Toll-like receptor (TLR) 7/8 stimulation activates antigen-presenting cells to prime new antigen-specific cytotoxic T cells via an innate immune system response, which is a critical first step in tumor growth inhibition by the adaptive immune system.  However, TLR 7/8 agonists tested in the clinic to date have caused grade 3 or 4 adverse effects attributed to high systemic exposure at efficacious doses resulting in cytokine release syndrome.<br/>NKTR-262 is a novel pro-drug that is administered via intratumoral injection, comprising a small molecule TLR 7/8 agonist conjugated to a PEG via hydrolysable linker.  NKTR-262 has been designed to reduce systemic exposure and improve tolerability of the active TLR 7/8 agonist, while affording local pharmacodynamic effects superior to existing TLR 7/8 agonists.  This is attributable to both its hydrodynamic size (to retain NKTR-262 in the tumor) and the rate of release of the active TLR 7/8 agonist from the administered inactive pro-drug.<br/>NKTR-214 (bempegaldesleukin) is a CD-122-peferential IL-2 pathway agonist that expands CD8+ T cells in the tumor microenvironment, which is currently in Phase 3 trials in several solid tumor indications.  We hypothesized that combination treatment with NKTR-262 and NKTR-214 could provide powerful and synergistic anti-tumor effects as NKTR-262 could potentiate the antigen-presenting cells and convert M2 macrophages to M1 macrophages, and NKTR-214 could stimulate expansion of “educated” CD8+ T cells, which then traffic to distant tumor sites resulting in tumor shrinkage.<br/>In preclinical studies, a single intratumoral administration of NKTR-262 combined with systemic administration of NKTR-214 produced a complete cure of treated and untreated tumors in multiple syngeneic models.  Currently, NKTR-262 is being evaluated in a Phase 1b/2 clinical trial in patients with locally advanced or metastatic solid tumors.<br/>

NKTR-262: Discovery of a novel TLR 7/8 agonist prodrug that demonstrates synergistic anti-tumor effect in combination with NKTR-214, a CD-122 preferential IL-2 pathway agonist

Macromolecular Chemistry: The Second Century

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ACS Spring 2020 National Meeting & Expo

The official archive and repository for all ACS Meetings & Expositions abstracts and select posters or presentations.