Novel Nano-Formulation For Multi-TLR Agonists To Boost Immune Responses Against Solid Tumors

SUMMARY

• Toll-like receptor (TLR) agonists are considered promising alternatives for the estimated 50 – 75% of all cancer patients who are non-responsive to checkpoint inhibitors, and immune activation is enhanced upon stimulation of two distinct TLRs. However, the use of multiple TLR agonists as an effective therapeutic strategy is presently limited by the tendency of these agonists to diffuse systemically. Their distinct PK/PD profiles and different diffusion rates hinder local efficacy and increase toxicity.
• Nano-encapsulation of TLR agonists has been explored for local immune activation, and linked TLR agonists have been shown to have immunostimulatory effects with improved pharmacokinetics. The inventors exploited these to develop a novel nano-formulation for linked multi-TLR agonists.
• The invention is a sugar-peptide hybrid nano-formulation for multi-TLR agonists. This formulation improves therapeutic efficacy, and it significantly reduces hematological toxicities as a result of reduced systemic diffusion as compared to unformulated agonists. 
• In a highly immunologically unresponsive melanoma model, mice injected with TLR2/6_7 heterodimers in the invention formulation at day 9, 15, and 21 showed significant improved survival and reduced tumor growth as compared to mice treated with unformulated agonists. In addition, hematological toxicities in these mice were similar to control, significantly lower than in mice treated with unformulated agonists.

FIGURE

ADVANTAGES

ADVANTAGES

• Exhibits long-term stability
• Reduces the hematological toxicities of multi-TLR agonists
• Increases the efficacy of multi-TLR agonists
• Boosts immune activation in immune-suppressive tumor microenvironment

APPLICATIONS

• Cancer immunotherapy (monotherapy)
• Cancer combination therapy (with checkpoint inhibitors)
• Vaccine adjuvant

PUBLICATIONS

• Manna S, Maiti S, Shen J, Du W, Esser-Kahn AP. Pathogen-like Nanoassemblies of Covalently Linked TLR Agonists Enhance CD8 and NK Cell-Mediated Antitumor Immunity. ACS Cent Sci. 2020 Nov 25;6(11):2071-2078. doi: 10.1021/acscentsci.0c01001. Epub 2020 Oct 27. PMID: 33274283; PMCID: PMC7706081.
• Previous related work: Tom et al. Modulation of Innate Immune Responses via Covalently Linked TLR Agonists. ACS Cent Sci. 2015 Nov 25; 1(8): 439–448.

Mar 2, 2020

Licensing,Co-Development

Preclinical in vivo

Patent Pending

Aaron Esser-Kahn

• PCT/US21/70024