title: 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.affiliation: Department of Microbiology, Division of Hematology and Oncology, David Geffen School of Medicine, University of California, Los Angeles, CA 90095-7364, USA.
authors.forename: Kham R
authors.initials: KR
authors.lastname: Trinh
authors.forename: Alex
authors.initials: A
authors.lastname: Vasuthasawat
authors.forename: Kristopher K
authors.initials: KK
authors.lastname: Steward
authors.forename: Reiko E
authors.initials: RE
authors.lastname: Yamada
authors.forename: John M
authors.initials: JM
authors.lastname: Timmerman
authors.forename: Sherie L
authors.initials: SL
authors.lastname: Morrison
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000235:genetics / Q000378:metabolism / Q000494:pharmacology*; D058846:Antibodies, Monoclonal, Murine-Derived / Q000494:pharmacology / Q000627:therapeutic use; D000915:Antibody Affinity / Q000235:genetics; D018951:Antigens, CD20 / Q000276:immunology; D017209:Apoptosis / Q000187:drug effects; D048708:Cell Growth Processes / Q000187:drug effects; D045744:Cell Line, Tumor; D019008:Drug Resistance, Neoplasm; D016898:Interferon-alpha / Q000494:pharmacology* / Q000627:therapeutic use; D016899:Interferon-beta / Q000235:genetics / Q000378:metabolism / Q000494:pharmacology*; D016393:Lymphoma, B-Cell / Q000276:immunology / Q000628:therapy*; D051379:Mice; D053633:Receptor, Interferon alpha-beta / Q000378:metabolism; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000378:metabolism / Q000494:pharmacology*; D000069283:Rituximab
chemical_list: D000911:Antibodies, Monoclonal; D058846:Antibodies, Monoclonal, Murine-Derived; D018951:Antigens, CD20; D016898:Interferon-alpha; D011993:Recombinant Fusion Proteins; D053633:Receptor, Interferon alpha-beta; D000069283:Rituximab; D016899:Interferon-beta