Abstract
2567 Background: Interleukin-21, a cytokine produced by activated T cells, has potent effects on growth, survival and activation status of T, B and natural killer (NK) cells. In vitro studies show increased NK cytolytic function following combined human recombinant (rIL-21) stimulation and Fc receptor engagement. We studied the effect of rIL-21 on antibody-dependent cellular cytotoxicity (ADCC) against trastuzumab-coated breast cancer targets. Methods: ADCC assays were performed on peripheral blood mononuclear cell preparations (MNCs) from cynomolgus monkeys and on enriched human NK cells, following in vitro treatment with rIL-21. Cynomolgus monkeys were treated with rIL-21 as part of an in vivo model of ADCC (Hughes, et al., ASCO submitted), and the ex vivo ADCC activity of MNCs from these animals was tested. Whole blood and MNCs were characterized by flow cytometry. Results: Human NK cells incubated with rIL-21 had 2 to 4-fold increased ADCC against breast cancer targets including Her2/neu-low lines MCF7 and HCC38 (p<.02). Cynomolgus MNCs cultured with rIL-21 showed variable ADCC activation. In animals treated with rIL-21, an immediate decline in ADCC activity correlated with the extravasation of NK cells from the peripheral blood. This was followed by a substantial increase in ADCC against BT-474 cells at later timepoints. Normalization for NK cell numbers showed increased lytic efficiency of NK cells, especially after two cycles of treatment. The percentage of perforin-positive MNCs increased following treatment, as did other biomarkers of immune activation including FcγRI and FcγRIII expression. Conclusion: Treatment of cynomolgus monkeys with rIL-21 increased the activity of MNCs in trastuzumab-mediated ex vivo ADCC assays. This lytic activation is consistent with the enhanced effector function observed after in vitro incubation of NK cells or MNCs with rIL-21. Thus, adjuvant treatment with rIL-21 may enhance monoclonal antibody therapy by improving ADCC. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration ZymoGenetics ZymoGenetics
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