{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,2,23]],"date-time":"2026-02-23T21:49:01Z","timestamp":1771883341401,"version":"3.50.1"},"reference-count":47,"publisher":"BMJ","issue":"2","license":[{"start":{"date-parts":[[2020,10,27]],"date-time":"2020-10-27T00:00:00Z","timestamp":1603756800000},"content-version":"unspecified","delay-in-days":26,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000902","name":"Pediatric Cancer Research Foundation","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100000902","id-type":"DOI","asserted-by":"publisher"}]},{"name":"New York Medical College School of Medicine Translational Science Institute Children Health Translational Research Award"}],"content-domain":{"domain":["bmj.com"],"crossmark-restriction":true},"short-container-title":["J Immunother Cancer"],"accepted":{"date-parts":[[2020,9,16]]},"published-print":{"date-parts":[[2020,10]]},"abstract":"<jats:sec>\n                  <jats:title>Background<\/jats:title>\n                  <jats:p>The prognosis of patients with relapsed or progressive B cell (CD20<jats:sup>+<\/jats:sup>) non-Hodgkin\u2019s lymphoma (B-NHL), including Burkitt lymphoma (BL), is dismal due to chemoradiotherapy resistance. Novel therapeutic strategies are urgently needed. N-820 is a fusion protein of N-803 (formerly known as ALT-803) to four single-chains of rituximab. This agent has tri-specific binding activity to CD20 and enhanced antibody-dependent cell-mediated cytotoxicity.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Methods<\/jats:title>\n                  <jats:p>We investigated the anti-tumor combinatorial effects of N-820 with ex vivo expanded peripheral blood natural killer (exPBNK) cells against rituximab-sensitive and rituximab-resistant CD20<jats:sup>+<\/jats:sup> BL in vitro using cytoxicity assays and in vivo using human BL xenografted NOD\/SCID\/IL2r\u03b3null (NSG) mice. We also investigated the cytokines\/chemokines\/growth factors released using ELISA and multiplex assay. Gene expression changes were examined using real-time PCR arrays.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Results<\/jats:title>\n                  <jats:p>N-820 significantly enhanced the expression of NK activating receptors (p&lt;0.001) and the proliferation of exPBNK cells with enhanced Ki67 expression and Stat5 phosphorylation (p&lt;0.001). N-820 significantly enhanced the secretion of cytokines, chemokines, and growth factors including GM-CSF, RANTES, MIP-1B (p&lt;0.001) from exPBNK cells as compared with the combination of rituximab+N-803. Importantly, N-820 significantly enhanced in vitro cytotoxicity (p&lt;0.001) of exPBNK with enhanced granzyme B and IFN-\u03b3 release (p&lt;0.001) against BL. Gene expression profiles in exPBNK stimulated by N-820+Raji-2R showed enhanced transcription of <jats:italic>CXCL9<\/jats:italic>, <jats:italic>CXCL1<\/jats:italic>, <jats:italic>CSF2<\/jats:italic>, <jats:italic>CSF3<\/jats:italic>, <jats:italic>GZMB,<\/jats:italic> and <jats:italic>IFNG<\/jats:italic>. Moreover, N-820 combined with exPBNK significantly inhibited rituximab-resistant BL growth (p&lt;0.05) and extended the survival (p&lt;0.05) of BL xenografted NSG mice.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Conclusions<\/jats:title>\n                  <jats:p>Our results provide the rationale for the development of a clinical trial of N-820 alone or in combination with endogenous or ex vivo expanded NK cells in patients with CD20<jats:sup>+<\/jats:sup> B-NHL failing prior rituximab containing chemoimmunotherapy regimens.<\/jats:p>\n               <\/jats:sec>","DOI":"10.1136\/jitc-2020-001238","type":"journal-article","created":{"date-parts":[[2020,10,27]],"date-time":"2020-10-27T17:15:25Z","timestamp":1603818925000},"page":"e001238","update-policy":"https:\/\/doi.org\/10.1136\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":14,"title":["Novel cytokine\u2013antibody fusion protein, N-820, to enhance the functions 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