web analytics

Small Molecule Immunopotentiator Conjugates of NF-KB Activators as Adjuvants With Enhanced Efficacy And Reduced Toxicity

Published:
Lead Inventor: Aaron Esser-Kahn
Print or Save to PDF

SUMMARY

  • Imidazoquinolinone derivatives that activate Toll-like receptor (TLR) 7/8 are small molecule immune potentiators (SMIPs) that have potent activity as vaccine adjuvants and as anti-tumor agents. However, these molecules have high bioavailability that results in unacceptable levels of systemic inflammation due to adjuvant toxicity greatly limiting their use.

  • The faculty inventor developed an alternative to small molecule adjuvant formulation where a TLR7/8 activating imidazoquinolinone is covalently linked to a NF-κB potentiator – altering the response that the molecule directly elicits from immune cells. This invention involves synthesis of novel imidazoquinolinone-NF-κB potentiator dimers.

  • With ovalbumin as a model antigen the inventors vaccinated mice and showed that these dimers reduce systemic toxicity to baseline levels while maintaining the adjuvanticity in a vaccine formulation. Additionally, they showed that select dimers increased survivability in a CT26 WT mouse colon carcinoma tumor model while eliciting low adjuvant toxicity.

FIGURE

In vivo tumor model experiment using SMIP-modulator dimers with peritumoral injection into subcutaneous CT-26 tumor model. Agonists were injected when tumors were about 75 cc in size followed by three additional injections every four days.

ADVANTAGES

ADVANTAGES

  • Significantly reduces systemic toxicity post in-vivo administration
  • Enhances efficacy

 

APPLICATIONS

  • Combines small molecule agonists with small molecule immunopotentiators to generate new molecules that serve as potent non-toxic adjuvants.

  • Broadens the use of SMIPs both as adjuvants in vaccines and in immunotherapy formulations for in-vivo administration of immune activators.