CD20-targeted tetrameric interferon-alpha, a novel and potent immunocytokine for the therapy of B-cell lymphomas.

Abstract

Interferon-alpha (IFN-alpha) has direct inhibitory effects on some tumors and is a potent stimulator of both the innate and adaptive immune systems. A tumor-targeting antibody-IFN-alpha conjugate (mAb-IFN-alpha) could kill by direct actions of the monoclonal antibody (mAb) and IFN-alpha on tumor cells and also potentiate a tumor-directed immune response. The modular Dock-and-Lock method (DNL) was used to generate 20-2b, the first immunocytokine having 4 cytokine (IFN-alpha2b) groups that are fused to the humanized anti-CD20 mAb, veltuzumab. Additional mAb-IFN-alpha constructs, each retaining potent IFN-alpha2b biologic activity, also were produced by DNL. The 20-2b shows enhanced antibody-dependent cellular cytotoxicity compared with veltuzumab but lacks complement-dependent cytotoxicity. The 20-2b inhibits in vitro proliferation of lymphoma cells and depletes them from whole human blood more potently than the combination of veltuzumab and a nontargeting, irrelevant, mAb-IFN-alpha. The 20-2b demonstrated superior therapeutic efficacy compared with veltuzumab or nontargeting mAb-IFN-alpha in 3 human lymphoma xenograft models, even though mouse immune cells respond poorly to human IFN-alpha2b. Targeting IFN-alpha with an anti-CD20 mAb makes the immunocytokine more potent than either agent alone. These findings suggest that 20-2b merits clinical evaluation as a new candidate antilymphoma therapeutic.

• Authors: Edmund A Rossi, David M Goldenberg, Thomas M Cardillo, Rhona Stein, Chien-Hsing Chang
• Journal: Blood (Blood) Vol. 114 Issue 18 Pg. 3864-71 (Oct 29 2009) ISSN: 1528-0020 [Electronic] United States
• PMID: 19710501 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)

Chemical References

• Antibodies, Monoclonal
• Antibodies, Monoclonal, Humanized
• Antineoplastic Agents
• Interferon alpha-2
• Interferon-alpha
• Recombinant Fusion Proteins
• Recombinant Proteins
• veltuzumab

Topics

• Animals
• Antibodies, Monoclonal (pharmacokinetics, pharmacology, therapeutic use)
• Antibodies, Monoclonal, Humanized
• Antineoplastic Agents (pharmacokinetics, pharmacology, therapeutic use)
• Humans
• Interferon alpha-2
• Interferon-alpha (pharmacokinetics, pharmacology, therapeutic use)
• Lymphoma, B-Cell (drug therapy)
• Male
• Mice
• Recombinant Fusion Proteins (pharmacokinetics, pharmacology, therapeutic use)
• Recombinant Proteins
• Xenograft Model Antitumor Assays