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MAbs. 2016 Oct;8(7):1386-1397. Epub 2016 Jun 30.

Targeted immunotherapy using anti-CD138-interferon α fusion proteins and bortezomib results in synergistic protection against multiple myeloma.

Author information

1
a Department of Microbiology, Immunology and Molecular Genetics , University of California Los Angeles , Los Angeles , CA , USA.
2
b Molecular Biology Institute, UCLA , Los Angeles , CA , USA.
3
c Greater Los Angeles Veterans Administration Healthcare Center , Los Angeles , CA , USA.
4
d Jonsson Comprehensive Cancer Center , Los Angeles , CA , USA.
5
e Division of Hematology and Oncology, Department of Medicine, David Geffen School of Medicine, UCLA , Los Angeles , CA , USA.

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.

KEYWORDS:

Antibody engineering; antibody immunotherapy; bortezomib; interferon α; multiple myeloma

PMID:
27362935
PMCID:
PMC5058616
DOI:
10.1080/19420862.2016.1207030
[Indexed for MEDLINE]
Free PMC Article

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