Methods of altering an immune response induced by CpG oligodeoxynucleotides
Inventors
KLINMAN, DENNIS M. • Gursel, Mayda • Gursel, Ihsan
Assignees
US Department of Health and Human Services
Publication Number
US-8470342-B2
Publication Date
2013-06-25
Expiration Date
2026-08-28
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Abstract
It is disclosed herein that agents that affect the activity and/or expression of CXCL16 can be used to alter the uptake of D-type CpG oligodeoxynucleotides (D ODNs). Methods of inducing an immune response are disclosed that include administering agents that increase the activity and/or expression of CXCL16 and a D ODN. Methods of decreasing an immune response to a CpG ODN are also disclosed. These methods include administering an agent that decreases the activity and/or expression of CXCL16. Compositions including one or more D-type ODNs and an agent that modulates that activity and/or expression of CXCL16 are provided.
Core Innovation
The invention discloses that agents affecting the activity and/or expression of the chemokine CXCL16 can be used to modulate the uptake of D-type CpG oligodeoxynucleotides (D ODNs). By increasing CXCL16 activity or expression, the uptake of D ODNs is enhanced, leading to an increased immune response induced by these oligonucleotides. Conversely, agents that decrease CXCL16 activity or expression reduce D ODN uptake and thereby decrease the immune response.
The problem addressed is the need to modulate the immune response induced by CpG ODNs by altering their uptake by immune cells. While CpG ODNs are known to stimulate immune responses through Toll-like receptor 9 (TLR9), specifically D-type ODNs require additional receptors for optimal recognition and uptake. The invention identifies CXCL16 as a receptor that mediates D ODN binding and uptake, providing methods and compositions to alter immune responses by modulating CXCL16 activity or expression in conjunction with D ODN administration.
Claims Coverage
The patent includes one independent claim focused on pharmaceutical compositions comprising D-type oligodeoxynucleotides and agents modulating CXCL16 expression or activity, with several inventive features.
Pharmaceutical composition comprising a D-type oligodeoxynucleotide and a metalloproteinase inhibitor
The composition includes a therapeutically effective amount of a D-type oligodeoxynucleotide with specific sequence characteristics and a metalloproteinase inhibitor such as GW280264X, G1254023X, GM6001, or pharmaceutically acceptable salts thereof.
Self-complementary sequences in D-type oligodeoxynucleotides
The D-type oligodeoxynucleotide comprises self-complementary sequences in regions Pu1 Py2 and Pu3 Py4, or the broader region X1X2X3 Pu1 Py2 and Pu3 Py4 X4X5X6, to enhance its immunostimulatory activity.
Specific nucleotide sequences for D-type oligodeoxynucleotides
The D ODN includes or consists of nucleotide sequences set forth in SEQ ID NO: 1 through SEQ ID NO: 17, which are identified as effective sequences.
Combination with anti-infectious agents or vaccines
The composition may further comprise therapeutically effective amounts of anti-infectious agents (antiviral, antifungal, antibacterial) and vaccines, including heat-killed, attenuated or live vaccines.
Various formulations and administration routes
The pharmaceutical compositions can be formulated for oral or topical administration and may include additional therapeutic agents.
The claims cover pharmaceutical compositions combining specific D-type oligodeoxynucleotides with agents that modulate CXCL16 expression or activity, particularly metalloproteinase inhibitors, encompassing defined nucleotide sequences and formulations designed to enhance immune responses via increased D ODN uptake.
Stated Advantages
Agents that increase CXCL16 activity or expression enhance the uptake of D-type CpG oligodeoxynucleotides, thereby increasing the induced immune response.
Agents that decrease CXCL16 activity or expression reduce D ODN uptake and diminish the immune response, allowing for controlled modulation of immunity.
Compositions including agents modulating CXCL16 and D-type ODNs can improve immune activation specificity and efficacy.
Documented Applications
Use in inducing immune responses to specific antigens including bacterial, viral, fungal, and tumor antigens.
Enhancement of vaccines, including live, attenuated, or heat-killed vaccines, for improved efficacy.
Treatment or prevention of autoimmune diseases by modulating immune responses via CXCL16 and D ODNs.
Therapeutic application in allergy treatment and amelioration of allergic reactions.
Cancer therapy including reduction of tumor burden by combining D ODNs with CXCL16 activity modulators and cancer vaccines.
Treatment or amelioration of infectious diseases caused by various infectious agents using D ODNs and CXCL16 modulators in combination with anti-infectious agents.
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