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

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

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.

MeSH terms

  • ADP-ribosyl Cyclase 1 / metabolism*
  • Animals
  • Cell Survival / drug effects
  • Cells, Cultured
  • Flow Cytometry
  • Humans
  • Interferon-alpha / pharmacology*
  • Interferon-alpha / therapeutic use
  • Macaca fascicularis
  • Multiple Myeloma / drug therapy
  • Multiple Myeloma / metabolism*
  • Mutation / genetics
  • Receptor, Interferon alpha-beta / genetics
  • Receptor, Interferon alpha-beta / metabolism
  • Xenograft Model Antitumor Assays

Substances

  • Interferon-alpha
  • Receptor, Interferon alpha-beta
  • ADP-ribosyl Cyclase 1

Grant support

All studies presented in this manuscript were funded solely by Teva Pharmaceuticals and was not by any outside sources. Teva Pharmaceuticals provided support in the form of salaries for authors SP, TT, MB, YY, AS, GM, CB, MS, HH, MR, AD, SN, and DW, but did not have any additional role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript. The specific roles of these authors are articulated in the 'author contributions' section. Authors JB, HC, and ES are part of a non-profit organization, Institute of Myeloma and Bone Cancer Research, which performed studies in this manuscript. Teva Pharmaceuticals funded these studies.