177Lu-Lilotomab Satetraxetan Has the Potential to Counteract Resistance to Rituximab in Non-Hodgkin Lymphoma
| Autor: | Ada H. V. Repetto-Llamazares, Jostein Dahle, Anne Hansen Ree, Marion Masitsa Malenge, Peter P. Ceuppens, Brian J. Middleton, Sebastian Patzke, Trond Stokke |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2020 |
| Předmět: |
0301 basic medicine
Radioimmunoconjugate medicine.medical_treatment NHL Flow cytometry 03 medical and health sciences 0302 clinical medicine rituximab resistance immune system diseases hemic and lymphatic diseases medicine Radiology Nuclear Medicine and imaging Basic CD20 Antibody-dependent cell-mediated cytotoxicity medicine.diagnostic_test biology business.industry 177Lu medicine.disease Lymphoma Raji cell 030104 developmental biology Oncology 030220 oncology & carcinogenesis Radioimmunotherapy Cancer research biology.protein radioimmunotherapy Rituximab business medicine.drug |
| Zdroj: | Journal of Nuclear Medicine |
| ISSN: | 1535-5667 0161-5505 |
| Popis: | 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 177Lu-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 177Lu-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 with 177Lu-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. 177Lu-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 with 177Lu-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 177Lu-lilotomab-satetraxetan synergistically suppressed Raji2R tumor growth in athymic Foxn1nu mice. Conclusion: 177Lu-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. |
| Databáze: | OpenAIRE |
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