Cargando…

SOT101 induces NK cell cytotoxicity and potentiates antibody-dependent cell cytotoxicity and anti-tumor activity

SOT101 is a superagonist fusion protein of interleukin (IL)-15 and the IL-15 receptor α (IL-15Rα) sushi+ domain, representing a promising clinical candidate for the treatment of cancer. SOT101 among other immune cells specifically stimulates natural killer (NK) cells and memory CD8(+) T cells with n...

Descripción completa

Detalles Bibliográficos
Autores principales: Antosova, Zuzana, Podzimkova, Nada, Tomala, Jakub, Augustynkova, Katerina, Sajnerova, Katerina, Nedvedova, Eva, Sirova, Milada, de Martynoff, Guy, Bechard, David, Moebius, Ulrich, Kovar, Marek, Spisek, Radek, Adkins, Irena
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9590108/
https://www.ncbi.nlm.nih.gov/pubmed/36300122
http://dx.doi.org/10.3389/fimmu.2022.989895
_version_ 1784814443921670144
author Antosova, Zuzana
Podzimkova, Nada
Tomala, Jakub
Augustynkova, Katerina
Sajnerova, Katerina
Nedvedova, Eva
Sirova, Milada
de Martynoff, Guy
Bechard, David
Moebius, Ulrich
Kovar, Marek
Spisek, Radek
Adkins, Irena
author_facet Antosova, Zuzana
Podzimkova, Nada
Tomala, Jakub
Augustynkova, Katerina
Sajnerova, Katerina
Nedvedova, Eva
Sirova, Milada
de Martynoff, Guy
Bechard, David
Moebius, Ulrich
Kovar, Marek
Spisek, Radek
Adkins, Irena
author_sort Antosova, Zuzana
collection PubMed
description SOT101 is a superagonist fusion protein of interleukin (IL)-15 and the IL-15 receptor α (IL-15Rα) sushi+ domain, representing a promising clinical candidate for the treatment of cancer. SOT101 among other immune cells specifically stimulates natural killer (NK) cells and memory CD8(+) T cells with no significant expansion or activation of the regulatory T cell compartment. In this study, we showed that SOT101 induced expression of cytotoxic receptors NKp30, DNAM-1 and NKG2D on human NK cells. SOT101 stimulated dose-dependent proliferation and the relative expansion of both major subsets of human NK cells, CD56(bright)CD16(-) and CD56(dim)CD16(+), and these displayed an enhanced cytotoxicity in vitro. Using human PBMCs and isolated NK cells, we showed that SOT101 added concomitantly or used for immune cell pre-stimulation potentiated clinically approved monoclonal antibodies Cetuximab, Daratumumab and Obinutuzumab in killing of tumor cells in vitro. The anti-tumor efficacy of SOT101 in combination with Daratumumab was assessed in a solid multiple myeloma xenograft in CB17 SCID mouse model testing several combination schedules of administration in the early and late therapeutic setting of established tumors in vivo. SOT101 and Daratumumab monotherapies decreased with various efficacy tumor growth in vivo in dependence on the advancement of the tumor development. The combination of both drugs showed the strongest anti-tumor efficacy. Specifically, the sequencing of both drugs did not matter in the early therapeutic setting where a complete tumor regression was observed in all animals. In the late therapeutic treatment of established tumors Daratumumab followed by SOT101 administration or a concomitant administration of both drugs showed a significant anti-tumor efficacy over the respective monotherapies. These results suggest that SOT101 might significantly augment the anti-tumor activity of therapeutic antibodies by increasing NK cell-mediated activity in patients. These results support the evaluation of SOT101 in combination with Daratumumab in clinical studies and present a rationale for an optimal clinical dosing schedule selection.
format Online
Article
Text
id pubmed-9590108
institution National Center for Biotechnology Information
language English
publishDate 2022
publisher Frontiers Media S.A.
record_format MEDLINE/PubMed
spelling pubmed-95901082022-10-25 SOT101 induces NK cell cytotoxicity and potentiates antibody-dependent cell cytotoxicity and anti-tumor activity Antosova, Zuzana Podzimkova, Nada Tomala, Jakub Augustynkova, Katerina Sajnerova, Katerina Nedvedova, Eva Sirova, Milada de Martynoff, Guy Bechard, David Moebius, Ulrich Kovar, Marek Spisek, Radek Adkins, Irena Front Immunol Immunology SOT101 is a superagonist fusion protein of interleukin (IL)-15 and the IL-15 receptor α (IL-15Rα) sushi+ domain, representing a promising clinical candidate for the treatment of cancer. SOT101 among other immune cells specifically stimulates natural killer (NK) cells and memory CD8(+) T cells with no significant expansion or activation of the regulatory T cell compartment. In this study, we showed that SOT101 induced expression of cytotoxic receptors NKp30, DNAM-1 and NKG2D on human NK cells. SOT101 stimulated dose-dependent proliferation and the relative expansion of both major subsets of human NK cells, CD56(bright)CD16(-) and CD56(dim)CD16(+), and these displayed an enhanced cytotoxicity in vitro. Using human PBMCs and isolated NK cells, we showed that SOT101 added concomitantly or used for immune cell pre-stimulation potentiated clinically approved monoclonal antibodies Cetuximab, Daratumumab and Obinutuzumab in killing of tumor cells in vitro. The anti-tumor efficacy of SOT101 in combination with Daratumumab was assessed in a solid multiple myeloma xenograft in CB17 SCID mouse model testing several combination schedules of administration in the early and late therapeutic setting of established tumors in vivo. SOT101 and Daratumumab monotherapies decreased with various efficacy tumor growth in vivo in dependence on the advancement of the tumor development. The combination of both drugs showed the strongest anti-tumor efficacy. Specifically, the sequencing of both drugs did not matter in the early therapeutic setting where a complete tumor regression was observed in all animals. In the late therapeutic treatment of established tumors Daratumumab followed by SOT101 administration or a concomitant administration of both drugs showed a significant anti-tumor efficacy over the respective monotherapies. These results suggest that SOT101 might significantly augment the anti-tumor activity of therapeutic antibodies by increasing NK cell-mediated activity in patients. These results support the evaluation of SOT101 in combination with Daratumumab in clinical studies and present a rationale for an optimal clinical dosing schedule selection. Frontiers Media S.A. 2022-10-10 /pmc/articles/PMC9590108/ /pubmed/36300122 http://dx.doi.org/10.3389/fimmu.2022.989895 Text en Copyright © 2022 Antosova, Podzimkova, Tomala, Augustynkova, Sajnerova, Nedvedova, Sirova, de Martynoff, Bechard, Moebius, Kovar, Spisek and Adkins https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Immunology
Antosova, Zuzana
Podzimkova, Nada
Tomala, Jakub
Augustynkova, Katerina
Sajnerova, Katerina
Nedvedova, Eva
Sirova, Milada
de Martynoff, Guy
Bechard, David
Moebius, Ulrich
Kovar, Marek
Spisek, Radek
Adkins, Irena
SOT101 induces NK cell cytotoxicity and potentiates antibody-dependent cell cytotoxicity and anti-tumor activity
title SOT101 induces NK cell cytotoxicity and potentiates antibody-dependent cell cytotoxicity and anti-tumor activity
title_full SOT101 induces NK cell cytotoxicity and potentiates antibody-dependent cell cytotoxicity and anti-tumor activity
title_fullStr SOT101 induces NK cell cytotoxicity and potentiates antibody-dependent cell cytotoxicity and anti-tumor activity
title_full_unstemmed SOT101 induces NK cell cytotoxicity and potentiates antibody-dependent cell cytotoxicity and anti-tumor activity
title_short SOT101 induces NK cell cytotoxicity and potentiates antibody-dependent cell cytotoxicity and anti-tumor activity
title_sort sot101 induces nk cell cytotoxicity and potentiates antibody-dependent cell cytotoxicity and anti-tumor activity
topic Immunology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9590108/
https://www.ncbi.nlm.nih.gov/pubmed/36300122
http://dx.doi.org/10.3389/fimmu.2022.989895
work_keys_str_mv AT antosovazuzana sot101inducesnkcellcytotoxicityandpotentiatesantibodydependentcellcytotoxicityandantitumoractivity
AT podzimkovanada sot101inducesnkcellcytotoxicityandpotentiatesantibodydependentcellcytotoxicityandantitumoractivity
AT tomalajakub sot101inducesnkcellcytotoxicityandpotentiatesantibodydependentcellcytotoxicityandantitumoractivity
AT augustynkovakaterina sot101inducesnkcellcytotoxicityandpotentiatesantibodydependentcellcytotoxicityandantitumoractivity
AT sajnerovakaterina sot101inducesnkcellcytotoxicityandpotentiatesantibodydependentcellcytotoxicityandantitumoractivity
AT nedvedovaeva sot101inducesnkcellcytotoxicityandpotentiatesantibodydependentcellcytotoxicityandantitumoractivity
AT sirovamilada sot101inducesnkcellcytotoxicityandpotentiatesantibodydependentcellcytotoxicityandantitumoractivity
AT demartynoffguy sot101inducesnkcellcytotoxicityandpotentiatesantibodydependentcellcytotoxicityandantitumoractivity
AT becharddavid sot101inducesnkcellcytotoxicityandpotentiatesantibodydependentcellcytotoxicityandantitumoractivity
AT moebiusulrich sot101inducesnkcellcytotoxicityandpotentiatesantibodydependentcellcytotoxicityandantitumoractivity
AT kovarmarek sot101inducesnkcellcytotoxicityandpotentiatesantibodydependentcellcytotoxicityandantitumoractivity
AT spisekradek sot101inducesnkcellcytotoxicityandpotentiatesantibodydependentcellcytotoxicityandantitumoractivity
AT adkinsirena sot101inducesnkcellcytotoxicityandpotentiatesantibodydependentcellcytotoxicityandantitumoractivity