Preclinical studies on targeted delivery of multiple IFNα2b to HLA-DR in diverse hematologic cancers

Blood. 2011 Aug 18;118(7):1877-84. doi: 10.1182/blood-2011-03-343145. Epub 2011 Jun 16.

Abstract

The short circulating half-life and side effects of IFNα affect its dosing schedule and efficacy. Fusion of IFNα to a tumor-targeting mAb (mAb-IFNα) can enhance potency because of increased tumor localization and improved pharmacokinetics. We used the Dock-and-Lock method to generate C2-2b-2b, a mAb-IFNα comprising tetrameric IFNα2b site-specifically linked to hL243 (humanized anti-HLA-DR). In vitro, C2-2b-2b inhibited various B-cell lymphoma leukemia and myeloma cell lines. In most cases, this immunocytokine was more effective than CD20-targeted mAb-IFNα or a mixture comprising the parental mAb and IFNα. Our findings indicate that responsiveness depends on HLA-DR expression/density and sensitivity to IFNα and hL243. C2-2b-2b induced more potent and longer-lasting IFNα signaling compared with nontargeted IFNα. Phosphorylation of STAT1 was more robust and persistent than that of STAT3, which may promote apoptosis. C2-2b-2b efficiently depleted lymphoma and myeloma cells from whole human blood but also exhibited some toxicity to B cells, monocytes, and dendritic cells. C2-2b-2b showed superior efficacy compared with nontargeting mAb-IFNα, peginterferonalfa-2a, or a combination of hL243 and IFNα, using human lymphoma and myeloma xenografts. These results suggest that C2-2b-2b should be useful in the treatment of various hematopoietic malignancies.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Antibodies, Monoclonal / immunology*
  • Antineoplastic Agents / administration & dosage
  • Antineoplastic Agents / immunology
  • Antineoplastic Agents / therapeutic use*
  • Apoptosis / drug effects
  • Cell Line, Tumor
  • Drug Delivery Systems
  • Female
  • HLA-DR Antigens / immunology*
  • Humans
  • Interferon alpha-2
  • Interferon-alpha / administration & dosage
  • Interferon-alpha / immunology
  • Interferon-alpha / therapeutic use*
  • Leukemia / drug therapy*
  • Leukemia / immunology
  • Lymphoma / drug therapy*
  • Lymphoma / immunology
  • Mice
  • Mice, SCID
  • Recombinant Proteins

Substances

  • Antibodies, Monoclonal
  • Antineoplastic Agents
  • HLA-DR Antigens
  • Interferon alpha-2
  • Interferon-alpha
  • Recombinant Proteins