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(177)Lu-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 β-particle–emitting radioimmunoconjugate (177)Lu-lilotomab-satetraxetan (Betalutin) was shown to up-regulate CD20 expression...

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Autores principales: Malenge, Marion M., Patzke, Sebastian, Ree, Anne H., Stokke, Trond, Ceuppens, Peter, Middleton, Brian, Dahle, Jostein, Repetto-Llamazares, Ada H.V.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Society of Nuclear Medicine 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7539655/
https://www.ncbi.nlm.nih.gov/pubmed/32245896
http://dx.doi.org/10.2967/jnumed.119.237230
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author Malenge, Marion M.
Patzke, Sebastian
Ree, Anne H.
Stokke, Trond
Ceuppens, Peter
Middleton, Brian
Dahle, Jostein
Repetto-Llamazares, Ada H.V.
author_facet Malenge, Marion M.
Patzke, Sebastian
Ree, Anne H.
Stokke, Trond
Ceuppens, Peter
Middleton, Brian
Dahle, Jostein
Repetto-Llamazares, Ada H.V.
author_sort Malenge, Marion M.
collection PubMed
description 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 that (177)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 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-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 (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.
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spelling pubmed-75396552020-10-15 (177)Lu-Lilotomab Satetraxetan Has the Potential to Counteract Resistance to Rituximab in Non-Hodgkin Lymphoma Malenge, Marion M. Patzke, Sebastian Ree, Anne H. Stokke, Trond Ceuppens, Peter Middleton, Brian Dahle, Jostein Repetto-Llamazares, Ada H.V. J Nucl Med Oncology 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 that (177)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 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-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 (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. Society of Nuclear Medicine 2020-10 /pmc/articles/PMC7539655/ /pubmed/32245896 http://dx.doi.org/10.2967/jnumed.119.237230 Text en © 2020 by the Society of Nuclear Medicine and Molecular Imaging. Immediate Open Access: Creative Commons Attribution 4.0 International License (CC BY) allows users to share and adapt with attribution, excluding materials credited to previous publications. License: https://creativecommons.org/licenses/by/4.0/.Details:http://jnm.snmjournals.org/site/misc/permission.xhtml.
spellingShingle Oncology
Malenge, Marion M.
Patzke, Sebastian
Ree, Anne H.
Stokke, Trond
Ceuppens, Peter
Middleton, Brian
Dahle, Jostein
Repetto-Llamazares, Ada H.V.
(177)Lu-Lilotomab Satetraxetan Has the Potential to Counteract Resistance to Rituximab in Non-Hodgkin Lymphoma
title (177)Lu-Lilotomab Satetraxetan Has the Potential to Counteract Resistance to Rituximab in Non-Hodgkin Lymphoma
title_full (177)Lu-Lilotomab Satetraxetan Has the Potential to Counteract Resistance to Rituximab in Non-Hodgkin Lymphoma
title_fullStr (177)Lu-Lilotomab Satetraxetan Has the Potential to Counteract Resistance to Rituximab in Non-Hodgkin Lymphoma
title_full_unstemmed (177)Lu-Lilotomab Satetraxetan Has the Potential to Counteract Resistance to Rituximab in Non-Hodgkin Lymphoma
title_short (177)Lu-Lilotomab Satetraxetan Has the Potential to Counteract Resistance to Rituximab in Non-Hodgkin Lymphoma
title_sort (177)lu-lilotomab satetraxetan has the potential to counteract resistance to rituximab in non-hodgkin lymphoma
topic Oncology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7539655/
https://www.ncbi.nlm.nih.gov/pubmed/32245896
http://dx.doi.org/10.2967/jnumed.119.237230
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