Targeting Attenuated Interferon-α to Myeloma Cells with a CD38 Antibody Induces Potent Tumor Regression with Reduced Off-Target Activity.

Interferon-α (IFNα) 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 IFNα'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 IFNα portion of the fusion protein rendering it relatively inactive on normal, CD38 negative cells. This anti-CD38-IFNα(attenuated) immunocytokine, or CD38-Attenukine™, exhibits 10,000-fold increased specificity for CD38 positive cells in vitro compared to native IFNα and, significantly, is ~6,000-fold less toxic to normal bone marrow cells in vitro than native IFNα. Moreover, the attenuating mutation significantly decreases IFNα biomarker activity in cynomolgus macaques indicating that this approach may yield a better safety profile in humans than native IFNα or a non-attenuated IFNα immunocytokine. In human xenograft MM tumor models, anti-CD38-IFNα(attenuated) exerts potent anti-tumor activity in mice, inducing complete tumor regression in most cases. Furthermore, anti-CD38-IFNα(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 IFNα can promote robust tumor killing while minimizing systemic toxicity.

Determination of chromosome 13 status in bone marrow cells of patients with multiple myeloma using combined morphologic and fluorescence in situ hybridization analysis.

Deletion of chromosome 13q is believed to be an adverse prognostic marker in patients with multiple myeloma (MM). Interphase fluorescence in situ hybridization (I-FISH) is the method of choice for detection of chromosome 13q deletion (del13q). However, I-FISH has high false-positive rates attributed to a low percentage of plasma cells (PC), which are responsible for MM, in bone marrow (BM) samples from MM patients. In an attempt to overcome this problem, combined morphologic and I-FISH analyses were performed by a unique system that allows rapid automatic scanning of a large number of cells with simultaneous determination of the lineage of specific cells carrying del13q. The percentage of PC with del13q in BM samples from 40 MM patients was calculated. In addition, we established a useful prognostic ratio defined as the number of PC with del13q divided by the number of non-PC with del13q (PDP/PDNP), which may help to precisely define the putative role of del13q in prediction response of MM patients to new therapeutic compounds. We suggest this technique as a novel sensitive and specific method for detection of del13q in a minor PC population of MM patients.