Activity of anti-CD20-interferon-α fusion protein against human B-cell lymphomas.

8047 Background: Interferon-α (IFNα) has anti-proliferative and pro-apoptotic effects against many cancers, including non-Hodgkin lymphomas (NHL), and immunostimulatory effects including activation of natural killer cells, dendritic cells, and T cell anti-tumor immunity. We recently reported the ability of an anti-CD20 antibody-IFNα fusion protein to induce apoptosis and promote in vivo eradication of CD20-expressing murine and human B cell lymphomas (C. Xuan et al, Blood 115:2864, 2010). We now report on the preclinical anti-lymphoma activity of an anti-CD20-human IFNα (anti-CD20-hIFNα) fusion protein. Methods: Anti-CD20-hIFNα was evaluated against a large panel of human B cell NHL lines representing aggressive histologies including Burkitt (Daudi, Raji, Ramos), diffuse large B cell (SUDHL-4, OCI-Ly2, OCI-Ly3, OCI-Ly19, HBL-1, RC-K8), and mantle cell (Granta-519) lymphomas. Cell proliferation was measured by [3H]-thymidine incorporation, and ADCC by LDH release using peripheral blood mononuclear cell effectors. NHL xenografts Daudi, Raji, and Namalwa were grown in SCID mice. Rituximab was compared to equimolar doses of fusion protein in each assay. Results: Against IFN-sensitive CD20-negative tumor cells, anti-CD20-hIFNα had attenuated bioactivity (10-15% that of recombinant IFNα). Anti-CD20-hIFNα fusion protein induced stronger direct growth inhibition than rituximab (23.3-93.1% vs. 0.0-39.8%), particularly against Burkitt (44.7-93.1% vs. 0.0-10.4%) and germinal center-type diffuse large B cell (59.0-88.8% vs. 10.5-39.8%) NHLs. ADCC activity of fusion protein against Daudi, Ramos, and Raji cells was identical to that of rituximab. Against established human NHL xenografts (Daudi, Raji, and Namalwa), fusion protein achieved improved survival compared to rituximab. Conclusions: Anti-CD20-hIFNα fusion protein has substantially stronger direct anti-proliferative effects than rituximab against human lymphomas, and retains potent ADCC activity. Fusion protein was also superior to rituximab in vivo against multiple human NHL xenografts. These results support the further development of anti-CD20-hIFNα fusion protein for treatment of B cell malignancies.