title: Upregulation of CD38 expression on multiple myeloma cells by all-trans retinoic acid improves the efficacy of daratumumab.
abstract: Daratumumab is an anti-CD38 monoclonal antibody with lytic activity against multiple myeloma (MM) cells, including ADCC (antibody-dependent cellular cytotoxicity) and CDC (complement-dependent cytotoxicity). Owing to a marked heterogeneity of response to daratumumab therapy in MM, we investigated determinants of the sensitivity of MM cells toward daratumumab-mediated ADCC and CDC. In bone marrow samples from 144 MM patients, we observed no difference in daratumumab-mediated lysis between newly diagnosed or relapsed/refractory patients. However, we discovered, next to an expected effect of effector (natural killer cells/monocytes) to target (MM cells) ratio on ADCC, a significant association between CD38 expression and daratumumab-mediated ADCC (127 patients), as well as CDC (56 patients). Similarly, experiments with isogenic MM cell lines expressing different levels of CD38 revealed that the level of CD38 expression is an important determinant of daratumumab-mediated ADCC and CDC. Importantly, all-trans retinoic acid (ATRA) increased CD38 expression levels but also reduced expression of the complement-inhibitory proteins CD55 and CD59 in both cell lines and primary MM samples. This resulted in a significant enhancement of the activity of daratumumab in vitro and in a humanized MM mouse model as well. Our results provide the preclinical rationale for further evaluation of daratumumab combined with ATRA in MM patients.
authors.affiliation: Department of Hematology, VU University Medical Center, Amsterdam, The Netherlands.|Department of Clinical Chemistry and Hematology, University Medical Center Utrecht, Utrecht, The Netherlands.|Department of Hematology, University Medical Center Utrecht, Utrecht, The Netherlands.
authors.forename: I S
authors.initials: IS
authors.lastname: Nijhof
authors.affiliation: Department of Hematology, VU University Medical Center, Amsterdam, The Netherlands.|Department of Cell Biology, University Medical Center Utrecht, Utrecht, The Netherlands.
authors.forename: R W J
authors.initials: RW
authors.lastname: Groen
authors.affiliation: Department of Hematology, VU University Medical Center, Amsterdam, The Netherlands.|Department of Hematology, University Medical Center Utrecht, Utrecht, The Netherlands.
authors.forename: H M
authors.initials: HM
authors.lastname: Lokhorst
authors.affiliation: Department of Hematology, VU University Medical Center, Amsterdam, The Netherlands.
authors.forename: B
authors.initials: B
authors.lastname: van Kessel
authors.affiliation: Laboratory for Translational Immunology, University Medical Center Utrecht, Utrecht, The Netherlands.
authors.forename: A C
authors.initials: AC
authors.lastname: Bloem
authors.affiliation: Laboratory for Translational Immunology, University Medical Center Utrecht, Utrecht, The Netherlands.
authors.forename: J
authors.initials: J
authors.lastname: van Velzen
authors.affiliation: Department of Hematology, VU University Medical Center, Amsterdam, The Netherlands.
authors.forename: R
authors.initials: R
authors.lastname: de Jong-Korlaar
authors.affiliation: Xpand Biotechnology BV, Bilthoven, The Netherlands.
authors.forename: H
authors.initials: H
authors.lastname: Yuan
authors.affiliation: Department of Hematology, VU University Medical Center, Amsterdam, The Netherlands.
authors.forename: W A
authors.initials: WA
authors.lastname: Noort
authors.affiliation: Department of Internal Medicine, Meander Medisch Centrum, Amersfoort, The Netherlands.
authors.forename: S K
authors.initials: SK
authors.lastname: Klein
authors.affiliation: Department of Hematology, VU University Medical Center, Amsterdam, The Netherlands.|Department of Cell Biology, University Medical Center Utrecht, Utrecht, The Netherlands.
authors.forename: A C M
authors.initials: AC
authors.lastname: Martens
authors.affiliation: Johnson & Johnson Pharmaceutical Research and Development, Spring House, PA, USA.
authors.forename: P
authors.initials: P
authors.lastname: Doshi
authors.affiliation: Johnson & Johnson Pharmaceutical Research and Development, Spring House, PA, USA.
authors.forename: K
authors.initials: K
authors.lastname: Sasser
authors.affiliation: Department of Hematology, VU University Medical Center, Amsterdam, The Netherlands.|Department of Clinical Chemistry and Hematology, University Medical Center Utrecht, Utrecht, The Netherlands.
authors.forename: T
authors.initials: T
authors.lastname: Mutis
authors.affiliation: Department of Hematology, VU University Medical Center, Amsterdam, The Netherlands.
authors.forename: N W C J
authors.initials: NW
authors.lastname: van de Donk
mesh_terms: D051997:ADP-ribosyl Cyclase 1 / Q000378:metabolism*; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D000911:Antibodies, Monoclonal / Q000008:administration & dosage; D000920:Antibody-Dependent Cell Cytotoxicity; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D001853:Bone Marrow / Q000187:drug effects / Q000473:pathology; D049109:Cell Proliferation / Q000187:drug effects; D003602:Cytotoxicity, Immunologic; D004268:DNA-Binding Proteins / Q000502:physiology; D004195:Disease Models, Animal; D019008:Drug Resistance, Neoplasm / Q000187:drug effects; D004357:Drug Synergism; D005260:Female; D005434:Flow Cytometry; D006801:Humans; D008297:Male; D008562:Membrane Glycoproteins / Q000378:metabolism*; D051379:Mice; D008875:Middle Aged; D009101:Multiple Myeloma / Q000188:drug therapy* / Q000378:metabolism* / Q000473:pathology; D009364:Neoplasm Recurrence, Local / Q000188:drug therapy* / Q000378:metabolism* / Q000473:pathology; D016879:Salvage Therapy; D014212:Tretinoin / Q000008:administration & dosage; D014407:Tumor Cells, Cultured
chemical_list: D000911:Antibodies, Monoclonal; D004268:DNA-Binding Proteins; D008562:Membrane Glycoproteins; C499308:Rag2 protein, mouse; C556306:daratumumab; D014212:Tretinoin; C498154:CD38 protein, human; D051997:ADP-ribosyl Cyclase 1