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

Autor:	Izumi Y; Department of Biodefense Research, Medical Research Institute, Tokyo Medical and Dental University (TMDU), Tokyo, Japan., Kanayama M; Department of Biodefense Research, Medical Research Institute, Tokyo Medical and Dental University (TMDU), Tokyo, Japan., Shen Z; Oncology Research Laboratories, Oncology R&D Unit, R&D Division, Kyowa Kirin Co., Ltd., Tokyo, Japan., Kai M; Oncology Research Laboratories, Oncology R&D Unit, R&D Division, Kyowa Kirin Co., Ltd., Tokyo, Japan., Kawamura S; Department of Biodefense Research, Medical Research Institute, Tokyo Medical and Dental University (TMDU), Tokyo, Japan., Akiyama M; Department of Biodefense Research, Medical Research Institute, Tokyo Medical and Dental University (TMDU), Tokyo, Japan.; Department of Hematology, Tokyo Medical and Dental University (TMDU), Tokyo, Japan., Yamamoto M; Department of Hematology, Tokyo Medical and Dental University (TMDU), Tokyo, Japan., Nagao T; Department of Hematology, Tokyo Medical and Dental University (TMDU), Tokyo, Japan., Okada K; Department of Hematology, Tokyo Medical and Dental University (TMDU), Tokyo, Japan., Kawamata N; Department of Hematology, Tokyo Medical and Dental University (TMDU), Tokyo, Japan., Toyota S; Department of Hematology, Yokosuka Kyosai Hospital, Kanagawa, Japan., Ohteki T; Department of Biodefense Research, Medical Research Institute, Tokyo Medical and Dental University (TMDU), Tokyo, Japan.
Jazyk:	angličtina
Zdroj:	Frontiers in immunology [Front Immunol] 2021 Feb 22; Vol. 12, pp. 618081. Date of Electronic Publication: 2021 Feb 22 (Print Publication: 2021).
DOI:	10.3389/fimmu.2021.618081
Abstrakt:	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. Competing Interests: MKai and ZS are employees of Kyowa Kirin Co., Ltd. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. (Copyright © 2021 Izumi, Kanayama, Shen, Kai, Kawamura, Akiyama, Yamamoto, Nagao, Okada, Kawamata, Toyota and Ohteki.)
Databáze:	MEDLINE
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