Targeted delivery of interferon-alpha via fusion to anti-CD20 results in potent antitumor activity against B-cell lymphoma.
The anti-CD20 antibody rituximab has substantially improved outcomes in patients with B-cell non-Hodgkin lymphomas. However, many patients are not cured by rituximab-based therapies, and overcoming de novo or acquired rituximab resistance remains an important challenge to successful treatment of B-cell malignancies. Interferon-alpha (IFNalpha) has potent immunostimulatory properties and antiproliferative effects against some B-cell cancers, but its clinical utility is limited by systemic toxicity. To improve the efficacy of CD20-targeted therapy, we constructed fusion proteins consisting of anti-CD20 and murine or human IFNalpha. Fusion proteins had reduced IFNalpha activity in vitro compared with native IFNalpha, but CD20 targeting permitted efficient antiproliferative and proapoptotic effects against an aggressive rituximab-insensitive human CD20(+) murine lymphoma (38C13-huCD20) and a human B-cell lymphoma (Daudi). In vivo efficacy was demonstrated against established 38C13-huCD20 grown in syngeneic immunocompetent mice and large, established Daudi xenografts grown in nude mice. Optimal tumor eradication required CD20 targeting, with 87% of mice cured of rituximab-insensitive tumors. Gene knockdown studies revealed that tumor eradication required expression of type I IFN receptors on the tumor cell surface. Targeting type I IFNs to sites of B-cell lymphoma by fusion to anti-CD20 antibodies represents a potentially useful strategy for treatment of B-cell malignancies.
Department of Microbiology, Immunology and Molecular Genetics, University of California Los Angeles, USA.
Caiyun
C
Xuan
Kristopher K
KK
Steward
John M
JM
Timmerman
Sherie L
SL
Morrison
D000818:Animals; D000911:Antibodies, Monoclonal / Q000235:genetics / Q000494:pharmacology*; D058846:Antibodies, Monoclonal, Murine-Derived; D000970:Antineoplastic Agents / Q000494:pharmacology*; D000998:Antiviral Agents / Q000494:pharmacology; D045744:Cell Line, Tumor; D016503:Drug Delivery Systems; D019008:Drug Resistance, Neoplasm / Q000187:drug effects*; D055785:Gene Knockdown Techniques; D006801:Humans; D016898:Interferon-alpha / Q000235:genetics / Q000494:pharmacology*; D016393:Lymphoma, B-Cell / Q000188:drug therapy*; D051379:Mice; D008819:Mice, Nude; D017471:Receptors, Interferon; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000494:pharmacology*; D000069283:Rituximab; D023041:Xenograft Model Antitumor Assays
D000911:Antibodies, Monoclonal; D058846:Antibodies, Monoclonal, Murine-Derived; D000970:Antineoplastic Agents; D000998:Antiviral Agents; D016898:Interferon-alpha; D017471:Receptors, Interferon; D011993:Recombinant Fusion Proteins; D000069283:Rituximab