Study of a new anti-CD37 monoclonal antibody radiolabelled with Lutetium-177 in a B-cell Non-Hodgkin Lymphoma: therapeutic efficacy and mechanisms of action

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 efficacy of the novel anti- CD37 antibody-radionuclide conjugate ¹⁷⁷Lu-lilotomab (Betalutin^R) was investigated in three NHL preclinical models and compared to both rituximab and ¹⁷⁷Lu-rituximab. The ¹⁷⁷Lu-cetuximab was also used as a non-targeting antibody for investigating the biological effects of ¹⁷⁷Lu alone. In vitro, clonogenic survival and proliferation assays showed that rituximab and ¹⁷⁷Lu-rituximab were more cytotoxic than lilotomab and ¹⁷⁷Lu-lilotomab in the radioresistant Ramos cell line. Conversely, in the radiosensitive follicular lymphoma DOHH2 cell line, ¹⁷⁷Lu-rituximab and ¹⁷⁷Lu-lilotomab showed similar efficacy. Mantle cell lymphoma (Rec-1 cells) showed intermediate radiosensitivity leading to intermediate response to ¹⁷⁷Lu-lilotomab. A radiobiological approach discriminating the cytotoxic effects of unlabelled antibodies and of radiation showed that synergy was observed between the cytotoxic effects of ¹⁷⁷Lu and of rituximab involved in ¹⁷⁷Lu-rituximab efficacy. Conversely, for ¹⁷⁷Lu-lilotomab, synergy between ¹⁷⁷Lu and lilotomab was only observed in DOHH2 cells. The high response of DOHH2 cells to ¹⁷⁷Lu-lilotomab was confirmed in vivo. Mice bearing subcutaneous DOHH2 or Ramos xenografts mouse models were intravenously injected with either ¹⁷⁷Lu-labelled- or unlabelled lilotomab and rituximab. ¹⁷⁷Lu-lilotomab and ¹⁷⁷Lu-rituximab showed the same therapeutic efficacy on DOHH2 tumours, although unlabelled lilotomab was less efficient than rituximab. Conversely, in Ramos tumour xenografts, the lower efficacy of ¹⁷⁷Lu-lilotomab compared with ¹⁷⁷Lu-rituximab could only be compensated by increasing ¹⁷⁷Lu-lilotomab tumour absorbed dose. At the molecular level, tumour cells radiation-response was shown to be dependent on their ability to undergo apoptosis. This was associated with a reduction of G2/M cell cycle arrest, itself under the control of Wee-1 and Myt-1-mediated phosphorylation of cyclin-dependent kinase-1 (CDK1) at tyrosine 15 and threonine 14. In conclusion, these results indicate that ¹⁷⁷Lu-lilotomab is an efficient therapeutic tool for NHL, particularly for tumours showing reduced CDK1 phosphorylation levels, such as in transformed follicular lymphoma (DOHH2 cells), and associated with synergistic cytotoxic effects between ¹⁷⁷Lu irradiation and lilotomab. (author)