¹⁷⁷Lu-Lilotomab Satetraxetan Has the Potential to Counteract Resistance to Rituximab in Non-Hodgkin Lymphoma

Patients with non-Hodgkin lymphoma (NHL) who are treated with rituximab may develop resistant disease, often associated with changes in expression of CD20. The next-generation -particle-emitting radioimmunoconjugate 177 Lu-lilotomab-satetraxetan (Betalutin) was shown to up-regulate CD20 expression in different rituximabsensitive NHL cell lines and to act synergistically with rituximab in a rituximab-sensitive NHL animal model. We hypothesized that 177 Lulilotomab-satetraxetan may be used to reverse rituximab resistance in NHL. Methods: The rituximab-resistant Raji2R and the parental Raji cell lines were used. CD20 expression was measured by flow cytometry. Antibody-dependent cellular cytotoxicity (ADCC) was measured by a bioluminescence reporter assay. The efficacies of combined treatments with 177 Lu-lilotomab-satetraxetan (150 or 350 MBq/kg) and rituximab (4 10 mg/kg) were compared with those of single agents or phosphate-buffered saline in a Raji2R-xenograft model. Cox regression and the Bliss independence model were used to assess synergism. Results: Rituximab binding in Raji2R cells was 36% 5% of that in the rituximab-sensitive Raji cells. 177 Lu-lilotomabsatetraxetan treatment of Raji2R cells increased the binding to 53% 3% of the parental cell line. Rituximab ADCC induction in Raji2R cells was 20% 2% of that induced in Raji cells, whereas treatment with 177 Lu-lilotomab-satetraxetan increased the ADCC induction to 30% 3% of that in Raji cells, representing a 50% increase (P , 0.05). The combination of rituximab with 350 MBq/kg 177 Lu-lilotomab-satetraxetan synergistically suppressed Raji2R tumor growth in athymic Foxn1 nu mice. Conclusion: 177 Lu-lilotomab-satetraxetan has the potential to reverse rituximab resistance; it can increase rituximab binding and ADCC activity in vitro and can synergistically improve antitumor efficacy in vivo.