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Daratumumab-(225)Actinium conjugate demonstrates greatly enhanced antitumor activity against experimental multiple myeloma tumors

Daratumumab is an anti-CD38 directed monoclonal antibody approved for the treatment of multiple myeloma (MM) and functions primarily via Fc-mediated effector mechanisms such as complement-dependent cytotoxicity (CDC), antibody-dependent cell cytotoxicity (ADCC), antibody-dependent cellular phagocyto...

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Autores principales: Dawicki, Wojciech, Allen, Kevin J.H., Jiao, Rubin, Malo, Mackenzie E., Helal, Muath, Berger, Mark S., Ludwig, Dale L., Dadachova, Ekaterina
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Taylor & Francis 2019
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6682347/
https://www.ncbi.nlm.nih.gov/pubmed/31413916
http://dx.doi.org/10.1080/2162402X.2019.1607673
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author Dawicki, Wojciech
Allen, Kevin J.H.
Jiao, Rubin
Malo, Mackenzie E.
Helal, Muath
Berger, Mark S.
Ludwig, Dale L.
Dadachova, Ekaterina
author_facet Dawicki, Wojciech
Allen, Kevin J.H.
Jiao, Rubin
Malo, Mackenzie E.
Helal, Muath
Berger, Mark S.
Ludwig, Dale L.
Dadachova, Ekaterina
author_sort Dawicki, Wojciech
collection PubMed
description Daratumumab is an anti-CD38 directed monoclonal antibody approved for the treatment of multiple myeloma (MM) and functions primarily via Fc-mediated effector mechanisms such as complement-dependent cytotoxicity (CDC), antibody-dependent cell cytotoxicity (ADCC), antibody-dependent cellular phagocytosis, and T-cell activation. However, not all patients respond to daratumumab therapy and management of MM remains challenging. Radioimmunotherapy with alpha particle-emitting radionuclides represents a promising approach to significantly enhance the potency of therapeutic antibodies in cancer treatment. Here we report the results of mechanistic and feasibility studies using daratumumab radiolabeled with an alpha-emitter (225)Actinium for therapy of MM. CD38-positivelymphoma Daudi cell line and MM cell lines KMS-28BM and KMS-28PE were treated in vitro with (225)Ac-daratumumab. (225)Ac-daratumumab Fc-functional properties were assessed with C1q binding and ADCC assays. The pharmacokinetics and tumor uptake of (111)In-daratumumab in Daudi tumor-bearing severe combined immunodeficiency (SCID) mice were measured with microSPECT/CT. The therapeutic effects of (225)Ac-daratumumab on Daudi and KSM28BM tumors in mice and treatment side effects were evaluated for 50 days posttreatment. The safety of (225)Ac-labeled antimurine CD38 mAb in immunocompetent mice was also evaluated. (225)Ac-daratumumab efficiently and specifically killed CD38-positive tumor cells in vitro, while its complement binding and ADCC functions remained unaltered. MicroSPECT/CT imaging demonstrated fast clearance of the radiolabeled daratumumab from the circulation and tissues, but prolonged retention in the tumor up to 10 days. Therapy and safety experiments with (225)Ac-daratumumab showed a significant increase in the antitumor potency in comparison to naked antibody without any significant side effects. Our results highlight the potential of targeting alpha-emitters to tumors as a therapeutic approach and suggest that (225)Ac-daratumumab may be a promising therapeutic strategy for the treatment of hematologic malignancies.
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spelling pubmed-66823472019-08-14 Daratumumab-(225)Actinium conjugate demonstrates greatly enhanced antitumor activity against experimental multiple myeloma tumors Dawicki, Wojciech Allen, Kevin J.H. Jiao, Rubin Malo, Mackenzie E. Helal, Muath Berger, Mark S. Ludwig, Dale L. Dadachova, Ekaterina Oncoimmunology Original Research Daratumumab is an anti-CD38 directed monoclonal antibody approved for the treatment of multiple myeloma (MM) and functions primarily via Fc-mediated effector mechanisms such as complement-dependent cytotoxicity (CDC), antibody-dependent cell cytotoxicity (ADCC), antibody-dependent cellular phagocytosis, and T-cell activation. However, not all patients respond to daratumumab therapy and management of MM remains challenging. Radioimmunotherapy with alpha particle-emitting radionuclides represents a promising approach to significantly enhance the potency of therapeutic antibodies in cancer treatment. Here we report the results of mechanistic and feasibility studies using daratumumab radiolabeled with an alpha-emitter (225)Actinium for therapy of MM. CD38-positivelymphoma Daudi cell line and MM cell lines KMS-28BM and KMS-28PE were treated in vitro with (225)Ac-daratumumab. (225)Ac-daratumumab Fc-functional properties were assessed with C1q binding and ADCC assays. The pharmacokinetics and tumor uptake of (111)In-daratumumab in Daudi tumor-bearing severe combined immunodeficiency (SCID) mice were measured with microSPECT/CT. The therapeutic effects of (225)Ac-daratumumab on Daudi and KSM28BM tumors in mice and treatment side effects were evaluated for 50 days posttreatment. The safety of (225)Ac-labeled antimurine CD38 mAb in immunocompetent mice was also evaluated. (225)Ac-daratumumab efficiently and specifically killed CD38-positive tumor cells in vitro, while its complement binding and ADCC functions remained unaltered. MicroSPECT/CT imaging demonstrated fast clearance of the radiolabeled daratumumab from the circulation and tissues, but prolonged retention in the tumor up to 10 days. Therapy and safety experiments with (225)Ac-daratumumab showed a significant increase in the antitumor potency in comparison to naked antibody without any significant side effects. Our results highlight the potential of targeting alpha-emitters to tumors as a therapeutic approach and suggest that (225)Ac-daratumumab may be a promising therapeutic strategy for the treatment of hematologic malignancies. Taylor & Francis 2019-05-01 /pmc/articles/PMC6682347/ /pubmed/31413916 http://dx.doi.org/10.1080/2162402X.2019.1607673 Text en © 2019 The Author(s). Published with license by Taylor & Francis Group, LLC. http://creativecommons.org/licenses/by-nc-nd/4.0/ This is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivatives License (http://creativecommons.org/licenses/by-nc-nd/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited, and is not altered, transformed, or built upon in any way.
spellingShingle Original Research
Dawicki, Wojciech
Allen, Kevin J.H.
Jiao, Rubin
Malo, Mackenzie E.
Helal, Muath
Berger, Mark S.
Ludwig, Dale L.
Dadachova, Ekaterina
Daratumumab-(225)Actinium conjugate demonstrates greatly enhanced antitumor activity against experimental multiple myeloma tumors
title Daratumumab-(225)Actinium conjugate demonstrates greatly enhanced antitumor activity against experimental multiple myeloma tumors
title_full Daratumumab-(225)Actinium conjugate demonstrates greatly enhanced antitumor activity against experimental multiple myeloma tumors
title_fullStr Daratumumab-(225)Actinium conjugate demonstrates greatly enhanced antitumor activity against experimental multiple myeloma tumors
title_full_unstemmed Daratumumab-(225)Actinium conjugate demonstrates greatly enhanced antitumor activity against experimental multiple myeloma tumors
title_short Daratumumab-(225)Actinium conjugate demonstrates greatly enhanced antitumor activity against experimental multiple myeloma tumors
title_sort daratumumab-(225)actinium conjugate demonstrates greatly enhanced antitumor activity against experimental multiple myeloma tumors
topic Original Research
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6682347/
https://www.ncbi.nlm.nih.gov/pubmed/31413916
http://dx.doi.org/10.1080/2162402X.2019.1607673
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