Monoclonal antibody Daratumumab promotes macrophage-mediated anti-myeloma phagocytic activity via engaging FC gamma receptor and activation of macrophages.

Publisher: Springer Country of Publication: Netherlands NLM ID: 0364456 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1573-4919 (Electronic) Linking ISSN: 03008177 NLM ISO Abbreviation: Mol Cell Biochem Subsets: MEDLINE

Publication: New York : Springer
Original Publication: The Hague, Dr. W. Junk B. V. Publishers.

Antibodies, Monoclonal*/immunology ; Antibodies, Monoclonal*/pharmacology ; Macrophages*/immunology ; Macrophages*/pathology ; Multiple Myeloma*/drug therapy ; Multiple Myeloma*/immunology ; Multiple Myeloma*/pathology ; Receptors, IgG*/immunology; Animals ; Humans ; Mice ; Mice, SCID

Daratumumab (DAR) is novel human anti-CD38 IgG1, high-affinity human monoclonal antibody having broad-spectrum killing activity. The antibody is recommended to treat multiple myeloma. Recently Antibody-dependent cellular phagocytosis (ADCP) have been identified as the potential mechanism of DAR in addition to complement-dependent cytotoxicity (CDC) and antibody-dependent cell-mediated cytotoxicity (ADCC). In the present study we evaluated the effect of Daratumumab on other effector cells of multiple myeloma. Luciferase ⁺ MM.1R GFP cells were selected for the study. For immune-compromised multiple myeloma tumour xenograft mouse model we used severe combined immunodeficient beige (SCID-beige), NOD SCID gamma (NSG) and C57Bl/6j mice. Bioluminescence imaging was carried by injecting luciferin, and in vivo confocal microscopy was done for tracing bone marrow niches. Spleen and tumours were submitted to immunophenotypic analysis. MTT assay was done for cell proliferation studies. We established tumour xenograft mouse model. It was found that DAR showed significant anti-tumour effect in tumour xenograft multiple myeloma mice. We found that DAR showed anti-tumour activity via Fc-FcγR interaction with macrophages. DAR induced phenotypic activation of macrophages in mice and resulted in ADCP of cancerous cells via interacting Fc-FcγR in vitro. The study suggested that DAR exerted anti-tumour activity in multiple myeloma by interacting with Fc-FcγR.
(© 2022. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Siegel R, Naishadham D, Jemal A (2012) Cancer statistics. CA Cancer J Clin 62(1):10–29. https://doi.org/10.3322/caac.20138. (PMID: 10.3322/caac.2013822237781)
Rajkumar SV (2011) Treatment of multiple myeloma. Nat Rev Clin Oncol. 8(8):479–91. https://doi.org/10.1038/nrclinonc.2011.63. (PMID: 10.1038/nrclinonc.2011.63215221243773461)
Yang Y (2015) Cancer immunotherapy: harnessing the immune system to battle cancer. J Clin Invest 125(9):3335–3337. https://doi.org/10.1172/JCI83871. (PMID: 10.1172/JCI83871263250314588312)
Weiner LM, Dhodapkar MV, Ferrone S (2009) Monoclonal antibodies for cancer immunotherapy. Lancet 373:1033–1040. https://doi.org/10.1007/s11033-018-4427-x. (PMID: 10.1007/s11033-018-4427-x193040162677705)
Scott AM, Wolchok JD, Old LJ (2012) Antibody therapy of cancer. Nat Rev Cancer 12:278–287. https://doi.org/10.1038/nrc3236. (PMID: 10.1038/nrc323622437872)
de Weers M, Tai YT, van der Veer MS, Bakker JM, Vink T, Jacobs DC, Oomen LA, Peipp M, Valerius T, Slootstra JW, Mutis T, Bleeker WK, Anderson KC, Lokhorst HM, van de Winkel JG, Parren PW (2011) Daratumumab, a novel therapeutic human CD38 monoclonal antibody, induces killing of multiple myeloma and other hematological tumors. J Immunol 186(3):1840–1848. https://doi.org/10.4049/jimmunol.1003032. (PMID: 10.4049/jimmunol.100303221187443)
Nimmerjahn F, Ravetch JV (2008) Fc gamma receptors as regulators of immune responses. Nat Rev Immunol 8:34–47. https://doi.org/10.1038/nri2206. (PMID: 10.1038/nri220618064051)
Veillette A, Guo H (2013) CS1, a SLAM family receptor involved in immune regulation, is a therapeutic target in multiple myeloma. Crit Rev Oncol Hematol 88:168–177. https://doi.org/10.1016/j.critrevonc.2013.04.003. (PMID: 10.1016/j.critrevonc.2013.04.00323731618)
Asimakopoulos F, Kim J, Denu RA, Hope C, Jensen JL, Ollar SJ, Hebron E, Flanagan C, Callander N, Hematti P (2013) Macrophages in multiple myeloma: emerging concepts and therapeutic implications. Leuk Lymphoma 54(10):2112–2121. https://doi.org/10.3109/10428194.2013.778409. (PMID: 10.3109/10428194.2013.778409234326913686978)
Weiskopf K, Weissman IL (2015) Macrophages are critical effectors of antibody therapies for cancer. MAbs 7:303–310. https://doi.org/10.1080/19420862.2015.1011450. (PMID: 10.1080/19420862.2015.1011450256679854622600)
Gül N, van Egmond M (2015) Antibody-dependent phagocytosis of tumor cells by macrophages: a potent effector mechanism of monoclonal antibody therapy of cancer. Can Res 75(23):5008–5013. https://doi.org/10.1158/0008-5472.CAN-15-1330. (PMID: 10.1158/0008-5472.CAN-15-1330)
Shi Y, Fan X, Deng H, Brezski RJ, Rycyzyn M, Jordan RE, Strohl WR, Zou Q, Zhang N, An Z (2015) Trastuzumab triggers phagocytic killing of high HER2 cancer cells in vitro and in vivo by interaction with Fcγ receptors on macrophages. J Immunol 194(9):4379–4386. https://doi.org/10.4049/jimmunol.1402891. (PMID: 10.4049/jimmunol.140289125795760)
Chao MP, Alizadeh AA, Tang C, Myklebust JH, Varghese B, Gill S, Jan M, Cha AC, Chan CK, Tan BT, Park CY, Zhao F, Kohrt HE, Malumbres R, Briones J, Gascoyne RD, Lossos IS, Levy R, Weissman IL, Majeti R (2010) Anti-CD47 antibody synergizes with rituximab to promote phagocytosis and eradicate non-Hodgkin lymphoma. Cell 142(5):699–713. https://doi.org/10.1016/j.cell.2010.07.044. (PMID: 10.1016/j.cell.2010.07.044208132592943345)
Overdijk MB, Verploegen S, Bögels M, van Egmond M, Lammerts van Bueren JJ, Mutis T, Groen RW, Breij E, Martens AC, Bleeker WK, Parren PW (2015) Antibody-mediated phagocytosis contributes to the anti-tumor activity of the therapeutic antibody daratumumab in lymphoma and multiple myeloma. MAbs 7(2):311–321. https://doi.org/10.1080/19420862.2015.1007813. (PMID: 10.1080/19420862.2015.1007813257607674622648)
Bezman NA, Jhatakia A, Kearney AY, Brender T, Maurer M, Henning K, Jenkins MR, Rogers AJ, Neeson PJ, Korman AJ, Robbins MD, Graziano RF (2017) PD-1 blockade enhances elotuzumab efficacy in mouse tumor models. Blood Adv 1(12):753–765. https://doi.org/10.1182/bloodadvances.2017004382. (PMID: 10.1182/bloodadvances.2017004382292967195728054)
Tomayko MM, Reynolds CP (1989) Determination of subcutaneous tumor size in athymic (nude) mice. Cancer Chemother Pharmacol 24:148–154. https://doi.org/10.1007/BF00300234. (PMID: 10.1007/BF003002342544306)
Cassetta L, Noy R, Swierczak A, Sugano G, Smith H, Wiechmann L, Pollard JW (2016) Isolation of mouse and human tumor-associated macrophages. Adv Exp Med Biol 899:211–229. https://doi.org/10.1007/978-3-319-26666-4_12. (PMID: 10.1007/978-3-319-26666-4_12273252695024544)
Rossi M, Botta C, Arbitrio M, Grembiale RD, Tagliaferri P, Tassone P (2018) Mouse models of multiple myeloma: technologic platforms and perspectives. Oncotarget 9(28):20119–20133. https://doi.org/10.18632/oncotarget.24614. (PMID: 10.18632/oncotarget.24614297320085929451)
Matas-Céspedes A, Vidal-Crespo A, Rodriguez V, Villamor N, Delgado J, Giné E, Roca-Ho H, Menéndez P, Campo E, López-Guillermo A, Colomer D, Roué G, Wiestner A, Parren PW, Doshi P, van Bueren JL, Pérez-Galán P (2017) The human CD38 monoclonal antibody daratumumab shows antitumor activity and hampers leukemia-microenvironment interactions in chronic lymphocytic leukemia. Clin Cancer Res 23(6):1493–1505. https://doi.org/10.1158/1078-0432.CCR-15-2095. (PMID: 10.1158/1078-0432.CCR-15-209527637890)
Wang C, Yu X, Cao Q, Wang Y, Zheng G, Tan TK, Zhao H, Zhao Y, Wang Y, Harris DCh (2013) Characterization of murine macrophages from bone marrow, spleen and peritoneum. BMC Immunol 14:6. https://doi.org/10.1186/1471-2172-14-6. (PMID: 10.1186/1471-2172-14-6233842303574850)
Qian BZ, Pollard JW (2010) Macrophage diversity enhances tumor progression and metastasis. Cell 141:39–51. https://doi.org/10.1016/j.cell.2010.03.014. (PMID: 10.1016/j.cell.2010.03.014203713444994190)
Suyanı E, Sucak GT, Akyürek N, Sahin S, Baysal NA, Yağcı M, Haznedar R (2013) Tumor-associated macrophages as a prognostic parameter in multiple myeloma. Ann Hematol 92(5):669–677. https://doi.org/10.1007/s00277-012-1652-6. (PMID: 10.1007/s00277-012-1652-623334187)
Andersen MN, Abildgaard N, Maniecki MB, Møller HJ, Andersen NF (2014) Monocyte/macrophage-derived soluble CD163: a novel biomarker in multiple myeloma. Eur J Haematol 93:41–47. https://doi.org/10.1111/ejh.12296. (PMID: 10.1111/ejh.1229624612259)
Noy R, Pollard JW (2014) Tumor-associated macrophages: from mechanisms to therapy. Immunity 41:49–61. https://doi.org/10.1016/j.immuni.2014.06.010. (PMID: 10.1016/j.immuni.2014.06.010250359534137410)
Gutiérrez-González A, Martínez-Moreno M, Samaniego R, Arellano-Sánchez N, Salinas-Muñoz L, Relloso M, Valeri A, Martínez-López J, Corbí ÁL, Hidalgo A, García-Pardo Á, Teixidó J, Sánchez-Mateos P (2016) Evaluation of the potential therapeutic benefits of macrophage reprogramming in multiple myeloma. Blood 128(18):2241–2252. https://doi.org/10.1182/blood-2016-01-695395. (PMID: 10.1182/blood-2016-01-69539527625360)
Georgoudaki AM, Prokopec KE, Boura VF, Hellqvist E, Sohn S, Östling J, Dahan R, Harris RA, Rantalainen M, Klevebring D, Sund M, Brage SE, Fuxe J, Rolny C, Li F, Ravetch JV, Karlsson MC (2016) Reprogramming tumor-associated macrophages by antibody targeting inhibits cancer progression and metastasis. Cell Rep 15(9):2000–2011. https://doi.org/10.1016/j.celrep.2016.04.084. (PMID: 10.1016/j.celrep.2016.04.08427210762)
Jensen JL, Rakhmilevich A, Heninger E, Broman AT, Hope C, Phan F, Miyamoto S, Maroulakou I, Callander N, Hematti P, Chesi M, Bergsagel PL, Sondel P, Asimakopoulos F (2015) Tumoricidal Effects of Macrophage-Activating Immunotherapy in a Murine Model of Relapsed/Refractory Multiple Myeloma. Cancer Immunol Res 8:881–890. https://doi.org/10.1158/2326-6066.CIR-15-0025-T. (PMID: 10.1158/2326-6066.CIR-15-0025-T)
Barnhart BC, Quigley M (2017) Role of Fc–FcgR interactions in the antitumor activity of therapeutic antibodies. Immunol Cell Biol 95:340–346. https://doi.org/10.1038/icb.2016.121. (PMID: 10.1038/icb.2016.12127974746)
Roussou M, Tasidou A, Dimopoulos MA, Kastritis E, Migkou M, Christoulas D, Gavriatopoulou M, Zagouri F, Matsouka C, Anagnostou D, Terpos E (2009) Increased expression of macrophage inflammatory protein-1alpha on trephine biopsies correlates with extensive bone disease, increased angiogenesis and advanced stage in newly diagnosed patients with multiple myeloma. Leukemia 23(11):2177–2181. https://doi.org/10.1038/leu.2009.130. (PMID: 10.1038/leu.2009.13019587705)
Zhu EF, Gai SA, Opel CF, Kwan BH, Surana R, Mihm MC, Kauke MJ, Moynihan KD, Angelini A, Williams RT, Stephan MT, Kim JS, Yaffe MB, Irvine DJ, Weiner LM, Dranoff G, Wittrup KD (2015) Synergistic innate and adaptive immune response to combination immunotherapy with anti-tumor antigen antibodies and extended serum half-life IL-2. Cancer Cell 27(4):489–501. https://doi.org/10.1016/j.ccell.2015.03.004. (PMID: 10.1016/j.ccell.2015.03.004258731724398916)
Viola D, Dona A, Caserta E, Troadec E, Besi F, McDonald T, Ghoda L, Gunes EG, Sanchez JF, Khalife J, Martella M, Karanes C, Htut M, Wang X, Rosenzweig M, Chowdhury A, Sborov D, Miles RR, Yazaki PJ, Ebner T, Hofmeister CC, Forman SJ, Rosen ST, Marcucci G, Shively J, Keats JJ, Krishnan A, Pichiorri F (2021) Daratumumab induces mechanisms of immune activation through CD38+ NK cell targeting. Leukemia 35(1):189–200. https://doi.org/10.1038/s41375-020-0810-4. (PMID: 10.1038/s41375-020-0810-432296125)
Chen L, Han X (2015) Anti-PD-1/PD-L1 therapy of human cancer: past, present, and future. J Clin Invest 125:3384–3391. https://doi.org/10.1172/JCI80011. (PMID: 10.1172/JCI80011263250354588282)
Dong H, Strome SE, Salomao DR, Tamura H, Hirano F, Flies DB, Roche PC, Lu J, Zhu G, Tamada K, Lennon VA, Celis E, Chen L (2002) Tumor-associated B7–H1 promotes T-cell apoptosis: a potential mechanism of immune evasion. Nat Med 8(8):793–800. https://doi.org/10.1038/nm730. (PMID: 10.1038/nm73012091876)
Taube JM, Anders RA, Young GD, Xu H, Sharma R, McMiller TL, Chen S, Klein AP, Pardoll DM, Topalian SL, Chen L (2012) Colocalization of inflammatory response with B7–h1 expression in human melanocytic lesions supports an adaptive resistance mechanism of immune escape. Sci Transl Med. 4(127):127ra37. https://doi.org/10.1126/scitranslmed.3003689. (PMID: 10.1126/scitranslmed.3003689224616413568523)
Schalper KA, Carvajal-Hausdorf D, McLaughlin J, Velcheti V, Chen L, Sanmamed M, Herbst RS, Rimm DL (2015) Clinical significance of PD-L1 protein expression on tumor-associated macrophages in lung cancer. J Immunother Cancer 3(Suppl 2):P415. https://doi.org/10.1186/2051-1426-3-S2-P415. (PMID: 10.1186/2051-1426-3-S2-P4154652522)
Webb JR, Milne K, Kroeger DR, Nelson BH (2016) PD-L1 expression is associated with tumor-infiltrating T cells and favorable prognosis in high-grade serous ovarian cancer. Gynecol Oncol 141:293–302. https://doi.org/10.1016/j.ygyno.2016.03.008. (PMID: 10.1016/j.ygyno.2016.03.00826972336)
Kim HR, Ha SJ, Hong MH, Heo SJ, Koh YW, Choi EC, Kim EK, Pyo KH, Jung I, Seo D, Choi J, Cho BC, Yoon SO (2016) PD-L1 expression on immune cells, but not on tumor cells, is a favorable prognostic factor for head and neck cancer patients. Sci Rep 6:36956. https://doi.org/10.1038/srep36956. (PMID: 10.1038/srep36956278413625107906)

20YXYJ0009(11) Xian Foundation for Development of Science and Technology, China

Keywords: Anti-tumour; Daratumumab; Fc-FcγR; Multiple myeloma

0 (Antibodies, Monoclonal)
0 (Receptors, IgG)
4Z63YK6E0E (daratumumab)

Date Created: 20220410 Date Completed: 20220629 Latest Revision: 20220705

20221213

10.1007/s11010-022-04390-8

35397683