Immunostimulatory combinations of TLR ligands and methods of use
Inventors
Berzofsky, Jay A. • Zhu, Qing • Belyakov, Igor
Assignees
HEALTH AND HUMAN SERVICES United States, Secretary of, Department of • US Department of Health and Human Services
Publication Number
US-9421254-B2
Publication Date
2016-08-23
Expiration Date
2028-09-24
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Abstract
The present invention provides immunostimulatory combinations of TLR ligands and therapeutic and/or prophylactic methods that include administering an immunostimulatory combination to a subject. In general, the immunostimulatory combinations described herein can provide an increased immune response compared to other immunostimulatory combinations and/or compositions.
Core Innovation
The invention provides immunostimulatory combinations of TLR ligands and therapeutic and/or prophylactic methods including administering an immunostimulatory combination to a subject. The immunostimulatory combinations described can provide an increased immune response compared to other immunostimulatory combinations and/or compositions. In particular, the invention features compositions comprising combinations of two or more Toll Like Receptor (TLR) agonists, including combinations where at least one agonist is a TLR3 agonist, and further combinations including TLR2 and TLR9 agonists.
The problem being solved is the unmet need for adjuvants that can effectively enhance immune response. Existing innate immune mechanisms are limited and may not be sufficiently enhanced by exposure to foreign substances, making therapies that promote innate immunity desirable. The invention addresses the need to stimulate the immune system more effectively in treating diseases or as vaccine adjuvants by providing synergistic combinations of TLR ligands that more robustly activate dendritic cells and induce T cell responses.
The invention demonstrates that combinations of TLR agonists, particularly involving TLR3 together with TLR2 and/or TLR9, synergistically activate dendritic cells (DCs) through MyD88-dependent pathways leading to enhanced production of cytokines such as IL-12 and TNF-alpha. This synergistic activation results in immediate induction of T cell responses, including antigen-specific CD8+ T cells with high functional avidity. Notably, each TLR agonist alone at suboptimal doses induces limited or no immune response, but in combination, they effectively stimulate immune activation, which has important implications for vaccine adjuvant design.
Claims Coverage
The patent claims include one independent composition claim and several method and pharmaceutical composition claims covering combinations of TLR agonists. The main inventive features focus on synergistic use of specific TLR agonists and induced immune activation.
Immunostimulatory composition with triple TLR agonists
An immunostimulatory composition comprising an effective amount of MALP-2 (TLR2 agonist), PolyI:C (TLR3 agonist), and CpG (TLR9 agonist), wherein this triple combination synergistically activates IL-15 and IL-12 production of dendritic cells compared to double combinations, thereby inducing high functional avidity T cells.
Inclusion of antigens in the composition
The immunostimulatory composition may further comprise one or more antigens, optionally conjugated to a TLR agonist, to enhance specific immune responses.
Method of activating dendritic cells
A method of activating dendritic cells in a subject by administering the triple combination of MALP-2, PolyI:C, and CpG, which synergistically activates IL-15 and IL-12 production and thereby induces high functional avidity T cells.
Method of activating antigen-specific CD8+ T cells
A method of activating antigen-specific CD8+ T cells in a subject comprising administering the immunostimulatory composition containing the three TLR agonists that synergistically activate dendritic cells.
Pharmaceutical composition for inducing high functional avidity T cells
A pharmaceutical composition comprising the triple combination of MALP-2, PolyI:C, and CpG that synergistically activates IL-15 and IL-12 production of dendritic cells to induce high functional avidity T cells.
The claims collectively cover compositions and methods involving a synergistic triple combination of TLR2, TLR3, and TLR9 agonists that activate dendritic cells and induce high functional avidity T cells, including use with antigens and as pharmaceutical compositions for immunostimulation.
Stated Advantages
The immunostimulatory combinations can provide an increased immune response compared to other immunostimulatory combinations and/or compositions.
The synergistic TLR ligand combinations potentiate dendritic cell activation leading to immediate induction of robust T cell responses.
The triple combination of TLR agonists induces higher functional avidity of antigen-specific T cells compared to double combinations.
These combinations allow effective immune activation at suboptimal doses of individual TLR agonists, potentially reducing side effects and improving vaccine efficacy.
Documented Applications
Use of immunostimulatory TLR ligand combinations for therapeutic or prophylactic vaccination including viral, bacterial, fungal, parasitic, tumor, alloantigen, or xenoantigen antigens.
Treatment of conditions such as neoplastic disease (including cancer), viral infections (e.g., HIV, Hepatitis C, HPV), bacterial infections, fungal infections, allergy, and autoimmune disease.
Induction of mucosal immunity and enhanced protection against viral challenge through intrarectal vaccination using TLR ligand combinations.
Use of the immunostimulatory compositions as vaccine adjuvants to safely and effectively enhance immune responses.
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