Targeted delivery of interferon alpha via fusion to anti-CD20 results in potent antitumor activity against B-cell lymphoma (131.30)

Abstract

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 (IFNα) has potent immunostimulatory properties and anti-proliferative 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 IFNα. Fusion proteins had reduced IFNα activity in vitro compared with native IFNα, but CD20 targeting permitted efficient anti-proliferative and pro-apoptotic 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.