CS1-specific single-domain antibodies labeled with Actinium-225 prolong survival and increase CD8+ T cells and PD-L1 expression in Multiple Myeloma

Multiple myeloma (MM) is a hematological malignancy characterized by the presence of clonal plasma cells in the bone marrow niche. Despite significant therapeutic advances, MM remains incurable for the majority of patients. Targeted radionuclide therapy (TRNT) has emerged as a promising treatment op...

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Autores principales:	Kim De Veirman, Janik Puttemans, Ahmet Krasniqi, Thomas Ertveldt, Heleen Hanssens, Ema Romao, Dirk Hose, Cleo Goyvaert, Philip Vlummens, Serge Muyldermans, Karine Breckpot, Frank Bruchertseifer, Alfred Morgenstern, Matthias D’Huyvetter, Nick Devoogdt
Formato:	article
Lenguaje:	EN
Publicado:	Taylor & Francis Group 2021
Materias:	multiple myeloma targeted radionuclide therapy single domain antibody cs1 Immunologic diseases. Allergy RC581-607 Neoplasms. Tumors. Oncology. Including cancer and carcinogens RC254-282
Acceso en línea:	https://doaj.org/article/5404affaa4564fd0a2b226d2759b274c
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spelling	oai:doaj.org-article:5404affaa4564fd0a2b226d2759b274c2021-11-11T14:23:43ZCS1-specific single-domain antibodies labeled with Actinium-225 prolong survival and increase CD8+ T cells and PD-L1 expression in Multiple Myeloma2162-402X10.1080/2162402X.2021.2000699https://doaj.org/article/5404affaa4564fd0a2b226d2759b274c2021-01-01T00:00:00Zhttp://dx.doi.org/10.1080/2162402X.2021.2000699https://doaj.org/toc/2162-402XMultiple myeloma (MM) is a hematological malignancy characterized by the presence of clonal plasma cells in the bone marrow niche. Despite significant therapeutic advances, MM remains incurable for the majority of patients. Targeted radionuclide therapy (TRNT) has emerged as a promising treatment option to eradicate residual cancer cells. In this study, we developed and characterized single-domain antibodies (sdAbs) against the MM-antigen CS1 and evaluated its therapeutic potential in MM using TRNT. We first validated CS1 as potential target for TRNT. CS1 is expressed in normal and malignant plasma cells in different disease stages including progression and relapse. It is expressed in dormant as well as proliferating MM cells, while low expression could be observed in environmental cells. Biodistribution studies demonstrated the specific uptake of anti-CS1 sdAbs in tissues of 5TMM cell infiltration including bone, spleen and liver. TRNT using anti-CS1 sdAbs labeled with actinium-225 significantly prolonged survival of syngeneic, immunocompetent 5T33MM mice. In addition, we observed an increase in CD8+ T-cells and more overall PD-L1 expression on immune and non-immune cells, implying an interferon gamma signature using actinium-225 labeled CS1-directed sdAbs. In this proof-of-principle study, we highlight, for the first time, the therapeutic potential and immunomodulating effects of anti-CS1 radionuclide therapy to target residual MM cells.Kim De VeirmanJanik PuttemansAhmet KrasniqiThomas ErtveldtHeleen HanssensEma RomaoDirk HoseCleo GoyvaertPhilip VlummensSerge MuyldermansKarine BreckpotFrank BruchertseiferAlfred MorgensternMatthias D’HuyvetterNick DevoogdtTaylor & Francis Grouparticlemultiple myelomatargeted radionuclide therapysingle domain antibodycs1Immunologic diseases. AllergyRC581-607Neoplasms. Tumors. Oncology. Including cancer and carcinogensRC254-282ENOncoImmunology, Vol 10, Iss 1 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	multiple myeloma targeted radionuclide therapy single domain antibody cs1 Immunologic diseases. Allergy RC581-607 Neoplasms. Tumors. Oncology. Including cancer and carcinogens RC254-282
spellingShingle	multiple myeloma targeted radionuclide therapy single domain antibody cs1 Immunologic diseases. Allergy RC581-607 Neoplasms. Tumors. Oncology. Including cancer and carcinogens RC254-282 Kim De Veirman Janik Puttemans Ahmet Krasniqi Thomas Ertveldt Heleen Hanssens Ema Romao Dirk Hose Cleo Goyvaert Philip Vlummens Serge Muyldermans Karine Breckpot Frank Bruchertseifer Alfred Morgenstern Matthias D’Huyvetter Nick Devoogdt CS1-specific single-domain antibodies labeled with Actinium-225 prolong survival and increase CD8+ T cells and PD-L1 expression in Multiple Myeloma
description	Multiple myeloma (MM) is a hematological malignancy characterized by the presence of clonal plasma cells in the bone marrow niche. Despite significant therapeutic advances, MM remains incurable for the majority of patients. Targeted radionuclide therapy (TRNT) has emerged as a promising treatment option to eradicate residual cancer cells. In this study, we developed and characterized single-domain antibodies (sdAbs) against the MM-antigen CS1 and evaluated its therapeutic potential in MM using TRNT. We first validated CS1 as potential target for TRNT. CS1 is expressed in normal and malignant plasma cells in different disease stages including progression and relapse. It is expressed in dormant as well as proliferating MM cells, while low expression could be observed in environmental cells. Biodistribution studies demonstrated the specific uptake of anti-CS1 sdAbs in tissues of 5TMM cell infiltration including bone, spleen and liver. TRNT using anti-CS1 sdAbs labeled with actinium-225 significantly prolonged survival of syngeneic, immunocompetent 5T33MM mice. In addition, we observed an increase in CD8+ T-cells and more overall PD-L1 expression on immune and non-immune cells, implying an interferon gamma signature using actinium-225 labeled CS1-directed sdAbs. In this proof-of-principle study, we highlight, for the first time, the therapeutic potential and immunomodulating effects of anti-CS1 radionuclide therapy to target residual MM cells.
format	article
author	Kim De Veirman Janik Puttemans Ahmet Krasniqi Thomas Ertveldt Heleen Hanssens Ema Romao Dirk Hose Cleo Goyvaert Philip Vlummens Serge Muyldermans Karine Breckpot Frank Bruchertseifer Alfred Morgenstern Matthias D’Huyvetter Nick Devoogdt
author_facet	Kim De Veirman Janik Puttemans Ahmet Krasniqi Thomas Ertveldt Heleen Hanssens Ema Romao Dirk Hose Cleo Goyvaert Philip Vlummens Serge Muyldermans Karine Breckpot Frank Bruchertseifer Alfred Morgenstern Matthias D’Huyvetter Nick Devoogdt
author_sort	Kim De Veirman
title	CS1-specific single-domain antibodies labeled with Actinium-225 prolong survival and increase CD8+ T cells and PD-L1 expression in Multiple Myeloma
title_short	CS1-specific single-domain antibodies labeled with Actinium-225 prolong survival and increase CD8+ T cells and PD-L1 expression in Multiple Myeloma
title_full	CS1-specific single-domain antibodies labeled with Actinium-225 prolong survival and increase CD8+ T cells and PD-L1 expression in Multiple Myeloma
title_fullStr	CS1-specific single-domain antibodies labeled with Actinium-225 prolong survival and increase CD8+ T cells and PD-L1 expression in Multiple Myeloma
title_full_unstemmed	CS1-specific single-domain antibodies labeled with Actinium-225 prolong survival and increase CD8+ T cells and PD-L1 expression in Multiple Myeloma
title_sort	cs1-specific single-domain antibodies labeled with actinium-225 prolong survival and increase cd8+ t cells and pd-l1 expression in multiple myeloma
publisher	Taylor & Francis Group
publishDate	2021
url	https://doaj.org/article/5404affaa4564fd0a2b226d2759b274c
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CS1-specific single-domain antibodies labeled with Actinium-225 prolong survival and increase CD8+ T cells and PD-L1 expression in Multiple Myeloma

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