Abstract
Background: A major mechanism of action for therapeutic antibodies is antibody-dependent cell-mediated cytotoxicity (ADCC). ALT-803 is an interleukin-15 superagonist complex that enhances ADCC against human carcinoma cells in vitro and exerts an antitumor activity in murine, rat, and human carcinomas in vivo. The authors investigated the ability of ALT-803 to modulate ADCC mediated by the humanized IgG1 monoclonal antibody (mAb) NEO-201 against human carcinoma cells.Materials and Methods: ALT-803 modulating activity on ADCC mediated by NEO-201 was evaluated on several NEO-201 ligand-expressing human carcinoma cells. Purified human natural killer (NK) cells from multiple healthy donors were treated with ALT-803 before their use as effectors in ADCC assay. Modulation of NK cell phenotype and cytotoxic function by exposure to ALT-803 was evaluated by flow cytometry and gene expression analysis.Results: ALT-803 significantly enhanced ADCC mediated by NEO-201. ALT-803 also upregulated NK activating receptors, antiapoptotic factors, and factors involved in the NK cytotoxicity, as well as downregulated gene expression of NK inhibiting receptors.Conclusions: These findings indicate that ALT-803 can enhance ADCC activity mediated by NEO-201, by modulating NK activation and cytotoxicity, suggesting a possible clinical use of ALT-803 in combination with NEO-201 for the treatment of human carcinomas.
Highlights
Conventional cancer therapies, such as surgery, radiation, and chemotherapy, are usually effective in treating patients with the primary tumors, but often fail in treating metastatic disease.[1,2] The development of immunotherapies for cancer has led to prolonged clinical responses in metastatic disease, even when traditional therapies have failed.[3]
ALT-803 upregulated natural killer (NK) activating receptors, antiapoptotic factors, and factors involved in the NK cytotoxicity, as well as downregulated gene expression of NK inhibiting receptors
ALT-803 enhances antibody-dependent cell-mediated cytotoxicity (ADCC) mediated by NEO-201 against human carcinoma cells
Summary
Conventional cancer therapies, such as surgery, radiation, and chemotherapy, are usually effective in treating patients with the primary tumors, but often fail in treating metastatic disease.[1,2] The development of immunotherapies for cancer has led to prolonged clinical responses in metastatic disease, even when traditional therapies have failed.[3]. The aim of cancer immunotherapy is to enhance antitumor immune responses to control the growth of both the primary tumor and cancer cells present in the blood circulation and metastases in distant organs.[6–10]. The authors investigated the ability of ALT-803 to modulate ADCC mediated by the humanized IgG1 monoclonal antibody (mAb) NEO-201 against human carcinoma cells. Materials and Methods: ALT-803 modulating activity on ADCC mediated by NEO-201 was evaluated on several NEO-201 ligand-expressing human carcinoma cells. Modulation of NK cell phenotype and cytotoxic function by exposure to ALT-803 was evaluated by flow cytometry and gene expression analysis. Conclusions: These findings indicate that ALT-803 can enhance ADCC activity mediated by NEO-201, by modulating NK activation and cytotoxicity, suggesting a possible clinical use of ALT-803 in combination with NEO-201 for the treatment of human carcinomas
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