{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,16]],"date-time":"2026-07-16T09:04:00Z","timestamp":1784192640566,"version":"3.55.0"},"reference-count":57,"publisher":"MDPI AG","issue":"7","license":[{"start":{"date-parts":[[2026,7,15]],"date-time":"2026-07-15T00:00:00Z","timestamp":1784073600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Pharmaceutics"],"abstract":"<jats:p>Background\/Objectives: Interleukin-15 (IL-15) is a promising immunotherapeutic cytokine, but its short half-life limits clinical utility. We developed a stable PEGylated receptor-linker IL-15 agonist (PEG-RLI) to improve pharmacokinetic properties while preserving biological activity and antitumor efficacy. Methods: PEG-RLI was synthesized by site-specific N-terminal conjugation of a 40 kDa methoxy polyethylene glycol (MeOPEG) to RLI. The conjugate was characterized for purity and receptor agonism. Pharmacokinetics were evaluated in mice, and pharmacodynamic effects on NK cells and CD8+ T cell subsets were assessed. Antitumor activity was tested in CT26 tumor-bearing mice alone and in combination with anti-PD-1 therapy. Results: PEGylation preserved RLI agonistic activity and extended its mouse half-life from approximately 3 h to approximately 15 h. PEG-RLI induced robust expansion of NK cells and CD8+ T cells, with preferential enrichment of CD8+ T cells and CD44hiCD8+ T cells. In CT26 solid tumors, PEG-RLI enhanced the antitumor efficacy of anti-PD-1 treatment. Conclusions: Stable PEGylation improved the pharmacokinetic profile of RLI while maintaining potent immunostimulatory activity. PEG-RLI preferentially expanded CD8+ T cells and showed promising efficacy with immune checkpoint blockade, supporting further development as a differentiated IL-15-based immunotherapeutic.<\/jats:p>","DOI":"10.3390\/pharmaceutics18070863","type":"journal-article","created":{"date-parts":[[2026,7,16]],"date-time":"2026-07-16T08:08:34Z","timestamp":1784189314000},"page":"863","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["PEG-RLI: A Long-Acting IL-15 Agonist That Produces Massive Levels of CD8+ and CD44hiCD8+ Cells for Cancer Immunotherapy"],"prefix":"10.3390","volume":"18","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-3457-4139","authenticated-orcid":false,"given":"Rocio Del Valle","family":"Fernandez","sequence":"first","affiliation":[{"name":"Prolynx Inc., 5858 Horton st, Suite 575, Emeryville, CA 94608, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0835-5124","authenticated-orcid":false,"given":"Guillermo","family":"Hails","sequence":"additional","affiliation":[{"name":"Prolynx Inc., 5858 Horton st, Suite 575, Emeryville, CA 94608, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8386-3922","authenticated-orcid":false,"given":"John A.","family":"Hangasky","sequence":"additional","affiliation":[{"name":"Prolynx Inc., 5858 Horton st, Suite 575, Emeryville, CA 94608, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gary W.","family":"Ashley","sequence":"additional","affiliation":[{"name":"Prolynx Inc., 5858 Horton st, Suite 575, Emeryville, CA 94608, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daniel V.","family":"Santi","sequence":"additional","affiliation":[{"name":"Prolynx Inc., 5858 Horton st, Suite 575, Emeryville, CA 94608, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,7,15]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"e1","DOI":"10.1182\/blood-2011-10-384362","article-title":"Circulating IL-15 exists as heterodimeric complex with soluble IL-15Ralpha in human and mouse serum","volume":"120","author":"Bergamaschi","year":"2012","journal-title":"Blood"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"3654","DOI":"10.1002\/j.1460-2075.1995.tb00035.x","article-title":"Identification and cloning of a novel IL-15 binding protein that is structurally related to the alpha chain of the IL-2 receptor","volume":"14","author":"Giri","year":"1995","journal-title":"EMBO J."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"85","DOI":"10.1016\/j.imlet.2009.09.009","article-title":"Trans-presentation: A novel mechanism regulating IL-15 delivery and responses","volume":"127","author":"Stonier","year":"2010","journal-title":"Immunol. 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