Anti-CD138-Targeted Interferon Is a Potent Therapeutic Against Multiple Myeloma

Abstract

Multiple myeloma (MM), a plasma cell malignancy, is the second most prevalent hematologic malignancy in the US. Although much effort has been made trying to understand the etiology and the complexities of this disease with the hope of developing effective therapies, MM remains incurable at this time. Because of their antiproliferative and proapoptotic activities, interferons (IFNs) have been used to treat various malignancies, including MM. Although some success has been observed, the inherent toxicities of IFNs limit their efficacy. To address this problem, we produced anti-CD138 antibody fusion proteins containing either IFNα2 or a mutant IFNα2 (IFNα2(YNS)) with the goal of targeting IFN to CD138-expressing cells, thereby achieving effective IFN concentrations at the site of the tumor in the absence of toxicity. The fusion proteins inhibited the proliferation and induced apoptosis of U266, ANBL-6, NCI-H929, and MM1-144 MM cell lines. The fusion proteins decreased the expression of IFN regulatory factor 4 (IRF4) in U266. In addition, the fusion proteins were effective against primary cells from MM patients, and treatment with fusion proteins prolonged survival in the U266 murine model of MM. These studies show that IFNα antibody fusion proteins can be effective novel therapeutics for the treatment of MM.

Targeted immunotherapy using anti-CD138-interferon α fusion proteins and bortezomib results in synergistic protection against multiple myeloma

“…27,28 Previous studies in our laboratory [8][9][10][11] have shown that genetic fusion of IFNs to an antibody is an effective strategy to specifically target IFN to the tumor microenvironment, reduce systemic toxicity, and increase half-life.…”

“…25 We have shown previously that targeting IFNa and IFNb fusion proteins is an effective strategy against lymphoma and MM. [8][9][10][11] Based on these studies, we initiated Phase 1 clinical testing of anti-CD20-IFNa to treat B-cell lymphomas (Clinical Trials.gov Identifier NCT02519270), underscoring the therapeutic potential of this approach. One of the goals of the study described here was to determine the effect of combining treatment using IFN fusion proteins with the FDA-approved drug, bortezomib.…”

“…While the half-life of IFNa is only 1 h, 26 we have shown that fusing it to IgG extends the half-life to 8 h. 10,11 In addition, the anti-CD138 portion of the fusion protein provides a binding specificity to target MM and deliver therapeutically useful levels of IFN without systemic toxicity. Indeed, we have shown the effectiveness of this strategy in targeting not only MM, 8 but also lymphoma using anti-CD20-IFNa2. 9 Two different in vivo models were used.…”

“…Therefore, we also tested fusion proteins containing IFNa14, which was reported to have the highest anti-proliferative activity among the 12 naturally-occurring IFNa against ovarian cancer cells, 16 and IFNa2 YNS , which carries 3 introduced mutations (H57Y, E58N, Q61S) conferring greater anti-tumor activity than wildtype IFNa2. 8,17 In addition, we tested whether the fusion proteins could synergize with bortezomib against MM.…”

“…This approach has been used effectively to target IFN to various tumors. [8][9][10][11] To target IFN to MM, we fused it to the B-B4 antibody that specifically binds CD138. 8,12 CD138, also known as syndecan-1, is highly expressed on mature plasma cells, making it a suitable target for MM.…”