The multi-functionality of N-809, a novel fusion protein encompassing anti-PD-L1 and the IL-15 superagonist fusion complex
| Autor: | Robby Newman, Jeffrey Schlom, Sofia R. Gameiro, Claire Smalley Rumfield, Y. Maurice Morillon, Hing C. Wong, Karin M. Knudson, Patrick Soon-Shiong, Christopher Szeto, Samuel T Pellom, Shahrooz Rabizadeh, Warren D. Marcus, Sarah R. Tritsch, Caroline Jochems |
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| Rok vydání: | 2018 |
| Předmět: |
0301 basic medicine
lcsh:Immunologic diseases. Allergy il-15 medicine.medical_treatment Immunology carcinoma anti-pd-l1 lcsh:RC254-282 03 medical and health sciences 0302 clinical medicine medicine cytokine Immunology and Allergy Cytotoxic T cell Original Research Antibody-dependent cell-mediated cytotoxicity n-803 biology Chemistry n-809 lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens Fusion protein Cell biology Granzyme B 030104 developmental biology Cytokine checkpoint inhibitor Oncology Perforin adcc Interleukin 15 030220 oncology & carcinogenesis biology.protein immunotherapy lcsh:RC581-607 CD8 alt-803 |
| Zdroj: | OncoImmunology, Vol 8, Iss 2 (2019) Oncoimmunology |
| ISSN: | 2162-4011 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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