Abstract
ABSTRACTHere we describe a novel bifunctional fusion protein, designated N-809. This molecule comprises the IL-15/IL15Rα superagonist complex containing the Fc-domain of IgG1 (N-803, formerly designated as ALT-803) fused to two single chain anti-PD-L1 domains. The fully human IgG1 portion of the N-809 molecule was designed to potentially mediate antibody dependent cellular cytotoxicity (ADCC). The studies reported here show that N-809 has the same ability to bind PD-L1 as an anti-PD-L1 monoclonal antibody. RNAseq studies show the ability of N-809 to alter the expression of an array of genes of both CD4+ and CD8+ human T cells, and to enhance their proliferation; CD8+ T cells exposed to N-809 also have enhanced ability to lyse human tumor cells. An array of genes was differentially expressed in human natural killer (NK) cells following N-809 treatment, and there was increased expression of several surface activating receptors; there was, however, no increase in the expression of inhibitory receptors known to be upregulated in exhausted NK cells. N-809 also increased the cytotoxic potential of NK cells, as shown by increased expression of granzyme B and perforin. The lysis of several tumor cell types was increased when either NK cells or tumor cells were exposed to N-809. Similarly, the highest level of ADCC was seen when both NK cells (from donors or cancer patients) and tumor cells were exposed to N-809. These studies thus demonstrate the multi-functionality of this novel agent.
Highlights
Cancer immunotherapy studies have demonstrated promising clinical response rates in patients with melanoma and subsets of patients with other solid tumors
Most antibodies directed against programmed cell death-1 (PD-1)/programmed cell death ligand-1 (PD-L1) are of the IgG4 isotype, or of the IgG1 isotype engineered with an Fc domain mutation to impair antibody dependent cellular cytotoxicity (ADCC) activity
Atezolizumab (Tecentriq®, Genentech) and avelumab (Bavencio®, EMD Serono) are fully human anti-PD-L1 therapies of the IgG1 isotype that have been FDA approved for the treatment of non-small cell lung cancer (NSCLC), bladder cancer, urothelial cancer, and metastatic Merkel cell carcinoma.[12,13,14,15]
Summary
Cancer immunotherapy studies have demonstrated promising clinical response rates in patients with melanoma and subsets of patients with other solid tumors. Those studies have involved monoclonal antibody (MAb) checkpoint inhibitors such as anti-CTLA4, anti‒programmed cell death-1 (PD-1), and anti‒programmed cell death ligand-1 (PD-L1), as well as cytokines such as IL-2 and IL-15.1–5 More recently, combination therapies employing two different checkpoint inhibitors or other immune stimulatory agents are being studied to enhance therapeutic outcomes.[6,7,8]. Atezolizumab (Tecentriq®, Genentech) and avelumab (Bavencio®, EMD Serono) are fully human anti-PD-L1 therapies of the IgG1 isotype that have been FDA approved for the treatment of non-small cell lung cancer (NSCLC), bladder cancer, urothelial cancer, and metastatic Merkel cell carcinoma.[12,13,14,15]
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