Targeting IFN-α to B Cell Lymphoma by a Tumor-Specific Antibody Elicits Potent Antitumor Activities

Abstract

IFN-α, a cytokine crucial for the innate immune response, also demonstrates antitumor activity. However, use of IFN-α as an anticancer drug is hampered by its short half-life and toxicity. One approach to improving IFN-α’s therapeutic index is to increase its half-life and tumor localization by fusing it to a tumor-specific Ab. In the present study, we constructed a fusion protein consisting of anti-HER2/neu-IgG3 and IFN-α (anti-HER2/neu-IgG3-IFN-α) and investigated its effect on a murine B cell lymphoma, 38C13, expressing human HER2/neu. Anti-HER2/neu-IgG3-IFN-α exhibited potent inhibition of 38C13/HER2 tumor growth in vivo. Administration of three daily 1-μg doses of anti-HER2/neu-IgG3-IFN-α beginning 1 day after tumor challenge resulted in 88% of the mice remaining tumor free. Remarkably, anti-HER2/neu-IgG3-IFN-α demonstrated potent activity against established 38C13/HER2 tumors, with complete tumor remission observed in 38% of the mice treated with three daily doses of 5 μg of the fusion protein (p = 0.0001). Ab-mediated targeting of IFN-α induced growth arrest and apoptosis of lymphoma cells contributing to the antitumor effect. The fusion protein also had a longer in vivo half-life than rIFN-α. These results suggest that IFN-α Ab fusion proteins may be effective in the treatment of B cell lymphoma.

Preclinical studies on targeted delivery of multiple IFNα2b to HLA-DR in diverse hematologic cancers

“…The literature suggests that targeted IFN␣ might also induce an acute tumor-directed immune response and evoke immune memory. 21,22 Because murine cells are considerably less sensitive (ϳ 4 logs) than human cells to human IFN␣2b, 23,24 the antitumor activity of mAb-IFN␣ in murine models is primarily because of the direct action of IFN␣2b on the tumor cells and cannot be attributed to immunoactivation in the host. In the ex vivo studies, C2-2b-2b depleted normal B cells, monocytes, and DCs.…”

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

“…Our strategy of fusing IFN to antibody has several major advantages in vivo. 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.…”

“…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.…”

“…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.…”