Monoclonal antibodies against surface antigens on MM cells, such as anti-SLAMF7 and anti-CD38 antibodies, represent an attractive therapeutic modality for the eradication of multiple myeloma (MM) cells. However, further exploration of target molecules is urgently needed for the development of more effective therapies. In the present study, we studied the expression of CD48 in a total of 74 primary MM samples derived from patients to evaluate SLAMF2 (CD48) as a candidate in mAb therapy for MM. Of 74 samples, 39 were subjected to SLAMF7 analysis. Most of the MM cells, defined as CD38 and CD138 double-positive cells, showed strong expression of CD48 or SLAMF7 independent of disease stage or treatment history. In these 39 samples, most MM cells showed expression of both SLAMF7 and CD48; however, several samples showed expression of either only CD48 or only SLAMF7, including seven cases that were only highly positive for SLAMF7, and five that were only highly positive for CD48. Our study demonstrates that the immune receptor CD48 is overexpressed on MM cells together with SLAMF7, and that CD48 may be considered as an alternative target for treatment of MM in cases showing weak expression of SLAMF7.
CD48 SLAMF Multiple myeloma Flow cytometry
This is a preview of subscription content, log in to check access.
We thank Ms. Chiori Fukuyama for her skillful technical assistance. The study received financial support from Bristol-Myers Squibb. We acknowledge the support of the Egyptian Ministry of Higher Education (Cultural Affairs Sector and Missions). This work was partly supported by a Grant-in-Aids for Scientific Research from the Ministry of Education, Culture, Sports, Science, and Technology (16K07179 & 16K09855), the National Cancer Center Research and Development Fund (26-A-4), and the Practical Research for Innovative Cancer Control from the Japan Agency for Medical Research and Development, AMED (15ck0106077h0002).
Compliance with ethical standards
Conflict of interest
MR received research funding from Celgene Co., Ltd. SI received research funding and declares Honoraria from Janssen Pharmaceutical K.K., and Celgene Co., Ltd. SI also received research funding from Kyowa Hakko Kirin Co., Ltd., Chugai Pharmaceutical Co., Ltd, Bristol-Myers Squibb, Takeda Yakuhin Co., Ltd., and Ono Pharmaceutical CO., Ltd.
Palumbo A, Mina R. Management of older adults with multiple myeloma. Blood Rev. 2013;27:133–42.CrossRefGoogle Scholar
Wang TF, Ahluwalia R, Fiala MA, Trinkaus KM, Cox DP, Jaenicke M, et al. The characteristics and outcomes of patients with multiple myeloma dual refractory or intolerant to bortezomib and lenalidomide in the era of carfilzomib and pomalidomide. Leuk Lymphoma. 2014;55:337–41.CrossRefGoogle Scholar
Tai YT, Li X, Tong X, Santos D, Otsuki T, Catley L, et al. Human anti-CD40 antagonist antibody triggers significant antitumor activity against human multiple myeloma. Cancer Res. 2005;65:5898–906.CrossRefGoogle Scholar
Phipps C, Chen Y, Gopalakrishnan S, Tan D. Daratumumab and its potential in the treatment of multiple myeloma: overview of the preclinical and clinical development. Ther Adv Hematol. 2015;6:120–7.CrossRefGoogle Scholar
van der Veer MS, de Weers M, van Kessel B, Bakker JM, Wittebol S, Parren PW, et al. Towards effective immunotherapy of myeloma: enhanced elimination of myeloma cells by combination of lenalidomide with the human CD38 monoclonal antibody daratumumab. Haematologica. 2011;96:284–90.CrossRefGoogle Scholar
Sondergeld P, van de Donk NW, Richardson PG, Plesner T. Monoclonal antibodies in myeloma. Clin Adv Hematol Oncol. 2015;13:599–609.Google Scholar
Yang J, Qian J, Wezeman M, Wang S, Lin P, Wang M, et al. Targeting beta2-microglobulin for induction of tumor apoptosis in human hematological malignancies. Cancer Cell. 2006;10:295–307.CrossRefGoogle Scholar
Hadari Y, Schlessinger J. FGFR3-targeted mAb therapy for bladder cancer and multiple myeloma. J Clin Investig. 2009;119:1077–9.CrossRefGoogle Scholar
Hosen N, Ichihara H, Mugitani A, Aoyama Y, Fukuda Y, Kishida S, et al. CD48 as a novel molecular target for antibody therapy in multiple myeloma. Br J Haematol. 2012;156:213–24.CrossRefGoogle Scholar
Muccio VE, Saraci E, Gilestro M, Gattei V, Zucchetto A, Astolfi M, et al. Multiple myeloma: new surface antigens for the characterization of plasma cells in the era of novel agents. Cytom Part B Clin Cytom. 2016;90:81–90.CrossRefGoogle Scholar
Calpe S, Wang N, Romero X, Berger SB, Lanyi A, Engel P, et al. The SLAM and SAP gene families control innate and adaptive immune responses. Adv Immunol. 2008;97:177–250.CrossRefGoogle Scholar
Cannons JL, Tangye SG, Schwartzberg PL. SLAM family receptors and SAP adaptors in immunity. Annu Rev Immunol. 2011;29:665–705.CrossRefGoogle Scholar
Collins SM, Bakan CE, Swartzel GD, Hofmeister CC, Efebera YA, Kwon H, et al. Elotuzumab directly enhances NK cell cytotoxicity against myeloma via CS1 ligation: evidence for augmented NK cell function complementing ADCC. Cancer Immunol Immunother. 2013;62:1841–9.CrossRefGoogle Scholar
Wang N, Morra M, Wu C, Gullo C, Howie D, Coyle T, et al. CD150 is a member of a family of genes that encode glycoproteins on the surface of hematopoietic cells. Immunogenetics. 2001;53:382–94.CrossRefGoogle Scholar
Boles KS, Stepp SE, Bennett M, Kumar V, Mathew PA. 2B4 (CD244) and CS1: novel members of the CD2 subset of the immunoglobulin superfamily molecules expressed on natural killer cells and other leukocytes. Immunol Rev. 2001;181:234–49.CrossRefGoogle Scholar
Thorley-Lawson DA, Poodry CA. Identification and isolation of the main component (gp350-gp220) of Epstein–Barr virus responsible for generating neutralizing antibodies in vivo. Immunol Rev. 2001;181:234–49.CrossRefGoogle Scholar
Sun H, Biggs JC, Smith GM. Antitumour activity of a chimeric antibody against the leucocyte antigen CD48. Cancer Immunol Immunother. 2000;48:595–602.CrossRefGoogle Scholar
Greenaway S, Henniker AJ, Walsh M, Bradstock KF. A pilot clinical trial of two murine monoclonal antibodies fixing human complement in patients with chronic lymphatic leukaemia. Leuk Lymphoma. 1994;13:323–31.CrossRefGoogle Scholar
Rajkumar SV, Dimopoulos MA, Palumbo A, Blade J, Merlini G, Mateos MV, et al. International Myeloma Working Group updated criteria for the diagnosis of multiple myeloma. Lancet Oncol. 2014;15:e538–48.CrossRefGoogle Scholar
Palumbo A, Avet-Loiseau H, Oliva S, Lokhorst HM, Goldschmidt H, Rosinol L, et al. Revised international staging system for multiple myeloma: a report from International Myeloma Working Group. J Clin Oncol. 2015;33:2863–9.CrossRefGoogle Scholar
Inagaki A, Tajima E, Uranishi M, Totani H, Asao Y, Ogura H, et al. Global real-time quantitative reverse transcription-polymerase chain reaction detecting proto-oncogenes associated with 14q32 chromosomal translocation as a valuable marker for predicting survival in multiple myeloma. Leuk Res. 2013;37:1648–55.CrossRefGoogle Scholar
Narita T, Ri M, Masaki A, Mori F, Ito A, Kusumoto S, et al. Lower expression of activating transcription factors 3 and 4 correlates with shorter progression-free survival in multiple myeloma patients receiving bortezomib plus dexamethasone therapy. Blood Cancer J. 2015;5:e373.CrossRefGoogle Scholar
Dimopoulos MA, Lonial S, Betts KA, Chen C, Zichlin ML, Brun A, et al. Elotuzumab plus lenalidomide and dexamethasone in relapsed/refractory multiple myeloma: extended 4-year follow-up and analysis of relative progression-free survival from the randomized ELOQUENT-2 trial. Cancer. 2018;124:4032–43.CrossRefGoogle Scholar
Dimopoulos MA, San-Miguel J, Belch A, White D, Benboubker L, Cook G, et al. Daratumumab plus lenalidomide and dexamethasone versus lenalidomide and dexamethasone in relapsed or refractory multiple myeloma: updated analysis of POLLUX. Haematologica. 2018;103:2088–96.CrossRefGoogle Scholar
Spencer A, Lentzsch S, Weisel K, Avet-Loiseau H, Mark TM, Spicka I, et al. Daratumumab plus bortezomib and dexamethasone versus bortezomib and dexamethasone in relapsed or refractory multiple myeloma: updated analysis of CASTOR. Haematologica. 2018;103:2079–87.CrossRefGoogle Scholar
Lewis TS, Olson D, Gordon K, Sandall S, Quick M, Finn M, et al. SGN-CD48A: a novel humanized anti-CD48 antibody-drug conjugate for the treatment of multiple myeloma. Blood. 2016;128:4470.Google Scholar