Anti-CD20-interferon-β fusion protein therapy of murine B-cell lymphomas.

Abstract

Type I interferons (IFNα/β) are cytokines with a broad spectrum of antitumor activities including antiproliferative, proapoptotic, and immunostimulatory effects, and are potentially useful in the treatment of B-cell malignancies and other cancers. To improve antitumor potency and diminish the systemic side effects of IFN, we recently developed anti-CD20-IFNα fusion proteins with in vitro and in vivo efficacy against both mouse and human lymphomas expressing CD20. As IFNβ binds more tightly to the IFNα/β receptor (IFNAR) and has more potent antitumor activities, we have now constructed an anti-CD20 fusion protein with murine IFNβ (mIFNβ). Anti-CD20-mIFNβ was more potent than recombinant mIFNβ and anti-CD20-mIFNα in inhibiting the proliferation of a mouse B-cell lymphoma expressing human CD20 (38C13-huCD20). Growth inhibition was accompanied by caspase-independent apoptosis and DNA fragmentation. The efficacy of anti-CD20-mIFNβ required the physical linkage of mIFNβ to anti-CD20 antibody. Importantly, anti-CD20-mIFNβ was active against tumor cells expressing low levels of IFNAR (38C13-huCD20 IFNAR). In vivo, established 38C13-huCD20 tumors were largely insensitive to rituximab or a nontargeted mIFNβ fusion protein, yet treatment with anti-CD20-mIFNβ eradicated 83% of tumors. Anti-CD20-mIFNβ was also more potent in vivo against 38C13-huCD20 than anti-CD20-mIFNα, curing 75% versus 25% of tumors (P=0.001). Importantly, although anti-CD20-mIFNα could not eradicate 38C13-huCD20 IFNAR tumors, anti-CD20-mIFNβ treatment prolonged survival (P=0.0003), and some animals remained tumor-free. Thus, antibody fusion proteins targeting mIFNβ to tumors show promise as therapeutic agents, especially for use against tumors resistant to the effects of mIFNα.

• Authors: Kham R Trinh, Alex Vasuthasawat, Kristopher K Steward, Reiko E Yamada, John M Timmerman, Sherie L Morrison
• Journal: Journal of immunotherapy (Hagerstown, Md. : 1997) (J Immunother) Vol. 36 Issue 5 Pg. 305-18 (Jun 2013) ISSN: 1537-4513 [Electronic] United States
• PMID: 23719241 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Antibodies, Monoclonal
• Antibodies, Monoclonal, Murine-Derived
• Antigens, CD20
• Interferon-alpha
• Recombinant Fusion Proteins
• Receptor, Interferon alpha-beta
• Rituximab
• Interferon-beta

Topics

• Animals
• Antibodies, Monoclonal (genetics, metabolism, pharmacology)
• Antibodies, Monoclonal, Murine-Derived (pharmacology, therapeutic use)
• Antibody Affinity (genetics)
• Antigens, CD20 (immunology)
• Apoptosis (drug effects)
• Cell Growth Processes (drug effects)
• Cell Line, Tumor
• Drug Resistance, Neoplasm
• Interferon-alpha (pharmacology, therapeutic use)
• Interferon-beta (genetics, metabolism, pharmacology)
• Lymphoma, B-Cell (immunology, therapy)
• Mice
• Receptor, Interferon alpha-beta (metabolism)
• Recombinant Fusion Proteins (genetics, metabolism, pharmacology)
• Rituximab