Targeting Attenuated Interferon-Alpha To Myeloma Cells With A Cd38 Antibody Induces Potent Tumor Regression With Reduced Off-Target Activity

Interferon-alpha (IFN alpha) has been prescribed to effectively treat multiple myeloma (MM) and other malignancies for decades. Its use has waned in recent years, however, due to significant toxicity and a narrow therapeutic index (TI). We sought to improve IFN alpha's TI by, first, attaching it to an anti-CD38 antibody, thereby directly targeting it to MM cells, and, second, by introducing an attenuating mutation into the IFN alpha portion of the fusion protein rendering it relatively inactive on normal, CD38 negative cells. This anti-CD38-IFN alpha(attenuated) immunocytokine, or CD38-Attenukine (TM), exhibits 10,000-fold increased specificity for CD38 positive cells in vitro compared to native IFN alpha and, significantly, is similar to 6,000-fold less toxic to normal bone marrow cells in vitro than native IFN alpha. Moreover, the attenuating mutation significantly decreases IFN alpha biomarker activity in cynomolgus macaques indicating that this approach may yield a better safety profile in humans than native IFN alpha or a non-attenuated IFN alpha immunocytokine. In human xenograft MM tumor models, anti-CD38-IFN alpha(attenuated) exerts potent anti-tumor activity in mice, inducing complete tumor regression in most cases. Furthermore, anti-CD38-IFN alpha(attenuated) is more efficacious than standard MM treatments (lenalidomide, bortezomib, dexamethasone) and exhibits strong synergy with lenalidomide and with bortezomib in xenograft models. Our findings suggest that tumor-targeted attenuated cytokines such as IFN alpha can promote robust tumor killing while minimizing systemic toxicity.