The therapeutic effectiveness of 177Lu-lilotomab in B-cell non- Hodgkin lymphoma involves modulation of G2/M cell cycle arrest - Archive ouverte HAL Access content directly
Journal Articles Leukemia Year : 2019

The therapeutic effectiveness of 177Lu-lilotomab in B-cell non- Hodgkin lymphoma involves modulation of G2/M cell cycle arrest

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Marta Jarlier

Abstract

Some patients with B-cell non-Hodkin lymphoma Lymphoma (NHL) become refractory to rituximab (anti-CD20 antibody) therapy associated with chemotherapy. Here, the effect of the anti-CD37 antibody-radionuclide conjugate lutetium-177 (177Lu)-lilotomab (Betalutin®) was investigated in preclinical models of NHL. In SCID mice bearing DOHH2 (transformed follicular lymphoma, FL) cell xenografts, 177Lu-lilotomab significantly delayed tumor growth, even at low activity (100 MBq/kg). In athymic mice bearing OCI-Ly8 (diffuse large B-cell lymphoma, DLBCL) or Ramos (Burkitt's lymphoma) cell xenografts, 177Lu-lilotomab activity had to be increased to 500 MBq/kg to show a significant tumor growth delay. Clonogenic and proliferation assays showed that DOHH2 cells were highly sensitive to 177Lu-lilotomab, while Ramos cells were the least sensitive, and U2932 (DLBCL), OCI-Ly8, and Rec-1 (mantle cell lymphoma) cells displayed intermediate sensitivity. The strong 177Lu-lilotomab cytotoxicity observed in DOHH2 cells correlated with reduced G2/M cell cycle arrest, lower WEE-1- and MYT-1-mediated phosphorylation of cyclin-dependent kinase-1 (CDK1), and higher apoptosis. In agreement, 177Lu-lilotomab efficacy in vitro, in vivo, and in patient samples was increased when combined with G2/M cell cycle arrest inhibitors (MK-1775 and PD-166285). These results indicate that 177Lu-lilotomab is particularly efficient in treating tumors with reduced inhibitory CDK1 phosphorylation, such as transformed FL.
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Dates and versions

inserm-03024614 , version 1 (25-11-2020)

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Alexandre Pichard, Sara Marcatili, Jihad Karam, Julie Constanzo, Riad Ladjohounlou, et al.. The therapeutic effectiveness of 177Lu-lilotomab in B-cell non- Hodgkin lymphoma involves modulation of G2/M cell cycle arrest. Leukemia, 2019, 34 (5), pp.1315-1328. ⟨10.1038/s41375-019-0677-4⟩. ⟨inserm-03024614⟩
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