Improving the Adjuvanticity of Small Molecule Immune Potentiators Using Covalently Linked NF-κB Modulators.

ABSTRACT: Small molecule immune potentiators (SMIPs) such as imidazoquinolinone derivatives that activate Toll-like receptor (TLR) 7/8 have immense potential as vaccine adjuvants and as antitumor agents. However, these molecules have high bioavailability that results in unacceptable levels of systemic inflammation due to adjuvant toxicity, thereby greatly limiting their use. To address this challenge, here we report the design and synthesis of novel imidazoquinolinone-NF-κB immunomodulator dimers. Employing in vitro assays, we screened a select library of synthesized dimers and selected viable candidates for further in vivo experiments. With ovalbumin as a model antigen, we vaccinated mice and demonstrated that these dimers reduce the systemic toxicity associated with SMIPs to baseline levels while simultaneously maintaining the adjuvanticity in a vaccine formulation. Additionally, we showed that select dimers improved efficacy in a CT26 mouse colon carcinoma tumor model while eliciting minimal adjuvant toxicity.

SUBMITTER: Kimani FW 

PROVIDER: S-EPMC8436408 | biostudies-literature | 2021 Sep

REPOSITORIES: biostudies-literature