Abstract
Currently, B-cell Non-Hodgkin Lymphoma (NHL) treatment relies on the anti-CD20 antibody rituximab and chemotherapy. However, some patients become refractory to this therapy. Here, the effect of the novel anti-CD37 antibody-radionuclide conjugate 177Lu-lilotomab (Betalutin®) was investigated in NHL preclinical models and compared to 177Lu-labeled rituximab (anti-CD20 antibody). We developed a radiobiological approach that discriminates between the cytotoxic effects of unlabeled antibodies and of radiation in human lymphoma cell lines. This method allowed showing that in vitro, rituximab and 177Lu-rituximab were more cytotoxic than lilotomab and 177Lu-lilotomab in the radioresistant Ramos Burkitt’s lymphoma cell line. Conversely, 177Lu-rituximab and 177Lu-lilotomab had similar efficacy in the radiosensitive follicular lymphoma DOHH2 cell line. Their cytotoxicity was lower in mantle cell lymphoma Rec-1 cells that are less radiosensitive than DOHH2 cells. These results were confirmed in vivo in mice treated by intravenous injection of these antibodies after subcutaneous xenografts of Ramos or DOHH2 cells. 177Lu-lilotomab and 177Lu-rituximab showed the same therapeutic efficacy in mice xenografted with radiosensitive DOHH2 cells, although unlabeled lilotomab was less efficient than rituximab. Conversely, in mice xenografted with radioresistant Ramos cells, the lower efficacy of 177Lu-lilotomab compared with 177Lu-rituximab could only be compensated by increasing 177Lu-lilotomab tumor absorbed dose. Mechanistically, the tumor cell response to radiation depended on the cell apoptotic response and reduction of G2/M cell cycle arrest through WEE-1 and MYT1-mediated phosphorylation of cyclin-dependent kinase-1 (CDK1) at tyrosine 15 and threonine 14. These results indicate that the synergistic interaction between 177Lu irradiation and lilotomab cytotoxic effects in tumors with reduced CDK1 phosphorylation levels can correct the lower therapeutic efficacy of lilotomab compared with rituximab.