Basic StudyBCMA-targeting Bispecific Antibody That Simultaneously Stimulates NKG2D-enhanced Efficacy Against Multiple MyelomaWang, Yang*; Li, Hui*; Xu, Wei*; Pan, Mingzhu*; Qiao, Chun†; Cai, Jialing*; Xu, Jingjing*; Wang, Min*; Zhang, Juan*Author Information *Antibody Engineering Laboratory, School of Life Science & Technology, China Pharmaceutical University †Department of Hematology, The First Affiliated Hospital of Nanjing Medical University, Jiangsu Province Hospital, Nanjing, China J.Z. and M.W. are co-corresponding author. Reprints: Juan Zhang, China Pharmaceutical University, #639 Longmian Avenue, Jiangning District, Nanjing 211198, China (e-mail: firstname.lastname@example.org). Journal of Immunotherapy: July/August 2020 - Volume 43 - Issue 6 - p 175-188 doi: 10.1097/CJI.0000000000000320 Buy SDC Metrics Abstract B-cell maturation antigen (BCMA) is a highly plasma cell-selective protein expressed on malignant plasma cells of patients with multiple myeloma (MM), and it is a defined therapeutic target. Major histocompatibility complex class I-related chain A (MICA) is frequently expressed in lymphoproliferative malignancies including MM. MICA activates natural killer (NK) cells and costimulates T cells by interaction with its immunoreceptor NK cell receptor G2D (NKG2D). Nonetheless, during full-blown MM, tumor cells promote efficient MICA shedding, which evokes NKG2D internalization and immune suppression. To enhance the directional killing efficacy of immune cells against myeloma cells, we constructed a novel bispecific antibody 2A9-MICA and explored its potential antimyeloma activity against MM. 2A9-MICA consists of human MICA extracellular region and a single–chain antibody fragment (scFv) that targets BCMA generated by phage display technology. In vitro, 2A9-MICA activated NK cell-mediated cytotoxicity and induced NK cells to kill BCMA–positive human myeloma cells. Moreover, in BCMA-positive, MM-bearing nude mice, 2A9-MICA specifically targeted tumor tissue, where it effectively recruited immune cells and inhibited tumor tissue growth showed superior antitumor activity. Taken together, bispecific antibody 2A9-MICA provides a new approach for MM-targeting immunotherapy and has attractive potential for clinical applications. Copyright © 2020 Wolters Kluwer Health, Inc. All rights reserved.