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

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 antibodie...

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Detalhes bibliográficos
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.
Formato: artículo
Estado:Versión publicada
Fecha de publicación:2011
País:Argentina
Recursos:Consejo Nacional de Investigaciones Científicas y Técnicas
Repositorio:CONICET Digital (CONICET)
Idioma:inglés
OAI Identifier:oai:ri.conicet.gov.ar:11336/12909
Acesso em linha:http://hdl.handle.net/11336/12909
Access Level:acceso abierto
Palavra-chave:Transferrin,
Monoclonal Antibody
iron deprivation
Cancer
https://purl.org/becyt/ford/3.4
https://purl.org/becyt/ford/3
Descrição
Resumo: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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