title: Targeted immunotherapy using anti-CD138-interferon α fusion proteins and bortezomib results in synergistic protection against multiple myeloma.
abstract: Although recent advances have substantially improved the management of multiple myeloma, it remains an incurable malignancy. We now demonstrate that anti-CD138 molecules genetically fused to type I interferons (IFN) synergize with the approved therapeutic bortezomib in arresting the proliferation of human multiple myeloma cell lines both in vitro and in vivo. The anti-CD138-IFNα14 fusion protein was active in inducing increased expression of signal transducer and activator of transcription 1 (STAT1) and its phosphorylation while the cell death pathway induced by bortezomib included generation of reactive oxygen species. Interferon regulatory factor 4 (IRF4), an important survival factor for myeloma cells, was down regulated following combination treatment. Induction of cell death appeared to be caspase-independent because treatment with inhibitors of caspase activation did not decrease the level of cell death. The observed caspase-independent synergistic cell death involved mitochondrial membrane depolarization, and poly(ADP-ribose) polymerase-1 (PARP-1) cleavage, and resulted in enhanced induction of apoptosis. Importantly, using 2 different in vivo xenograft models, we found that combination therapy of anti-CD138-IFNα14 and bortezomib was able to cure animals with established tumors (7 of 8 using OCI-My5 or 8 of 8 using NCI-H929). Thus, the combination of anti-CD138-IFNα with bortezomib shows great promise as a novel therapeutic approach for the treatment of multiple myeloma, a malignancy for which there are currently no cures.
authors.affiliation: a Department of Microbiology, Immunology and Molecular Genetics , University of California Los Angeles , Los Angeles , CA , USA.|b Molecular Biology Institute, UCLA , Los Angeles , CA , USA.
authors.forename: Alex
authors.initials: A
authors.lastname: Vasuthasawat
authors.affiliation: a Department of Microbiology, Immunology and Molecular Genetics , University of California Los Angeles , Los Angeles , CA , USA.|b Molecular Biology Institute, UCLA , Los Angeles , CA , USA.
authors.forename: Esther M
authors.initials: EM
authors.lastname: Yoo
authors.affiliation: a Department of Microbiology, Immunology and Molecular Genetics , University of California Los Angeles , Los Angeles , CA , USA.|b Molecular Biology Institute, UCLA , Los Angeles , CA , USA.
authors.forename: Kham R
authors.initials: KR
authors.lastname: Trinh
authors.affiliation: c Greater Los Angeles Veterans Administration Healthcare Center , Los Angeles , CA , USA.|d Jonsson Comprehensive Cancer Center , Los Angeles , CA , USA.|e Division of Hematology and Oncology, Department of Medicine, David Geffen School of Medicine, UCLA , Los Angeles , CA , USA.
authors.forename: Alan
authors.initials: A
authors.lastname: Lichtenstein
authors.affiliation: d Jonsson Comprehensive Cancer Center , Los Angeles , CA , USA.|e Division of Hematology and Oncology, Department of Medicine, David Geffen School of Medicine, UCLA , Los Angeles , CA , USA.
authors.forename: John M
authors.initials: JM
authors.lastname: Timmerman
authors.affiliation: a Department of Microbiology, Immunology and Molecular Genetics , University of California Los Angeles , Los Angeles , CA , USA.|b Molecular Biology Institute, UCLA , Los Angeles , CA , USA.
authors.forename: Sherie L
authors.initials: SL
authors.lastname: Morrison
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage*; D017209:Apoptosis / Q000187:drug effects; D000069286:Bortezomib / Q000008:administration & dosage*; D004357:Drug Synergism; D006801:Humans; D007167:Immunotherapy / Q000379:methods*; D016898:Interferon-alpha / Q000008:administration & dosage*; D051379:Mice; D009101:Multiple Myeloma; D011993:Recombinant Fusion Proteins / Q000008:administration & dosage; D015398:Signal Transduction / Q000187:drug effects; D053668:Syndecan-1 / Q000037:antagonists & inhibitors*; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D016898:Interferon-alpha; D011993:Recombinant Fusion Proteins; C508241:SDC1 protein, human; D053668:Syndecan-1; D000069286:Bortezomib
keywords: Antibody engineering; antibody immunotherapy; bortezomib; interferon α; multiple myeloma