Lu-177-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 beta-particle-emitting radioimmunoconjugate Lu-177-lilotomab-satetraxetan (Betalutin) was shown to up-regulate CD20 expression in different rituximab-sensitive 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 Lu-177-lilotomab-satetraxetan (150 or 350 MBq/kg) and rituximab (4 x 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. Lu-177-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 Lu-177-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 Lu-177-lilotomab-satetraxetan synergistically suppressed Raji2R tumor growth in athymic Foxn1nu mice. Conclusion: Lu-177-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.