1. 177 Lu-Lilotomab Satetraxetan Has the Potential to Counteract Resistance to Rituximab in Non-Hodgkin Lymphoma.
- Author
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Malenge MM, Patzke S, Ree AH, Stokke T, Ceuppens P, Middleton B, Dahle J, and Repetto-Llamazares AHV
- Subjects
- Animals, Antibody-Dependent Cell Cytotoxicity, Apoptosis drug effects, Apoptosis radiation effects, Cell Line, Tumor, Drug Resistance, Neoplasm, Humans, Lymphoma, Non-Hodgkin drug therapy, Lymphoma, Non-Hodgkin mortality, Lymphoma, Non-Hodgkin pathology, Mice, Rituximab metabolism, Xenograft Model Antitumor Assays, Antibodies, Monoclonal therapeutic use, Immunoconjugates therapeutic use, Lymphoma, Non-Hodgkin radiotherapy, Radioimmunotherapy, Rituximab therapeutic use
- Abstract
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 β-particle-emitting radioimmunoconjugate
177 Lu-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 that177 Lu-lilotomab-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 with177 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-lilotomab-satetraxetan 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 with177 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/kg177 Lu-lilotomab-satetraxetan synergistically suppressed Raji2R tumor growth in athymic Foxn1nu mice. Conclusion: Lu-lilotomab-satetraxetan has the potential to reverse rituximab resistance; it can increase rituximab binding and ADCC activity177 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 ., (© 2020 by the Society of Nuclear Medicine and Molecular Imaging.)- Published
- 2020
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