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An Antibody-Drug Conjugate That Selectively Targets Human Monocyte Progenitors for Anti-Cancer Therapy

As hematopoietic progenitors supply a large number of blood cells, therapeutic strategies targeting hematopoietic progenitors are potentially beneficial to eliminate unwanted blood cells, such as leukemic cells and immune cells causing diseases. However, due to their pluripotency, targeting those ce...

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Autores principales: Izumi, Yuta, Kanayama, Masashi, Shen, Zhongchuzi, Kai, Masayuki, Kawamura, Shunsuke, Akiyama, Megumi, Yamamoto, Masahide, Nagao, Toshikage, Okada, Keigo, Kawamata, Norihiko, Toyota, Shigeo, Ohteki, Toshiaki
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7937628/
https://www.ncbi.nlm.nih.gov/pubmed/33692791
http://dx.doi.org/10.3389/fimmu.2021.618081
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author Izumi, Yuta
Kanayama, Masashi
Shen, Zhongchuzi
Kai, Masayuki
Kawamura, Shunsuke
Akiyama, Megumi
Yamamoto, Masahide
Nagao, Toshikage
Okada, Keigo
Kawamata, Norihiko
Toyota, Shigeo
Ohteki, Toshiaki
author_facet Izumi, Yuta
Kanayama, Masashi
Shen, Zhongchuzi
Kai, Masayuki
Kawamura, Shunsuke
Akiyama, Megumi
Yamamoto, Masahide
Nagao, Toshikage
Okada, Keigo
Kawamata, Norihiko
Toyota, Shigeo
Ohteki, Toshiaki
author_sort Izumi, Yuta
collection PubMed
description As hematopoietic progenitors supply a large number of blood cells, therapeutic strategies targeting hematopoietic progenitors are potentially beneficial to eliminate unwanted blood cells, such as leukemic cells and immune cells causing diseases. However, due to their pluripotency, targeting those cells may impair the production of multiple cell lineages, leading to serious side effects such as anemia and increased susceptibility to infection. To minimize those side effects, it is important to identify monopotent progenitors that give rise to a particular cell lineage. Monocytes and monocyte-derived macrophages play important roles in the development of inflammatory diseases and tumors. Recently, we identified human monocyte-restricted progenitors, namely, common monocyte progenitors and pre-monocytes, both of which express high levels of CD64, a well-known monocyte marker. Here, we introduce a dimeric pyrrolobenzodiazepine (dPBD)-conjugated anti-CD64 antibody (anti-CD64-dPBD) that selectively induces the apoptosis of proliferating human monocyte-restricted progenitors but not non-proliferating mature monocytes. Treatment with anti-CD64-dPBD did not affect other types of hematopoietic cells including hematopoietic stem and progenitor cells, neutrophils, lymphocytes and platelets, suggesting that its off-target effects are negligible. In line with these findings, treatment with anti-CD64-dPBD directly killed proliferating monocytic leukemia cells and prevented monocytic leukemia cell generation from bone marrow progenitors of chronic myelomonocytic leukemia patients in a patient-derived xenograft model. Furthermore, by depleting the source of monocytes, treatment with anti-CD64-dPBD ultimately eliminated tumor-associated macrophages and significantly reduced tumor size in humanized mice bearing solid tumors. Given the selective action of anti-CD64-dPBD on proliferating monocyte progenitors and monocytic leukemia cells, it should be a promising tool to target cancers and other monocyte-related inflammatory disorders with minimal side effects on other cell lineages.
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spelling pubmed-79376282021-03-09 An Antibody-Drug Conjugate That Selectively Targets Human Monocyte Progenitors for Anti-Cancer Therapy Izumi, Yuta Kanayama, Masashi Shen, Zhongchuzi Kai, Masayuki Kawamura, Shunsuke Akiyama, Megumi Yamamoto, Masahide Nagao, Toshikage Okada, Keigo Kawamata, Norihiko Toyota, Shigeo Ohteki, Toshiaki Front Immunol Immunology As hematopoietic progenitors supply a large number of blood cells, therapeutic strategies targeting hematopoietic progenitors are potentially beneficial to eliminate unwanted blood cells, such as leukemic cells and immune cells causing diseases. However, due to their pluripotency, targeting those cells may impair the production of multiple cell lineages, leading to serious side effects such as anemia and increased susceptibility to infection. To minimize those side effects, it is important to identify monopotent progenitors that give rise to a particular cell lineage. Monocytes and monocyte-derived macrophages play important roles in the development of inflammatory diseases and tumors. Recently, we identified human monocyte-restricted progenitors, namely, common monocyte progenitors and pre-monocytes, both of which express high levels of CD64, a well-known monocyte marker. Here, we introduce a dimeric pyrrolobenzodiazepine (dPBD)-conjugated anti-CD64 antibody (anti-CD64-dPBD) that selectively induces the apoptosis of proliferating human monocyte-restricted progenitors but not non-proliferating mature monocytes. Treatment with anti-CD64-dPBD did not affect other types of hematopoietic cells including hematopoietic stem and progenitor cells, neutrophils, lymphocytes and platelets, suggesting that its off-target effects are negligible. In line with these findings, treatment with anti-CD64-dPBD directly killed proliferating monocytic leukemia cells and prevented monocytic leukemia cell generation from bone marrow progenitors of chronic myelomonocytic leukemia patients in a patient-derived xenograft model. Furthermore, by depleting the source of monocytes, treatment with anti-CD64-dPBD ultimately eliminated tumor-associated macrophages and significantly reduced tumor size in humanized mice bearing solid tumors. Given the selective action of anti-CD64-dPBD on proliferating monocyte progenitors and monocytic leukemia cells, it should be a promising tool to target cancers and other monocyte-related inflammatory disorders with minimal side effects on other cell lineages. Frontiers Media S.A. 2021-02-22 /pmc/articles/PMC7937628/ /pubmed/33692791 http://dx.doi.org/10.3389/fimmu.2021.618081 Text en Copyright © 2021 Izumi, Kanayama, Shen, Kai, Kawamura, Akiyama, Yamamoto, Nagao, Okada, Kawamata, Toyota and Ohteki http://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
Izumi, Yuta
Kanayama, Masashi
Shen, Zhongchuzi
Kai, Masayuki
Kawamura, Shunsuke
Akiyama, Megumi
Yamamoto, Masahide
Nagao, Toshikage
Okada, Keigo
Kawamata, Norihiko
Toyota, Shigeo
Ohteki, Toshiaki
An Antibody-Drug Conjugate That Selectively Targets Human Monocyte Progenitors for Anti-Cancer Therapy
title An Antibody-Drug Conjugate That Selectively Targets Human Monocyte Progenitors for Anti-Cancer Therapy
title_full An Antibody-Drug Conjugate That Selectively Targets Human Monocyte Progenitors for Anti-Cancer Therapy
title_fullStr An Antibody-Drug Conjugate That Selectively Targets Human Monocyte Progenitors for Anti-Cancer Therapy
title_full_unstemmed An Antibody-Drug Conjugate That Selectively Targets Human Monocyte Progenitors for Anti-Cancer Therapy
title_short An Antibody-Drug Conjugate That Selectively Targets Human Monocyte Progenitors for Anti-Cancer Therapy
title_sort antibody-drug conjugate that selectively targets human monocyte progenitors for anti-cancer therapy
topic Immunology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7937628/
https://www.ncbi.nlm.nih.gov/pubmed/33692791
http://dx.doi.org/10.3389/fimmu.2021.618081
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