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



    • 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.



    Toxicity (A-B) and survival (C) analysis of B16.F10 melanoma mice treated peritumorally with: PBS (black solid line), unlinked (red dashed line), linked (blue dotted line), or sugar-assisted peptide (SAP, orange solid line) formulations.




    • 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



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





    • PCT/US21/70024



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