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(212)Pb α-Radioimmunotherapy Targeting CD38 in Multiple Myeloma: A Preclinical Study

Multiple myeloma (MM) is a plasma cell cancer and represents the second most frequent hematologic malignancy. Despite new treatments and protocols, including high-dose chemotherapy associated with autologous stem cell transplantation, the prognosis of MM patients is still poor. α-radioimmunotherapy...

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Autores principales: Quelven, Isabelle, Monteil, Jacques, Sage, Magali, Saidi, Amal, Mounier, Jérémy, Bayout, Audrey, Garrier, Julie, Cogne, Michel, Durand-Panteix, Stéphanie
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Society of Nuclear Medicine 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7383085/
https://www.ncbi.nlm.nih.gov/pubmed/31862796
http://dx.doi.org/10.2967/jnumed.119.239491
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author Quelven, Isabelle
Monteil, Jacques
Sage, Magali
Saidi, Amal
Mounier, Jérémy
Bayout, Audrey
Garrier, Julie
Cogne, Michel
Durand-Panteix, Stéphanie
author_facet Quelven, Isabelle
Monteil, Jacques
Sage, Magali
Saidi, Amal
Mounier, Jérémy
Bayout, Audrey
Garrier, Julie
Cogne, Michel
Durand-Panteix, Stéphanie
author_sort Quelven, Isabelle
collection PubMed
description Multiple myeloma (MM) is a plasma cell cancer and represents the second most frequent hematologic malignancy. Despite new treatments and protocols, including high-dose chemotherapy associated with autologous stem cell transplantation, the prognosis of MM patients is still poor. α-radioimmunotherapy (α-RIT) represents an attractive treatment strategy because of the high-linear-energy transfer and short pathlength of α-radiation in tissues, resulting in high tumor cell killing and low toxicity to surrounding tissues. In this study, we investigated the potential of α-RIT with (212)Pb-daratumumab (anti-hCD38), in both in vitro and in vivo models, as well as an antimouse CD38 antibody using in vivo models. Methods: Inhibition of cell proliferation after incubation of the RPMI8226 cell line with an increasing activity (0.185–3.7 kBq/mL) of (212)Pb-isotypic control or (212)Pb-daratumumab was evaluated. Biodistribution was performed in vivo by SPECT/CT imaging and after death. Dose-range–finding and acute toxicity studies were conducted. Because daratumumab does not bind the murine CD38, biodistribution and dose-range finding were also determined using an antimurine CD38 antibody. To evaluate the in vivo efficacy of (212)Pb-daratumumab, mice were engrafted subcutaneously with 5 × 10(6) RPMI8226 cells. Mice were treated 13 d after engraftment with an intravenous injection of (212)Pb-daratumumab or control solution. Therapeutic efficacy was monitored by tumor volume measurements and overall survival. Results: Significant inhibition of proliferation of the human myeloma RPMI8226 cell line was observed after 3 d of incubation with (212)Pb-daratumumab, compared with (212)Pb-isotypic control or cold antibodies. Biodistribution studies showed a specific tumoral accumulation of daratumumab. No toxicity was observed with (212)Pb-daratumumab up to 370 kBq because of lack of cross-reactivity. Nevertheless, acute toxicity experiments with (212)Pb-anti-mCD38 established a toxic activity of 277.5 kBq. To remain within realistically safe treatment activities for efficacy studies, mice were treated with 185 kBq or 277.5 kBq of (212)Pb-daratumumab. Marked tumor growth inhibition compared with controls was observed, with a median survival of 55 d for 277.5 kBq of (212)Pb-daratumumab instead of 11 d for phosphate-buffered saline. Conclusion: These results showed (212)Pb-daratumumab to have efficacy in xenografted mice, with significant tumor regression and increased survival. This study highlights the potency of α-RIT in MM treatment.
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spelling pubmed-73830852020-08-07 (212)Pb α-Radioimmunotherapy Targeting CD38 in Multiple Myeloma: A Preclinical Study Quelven, Isabelle Monteil, Jacques Sage, Magali Saidi, Amal Mounier, Jérémy Bayout, Audrey Garrier, Julie Cogne, Michel Durand-Panteix, Stéphanie J Nucl Med Radionuclide Therapy Multiple myeloma (MM) is a plasma cell cancer and represents the second most frequent hematologic malignancy. Despite new treatments and protocols, including high-dose chemotherapy associated with autologous stem cell transplantation, the prognosis of MM patients is still poor. α-radioimmunotherapy (α-RIT) represents an attractive treatment strategy because of the high-linear-energy transfer and short pathlength of α-radiation in tissues, resulting in high tumor cell killing and low toxicity to surrounding tissues. In this study, we investigated the potential of α-RIT with (212)Pb-daratumumab (anti-hCD38), in both in vitro and in vivo models, as well as an antimouse CD38 antibody using in vivo models. Methods: Inhibition of cell proliferation after incubation of the RPMI8226 cell line with an increasing activity (0.185–3.7 kBq/mL) of (212)Pb-isotypic control or (212)Pb-daratumumab was evaluated. Biodistribution was performed in vivo by SPECT/CT imaging and after death. Dose-range–finding and acute toxicity studies were conducted. Because daratumumab does not bind the murine CD38, biodistribution and dose-range finding were also determined using an antimurine CD38 antibody. To evaluate the in vivo efficacy of (212)Pb-daratumumab, mice were engrafted subcutaneously with 5 × 10(6) RPMI8226 cells. Mice were treated 13 d after engraftment with an intravenous injection of (212)Pb-daratumumab or control solution. Therapeutic efficacy was monitored by tumor volume measurements and overall survival. Results: Significant inhibition of proliferation of the human myeloma RPMI8226 cell line was observed after 3 d of incubation with (212)Pb-daratumumab, compared with (212)Pb-isotypic control or cold antibodies. Biodistribution studies showed a specific tumoral accumulation of daratumumab. No toxicity was observed with (212)Pb-daratumumab up to 370 kBq because of lack of cross-reactivity. Nevertheless, acute toxicity experiments with (212)Pb-anti-mCD38 established a toxic activity of 277.5 kBq. To remain within realistically safe treatment activities for efficacy studies, mice were treated with 185 kBq or 277.5 kBq of (212)Pb-daratumumab. Marked tumor growth inhibition compared with controls was observed, with a median survival of 55 d for 277.5 kBq of (212)Pb-daratumumab instead of 11 d for phosphate-buffered saline. Conclusion: These results showed (212)Pb-daratumumab to have efficacy in xenografted mice, with significant tumor regression and increased survival. This study highlights the potency of α-RIT in MM treatment. Society of Nuclear Medicine 2020-07 /pmc/articles/PMC7383085/ /pubmed/31862796 http://dx.doi.org/10.2967/jnumed.119.239491 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 Radionuclide Therapy
Quelven, Isabelle
Monteil, Jacques
Sage, Magali
Saidi, Amal
Mounier, Jérémy
Bayout, Audrey
Garrier, Julie
Cogne, Michel
Durand-Panteix, Stéphanie
(212)Pb α-Radioimmunotherapy Targeting CD38 in Multiple Myeloma: A Preclinical Study
title (212)Pb α-Radioimmunotherapy Targeting CD38 in Multiple Myeloma: A Preclinical Study
title_full (212)Pb α-Radioimmunotherapy Targeting CD38 in Multiple Myeloma: A Preclinical Study
title_fullStr (212)Pb α-Radioimmunotherapy Targeting CD38 in Multiple Myeloma: A Preclinical Study
title_full_unstemmed (212)Pb α-Radioimmunotherapy Targeting CD38 in Multiple Myeloma: A Preclinical Study
title_short (212)Pb α-Radioimmunotherapy Targeting CD38 in Multiple Myeloma: A Preclinical Study
title_sort (212)pb α-radioimmunotherapy targeting cd38 in multiple myeloma: a preclinical study
topic Radionuclide Therapy
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7383085/
https://www.ncbi.nlm.nih.gov/pubmed/31862796
http://dx.doi.org/10.2967/jnumed.119.239491
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