez”; México
Fil: López Valdés, Héctor E.. University of California at Los Angeles; Estados Unidos
Fil: Casero, David. University of California at Los Angeles; Estados Unidos
Fil: Daniels, Tracy R.. University of California at Los Angeles; Estados Unidos
Fil: Patel, Shabnum. University of California at Los Angeles; Estados Unidos
Fil: Avila, David. University of California at Los Angeles; Estados Unidos
Fil: Leuchter, Richard. University of California at Los Angeles; Estados Unidos
Fil: So, Sokuntheavy. University of California at Los Angeles; Estados Unidos
Fil: Ortiz Sánchez, Elizabeth. University of California at Los Angeles; Estados Unidos
Fil: Bonavida, Benjamin. University of California at Los Angeles; Estados Unidos
Fil: Martínez Maza, Otoniel. University of California at Los Angeles; Estados Unidos
Fil: Charles, Andrew C.. University of California at Los Angeles; Estados Unidos
Fil: Pellegrini, Matteo. University of California at Los Angeles; Estados Unidos
Fil: Helguera, Gustavo Fernando. University of California at Los Angeles; Estados Unidos. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay; Argentina
Fil: Penichet, Manuel L.. University of California at Los Angeles; Estados Unidos