Accueil > Publications > 2019 > A recycling anti-transferrin receptor-1 monoclonal antibody as an efficient (...)

Neiveyans M, Melhem R, Arnoult C, Bourquard T, Jarlier M, Busson M, Laroche A, Cerutti M, Pugnière M, Ternant D, Gaborit N, Chardès T, Poupon A, Gouilleux-Gruart V, Pèlegrin A, Poul MA.

A recycling anti-transferrin receptor-1 monoclonal antibody as an efficient therapy for erythroleukemia through target up-regulation and antibody-dependent cytotoxic effector functions.

MAbs. 2019 Apr ;11(3):593-605. doi : 10.1080/19420862.2018.1564510. Epub 2019 Feb 18.

Abstract

Targeting transferrin receptor 1 (TfR1) with monoclonal antibodies is a promising therapeutic strategy in cancer as tumor cells often overexpress TfR1 and show increased iron needs. We have re-engineered six anti-human TfR1 single-chain variable fragment (scFv) antibodies into fully human scFv2-Fcγ1 and IgG1 antibodies. We selected the more promising candidate (H7), based on its ability to inhibit TfR1-mediated iron-loaded transferrin internalization in Raji cells (B-cell lymphoma). The H7 antibody displayed nanomolar affinity for its target in both formats (scFv2-Fcγ1 and IgG1), but cross-reacted with mouse TfR1 only in the scFv2-Fc format. H7 reduced the intracellular labile iron pool and, contrary to what has been observed with previously described anti-TfR1 antibodies, upregulated TfR1 level in Raji cells. H7 scFv2-Fc format elimination half-life was similar in FcRn knock-out and wild type mice, suggesting that TfR1 recycling contributes to prevent H7 elimination in vivo. In vitro, H7 inhibited the growth of erythroleukemia and B-cell lymphoma cell lines (IC50 0.1 µg/mL) and induced their apoptosis. Moreover, the Im9 B-cell lymphoma cell line, which is resistant to apoptosis induced by rituximab (anti-CD20 antibody), was sensitive to H7. In vivo, tumor regression was observed in nude mice bearing ERY-1 erythroleukemia cell xenografts treated with H7 through a mechanism that involved iron deprivation and antibody-dependent cytotoxic effector functions. Therefore, targeting TfR1 using the fully human anti-TfR1 H7 is a promising tool for the treatment of leukemia and lymphoma.

PubMed

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