Multiple myeloma (MM) remains an incurable disease despite recent approvals of novel therapies. Treatments which utilize alkylating agents, corticosteroids, proteasome inhibitors and immunomodulatory drugs have provided significant survival benefits; however, tumor relapse eventually occurs with the use of these agents. The cytokine, interferon-α (IFNα), has been used clinically to treat MM for over 30 years. IFNα exerts good anti-myeloma tumor activity but durable responses are rarely achieved due to dose limiting toxicities. Tumor specificity can be modestly increased by attaching IFNα to an anti-CD38 antibody, thus targeting the cytokine to MM cells. However, by introducing an attenuating mutation to the IFNα portion of this fusion protein, the activity of the cytokine is dramatically reduced on CD38 negative cells while exhibiting a similar potency to native IFNα on CD38+ MM cells. As a result, the anti-CD38-attenuated IFNα, referred to as anti-CD38-attenukine™, has over 10,000-fold greater myeloma-specificity than native IFNα in vitro. In vivo, even though the off-target activity is decreased, anti-CD38-attenukine™ has profound anti-tumor effects in murine MM and NHL xenograft models. Treatment with this fusion protein can cure mice with large (>700mm3) tumors—an effect not observed with any other MM agents tested. Here we report that in a Velcade (bortezomib) refractory, IFNα-insensitive primary MM xenograft model, the combination of Velcade with anti-CD38-attenukine™ has potent anti-tumor activity, resulting in tumour elimination and curing of mice. Our findings indicate that anti-CD38-attenukine™ may be a well tolerated, potent anti-MM treatment that may be utilized alone or in combination with Velcade.

Citation Format: Sarah Pogue, Tetsuya Taura, Mingying Bi, Glen Mikesell, Yong Yun, Angela Sho, Eric Sanchez, Haiming Chen, James Berenson, Collette Behrens, Maxwell Stevens, Teresa Domagala, Maya Sokolovsky, Hussein Hallak, Moti Rosenstock, Anthony Doyle, David Wilson. Anti-CD38-attenukine: A myeloma-targeting immunocytokine containing an engineered IFNα that provides >10,000-fold enhanced tumor-specific activity compared to native IFNα. [abstract]. In: Proceedings of the AACR Special Conference on Hematologic Malignancies: Translating Discoveries to Novel Therapies; Sep 20-23, 2014; Philadelphia, PA. Philadelphia (PA): AACR; Clin Cancer Res 2015;21(17 Suppl):Abstract nr A13.