A recycling anti-transferrin receptor-1 monoclonal antibody as an efficient therapy for erythroleukemia through target up-regulation and antibody-dependent cytotoxic effector functions.
Madeline NeiveyansRana MelhemChristophe ArnoultThomas BourquardMarta JarlierMuriel BussonAdrien LarocheMartine CeruttiMartine PugnièreDavid TernantNadège GaboritThierry ChardèsAnne PouponValérie Gouilleux-GruartAndre PèlegrinMarie-Alix PoulPublished in: mAbs (2019)
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.
Keyphrases
- cell cycle arrest
- diffuse large b cell lymphoma
- endothelial cells
- wild type
- induced apoptosis
- cell death
- monoclonal antibody
- endoplasmic reticulum stress
- oxidative stress
- induced pluripotent stem cells
- high glucose
- bone marrow
- regulatory t cells
- stem cells
- cancer therapy
- dendritic cells
- drug delivery
- type diabetes
- squamous cell carcinoma
- cell proliferation
- drug induced
- signaling pathway
- adipose tissue
- mesenchymal stem cells
- mass spectrometry
- diabetic rats
- immune response
- papillary thyroid
- smoking cessation