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-IFNa14 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-IFNa14 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-IFNa 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.

Evaluation of CD229 as a new alternative plasma cell gating marker in the flow cytometric immunophenotyping of monoclonal gammopathies

“…PC in MM patients treated with daratumumab exhibit a significant reduction in the expression of CD38, thereby limiting the use of CD38 for gating of PC for monitoring residual disease. Clinical trials using anti-CD138 Moab for the treatment of MM are also being conducted (41). Thus, PC gating based on only CD38 and CD138 may not be sufficient for accurate quantitation of PC, and new alternative robust and reliable gating markers are required.…”

Drug targets and resistance mechanisms in multiple myeloma

“…Another in vivo study observed the effect of a combination therapy of anti-CD138-IFNα14 fusion protein and BTZ. It cured tumors in animals [246] .…”

Targeted Therapy With Immunoconjugates for Multiple Myeloma

“…Despite the clinical benefit of adding IFNα to induction treatment or as maintenance therapy in MM patients (157), substantial dose-related side effects resulted in treatment discontinuation in a high proportion of patients (158,159). However, to reduce toxicity, IFNα can also be conjugated to MM cell-targeting antibodies (147,(160)(161)(162)(163).…”

“…These immunocytokines combine the specificity of an anti-CD138 IgG1 mAb with the anti-MM activity of an IFNα14, IFNα2, or IFNα2 YNS (high-affinity IFNα2 mutant) moiety (161,163). Preclinical studies showed that these immunocytokines had higher anti-MM activity against MM cell lines compared with an anti-CD20-IFNα2 control immunocytokine.…”

“…Treatment was associated with a decreased expression of IFN regulatory factor 4 (IRF4), which is a survival factor for MM cells (169,170). Notably, synergistic activity was observed when immunocytokines were combined with bortezomib (163). In mice, treatment with either immunocytokine reduced MM tumor growth and prolonged survival, and cotreatment of anti-CD138-IFNα14 with bortezomib further improved antitumor activity compared with either treatment alone.…”