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PLoS One. 2016 Sep 9;11(9):e0162472. doi: 10.1371/journal.pone.0162472. eCollection 2016.

Targeting Attenuated Interferon-α to Myeloma Cells with a CD38 Antibody Induces Potent Tumor Regression with Reduced Off-Target Activity.

Author information

1
Teva Pharmaceuticals, Global Branded Biologics Division, Redwood City, California, United States of America.
2
Teva Pharmaceuticals, Global Branded Biologics Division, Sydney, Australia.
3
Teva Pharmaceuticals, Global Branded Biologics Division, Netanya, Israel.
4
The Institute for Myeloma and Bone Cancer Research, West Hollywood, California, United States of America.

Abstract

Interferon-α (IFNα) has been prescribed to effectively treat multiple myeloma (MM) and other malignancies for decades. Its use has waned in recent years, however, due to significant toxicity and a narrow therapeutic index (TI). We sought to improve IFNα's TI by, first, attaching it to an anti-CD38 antibody, thereby directly targeting it to MM cells, and, second, by introducing an attenuating mutation into the IFNα portion of the fusion protein rendering it relatively inactive on normal, CD38 negative cells. This anti-CD38-IFNα(attenuated) immunocytokine, or CD38-Attenukine™, exhibits 10,000-fold increased specificity for CD38 positive cells in vitro compared to native IFNα and, significantly, is ~6,000-fold less toxic to normal bone marrow cells in vitro than native IFNα. Moreover, the attenuating mutation significantly decreases IFNα biomarker activity in cynomolgus macaques indicating that this approach may yield a better safety profile in humans than native IFNα or a non-attenuated IFNα immunocytokine. In human xenograft MM tumor models, anti-CD38-IFNα(attenuated) exerts potent anti-tumor activity in mice, inducing complete tumor regression in most cases. Furthermore, anti-CD38-IFNα(attenuated) is more efficacious than standard MM treatments (lenalidomide, bortezomib, dexamethasone) and exhibits strong synergy with lenalidomide and with bortezomib in xenograft models. Our findings suggest that tumor-targeted attenuated cytokines such as IFNα can promote robust tumor killing while minimizing systemic toxicity.

PMID:
27611189
PMCID:
PMC5017640
DOI:
10.1371/journal.pone.0162472
[Indexed for MEDLINE]
Free PMC Article

Conflict of interest statement

This study was funded by Teva Pharmaceuticals. Sarah L. Pogue, Tetsuya Taura, Mingying Bi, Yong Yun, Angela Sho, Glen Mikesell, Collette Behrens, Maya Sokolovsky, Hussein Hallak, Moti Rosenstock, Anthony Doyle, Steffen Nock, and David S. Wilson are employed by Teva Pharmaceuticals. In addition, Sarah Pogue, David Wilson, Tetsuya Taura, Anthony Doyle, and Glen Mikesell have filed an International Patent Application WO 2013/059885 entitled: Polypeptide Constructs and Uses Thereof. This manuscript describes a research molecule, CD38-Attenukine™ that is being developed as a Teva product to treat myeloma. There are no marketed products to declare. These declarations do not alter our adherence to all the PLOS ONE policies on sharing data and materials, as detailed online in the guide for authors.

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