A recycling anti-transferrin receptor-1 monoclonal antibody as an efficient therapy for erythroleukemia through target up-regulation and antibody-dependent cytotoxic effector functions. Issue 3 (3rd April 2019)

• Record Type: Journal Article
• Authors: Neiveyans, Madeline; Melhem, Rana; Arnoult, Christophe; Bourquard, Thomas; Jarlier, Marta; Busson, Muriel; Laroche, Adrien; Cerutti, Martine; Pugnière, Martine; Ternant, David; Gaborit, Nadège; Chardès, Thierry; Poupon, Anne; Gouilleux-Gruart, Valérie; Pèlegrin, Andre; Poul, Marie-Alix
• Is Part Of: MAbs. Volume 11:Issue 3(2019)
• Page Start: 593
• Page End: 605
• Publication Date: 2019-04-03
• Subjects: Transferrin receptor 1 -- iron metabolism -- leukemia -- therapeutic antibody; Monoclonal antibodies -- Therapeutic use -- Periodicals; Monoclonal antibodies -- Periodicals; Antibodies, Monoclonal -- Periodicals; 616.0798
• DOI: 10.1080/19420862.2018.1564510
• Languages: English
• ISSNs: 1942-0862

Abstract

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.