The multi-functionality of N-809, a novel fusion protein encompassing anti-PD-L1 and the IL-15 superagonist fusion complex

• Main Authors: Caroline Jochems, Sarah R. Tritsch, Karin M. Knudson, Sofia R. Gameiro, Claire Smalley Rumfield, Samuel T. Pellom, Y. Maurice Morillon, Robby Newman, Warren Marcus, Christopher Szeto, Shahrooz Rabizadeh, Hing C. Wong, Patrick Soon-Shiong, Jeffrey Schlom
• Format: Article
• Language: English
• Published: Taylor & Francis Group 2019-02-01
• Series: OncoImmunology
• Subjects: alt-803; n-803; il-15; n-809; anti-pd-l1; immunotherapy; checkpoint inhibitor; cytokine; carcinoma; adcc
• Online Access: http://dx.doi.org/10.1080/2162402X.2018.1532764

Here 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.