Combination with a Defucosylated Anti-HM1.24 Monoclonal Antibody plus Lenalidomide Induces Marked ADCC against Myeloma Cells and Their Progenitors

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

doi:10.1371/journal.pone.0083905

Takeshi Harada, Masami Iwasa + Show 16 more

Open Access

https://doi.org/10.1371/journal.pone.0083905

Copy DOI

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.

Highlights

Multiple myeloma (MM) is characterized by the accumulation of neoplastic plasma cells in the bone marrow [1]
This result suggests that monoclonal antibody (mAb) against surface molecules commonly shared by MM cells and their progenitors are able to impair clonogenic MM cells or MM cancer stem cells (CSCs), MM CSCs are resistant to chemotherapeutic agents
We evaluated whether pretreatment of PBMCs with Len further enhances the antibody-dependent cellular cytotoxicity (ADCC) activity of YB-antiHM1.24 mAb (AHM)

Summary

Introduction

Multiple myeloma (MM) is characterized by the accumulation of neoplastic plasma cells in the bone marrow [1]. We are currently focusing on the development of monoclonal antibody (mAb)-based immunotherapies that can target MM CSCs. Our recent study has shown that a small molecule antibody specific to human leukocyte antigen (HLA) class I can inhibit side population (SP) cells with the characteristics of CSCs in MM which express high levels of HLA [6]. Our recent study has shown that a small molecule antibody specific to human leukocyte antigen (HLA) class I can inhibit side population (SP) cells with the characteristics of CSCs in MM which express high levels of HLA [6] This result suggests that mAbs against surface molecules commonly shared by MM cells and their progenitors are able to impair clonogenic MM cells or MM CSCs, MM CSCs are resistant to chemotherapeutic agents

Methods

Results

Conclusion