Combination with a defucosylated anti-HM1.24 monoclonal antibody plus lenalidomide induces marked ADCC against myeloma cells and their progenitors

Takeshi Harada; Shuji Ozaki; Asuka Oda; Daisuke Tsuji; Akishige Ikegame; Masami Iwasa; Kengo Udaka; Shiro Fujii; Shingen Nakamura; Hirokazu Miki; Kumiko Kagawa; Yoshiaki Kuroda; Shigeto Kawai; Kohji Itoh; Hisafumi Yamada-Okabe; Toshio Matsumoto; Masahiro Abe

doi:10.1371/journal.pone.0083905

Combination with a defucosylated anti-HM1.24 monoclonal antibody plus lenalidomide induces marked ADCC against myeloma cells and their progenitors

PLoS One. 2013 Dec 26;8(12):e83905. doi: 10.1371/journal.pone.0083905. eCollection 2013.

Authors

Takeshi Harada¹, Shuji Ozaki², Asuka Oda¹, Daisuke Tsuji³, Akishige Ikegame⁴, Masami Iwasa¹, Kengo Udaka¹, Shiro Fujii¹, Shingen Nakamura¹, Hirokazu Miki¹, Kumiko Kagawa¹, Yoshiaki Kuroda⁵, Shigeto Kawai⁶, Kohji Itoh³, Hisafumi Yamada-Okabe⁷, Toshio Matsumoto¹, Masahiro Abe¹

Affiliations

¹ Department of Medicine and Bioregulatory Sciences, Graduate School of Medical Sciences, University of Tokushima, Tokushima, Japan.
² Department of Hematology, Tokushima Prefectural Central Hospital, Tokushima, Japan.
³ Department of Medicinal Biotechnology, Graduate School of Pharmaceutical Sciences, University of Tokushima, Tokushima, Japan.
⁴ Division of Medical Technology, Tokushima University Hospital, Tokushima, Japan.
⁵ Department of Hematology and Oncology, RIRBM, Hiroshima University, Hiroshima, Japan.
⁶ Research Division, Forerunner Pharma Research Co. Ltd., Tokyo, Japan.
⁷ Research Division, Chugai Pharmaceutical Co. Ltd., Kanagawa, Japan.

Abstract

The immunomodulatory drug lenalidomide (Len) has drawn attention to potentiate antibody-dependent cellular cytotoxicity (ADCC)-mediated immunotherapies. We developed the defucosylated version (YB-AHM) of humanized monoclonal antibody against HM1.24 (CD317) overexpressed in multiple myeloma (MM) cells. In this study, we evaluated ADCC by YB-AHM and Len in combination against MM cells and their progenitors. YB-AHM was able to selectively kill via ADCC MM cells in bone marrow samples from patients with MM with low effector/target ratios, which was further enhanced by treatment with Len. Interestingly, Len also up-regulated HM1.24 expression on MM cells in an effector-dependent manner. HM1.24 was found to be highly expressed in a drug-resistant clonogenic "side population" in MM cells; and this combinatory treatment successfully reduced SP fractions in RPMI 8226 and KMS-11 cells in the presence of effector cells, and suppressed a clonogenic potential of MM cells in colony-forming assays. Collectively, the present study suggests that YB-AHM and Len in combination may become an effective therapeutic strategy in MM, warranting further study to target drug-resistant MM clonogenic cells.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Aged
Aged, 80 and over
Antibodies, Monoclonal, Humanized / immunology
Antibodies, Monoclonal, Humanized / metabolism
Antibodies, Monoclonal, Humanized / pharmacology*
Antibody-Dependent Cell Cytotoxicity / drug effects*
Antigens, CD / immunology*
Antigens, CD / metabolism
Antineoplastic Combined Chemotherapy Protocols
Cell Line, Tumor
Drug Synergism
Female
GPI-Linked Proteins / immunology
GPI-Linked Proteins / metabolism
Glycosylation
Humans
Immunotherapy
Lenalidomide
Male
Middle Aged
Multiple Myeloma / immunology*
Multiple Myeloma / pathology*
Neoplastic Stem Cells / drug effects*
Neoplastic Stem Cells / immunology
Neoplastic Stem Cells / pathology
Side-Population Cells / drug effects
Side-Population Cells / pathology
Thalidomide / analogs & derivatives*
Thalidomide / pharmacology
Up-Regulation / drug effects

Substances

Antibodies, Monoclonal, Humanized
Antigens, CD
BST2 protein, human
GPI-Linked Proteins
Thalidomide
Lenalidomide

Grants and funding

This work was supported in part by Grants-in-Aid for Scientific Research (C) for S.O. and M.A. and (A) for T.M. from the Ministry of Education, Culture, Sports, Science and Technology of Japan. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. No additional external funding received for this study.