Therapeutic antitumor combination of a TLR4 ligand with other treatments
Inventors
Oppenheim, Joost J. • Yang, De • Han, Zhen • Barchi, Jr., Joseph John • Bustin, Michael
Assignees
United Slates Of America REPRESENTED BY SECRETARY Department Of Health And Human Services AS • US Department of Health and Human Services
Publication Number
US-11266746-B2
Publication Date
2022-03-08
Expiration Date
2037-02-24
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Abstract
Methods of treating cancer or reducing the incidence of relapse of a cancer in a subject comprising co-administration of Toll-like receptor (TLR) 4 ligand, such as an HMGN1 protein, and a TLR 7 or 8 ligand, and optionally an immune checkpoint inhibitor, to the subject in need of such therapy. The TLR4-mediated immune-stimulating effect is synergistically enhanced by ligands of TLR7 or 8, and the immune checkpoint inhibitor. Also described here is a nanoparticle delivery platform for the co-administration of the TLR 4 ligand and the TLR 7 or 8 ligand.
Core Innovation
This disclosure provides methods for treating cancer or reducing the incidence of cancer relapse by co-administering a Toll-like receptor (TLR) 4 ligand, such as High Mobility Group Nucleosome-binding protein 1 (HMGN1), with a TLR7 or TLR8 ligand, and optionally an immune checkpoint inhibitor. The combination synergistically enhances the TLR4-mediated immune-stimulating effect. The invention also includes a nanoparticle delivery platform for co-administration of the TLR4 ligand and the TLR7 or TLR8 ligand.
The problem being solved is the need for safer, more effective cancer treatments. Existing knowledge shows that HMGN1 has immunostimulating effects and potential antitumor activities, but prior to this disclosure, it was not shown whether HMGN1 alone or in combination could therapeutically treat pre-existing tumors. The disclosed methods and compositions aim to provide enhanced antitumor immune responses and effective eradication of established tumors.
Claims Coverage
The patent contains one independent claim focused on methods and compositions for cancer treatment involving specific ligands and inhibitors. The main inventive features relate to combinations of TLR4 ligand HMGN1, TLR7 or TLR8 ligands, immune checkpoint inhibitors, and nanoparticle compositions.
Co-administration of HMGN1, TLR7 or TLR8 ligand, and immune checkpoint inhibitor for cancer treatment
A method comprising co-administering a TLR4 ligand (HMGN1 protein), a TLR7 or TLR8 ligand, and a checkpoint inhibitor to a subject thereby treating cancer or reducing relapse incidence.
Administration without tumor antigen
The combination of HMGN1 protein, TLR7 or TLR8 ligand, and immune checkpoint inhibitor is administered in the absence of a tumor antigen.
Use of specific TLR7 or TLR8 ligands
The TLR7 or TLR8 ligand may be selected from resiquimod, imiquimod, imidazoquinoline derivatives, 852A, VTX1463, AZD8848, ANA773, or combinations thereof.
Selection of immune checkpoint inhibitors
The immune checkpoint inhibitor may be cyclophosphamide, antibodies targeting immune checkpoints (such as anti-CTLA4, anti-PD1, anti-PDL1, anti-PDL2, anti-LAG-3, anti-BTLA, anti-B7H3, anti-B7H4, anti-TIM3, or anti-A2aR), or combinations of these.
Specific therapeutic combinations involving cyclophosphamide or anti-CTLA antibody
Methods include co-administration of HMGN1 protein, resiquimod, and cyclophosphamide, with cyclophosphamide doses up to about 100 mg/kg, or co-administration of HMGN1, resiquimod, and an anti-CTLA antibody.
Administration routes and tumor types
Co-administration involves intratumoral, intraperitoneal, intravenous, or intramuscular injection, with HMGN1 optionally administered intratumorally. The cancer treated may be solid tumors including thymoma, colon, kidney, or liver cancer.
Co-administration via nanoparticle compositions
Methods include administering a composition comprising a nanoparticle adsorbed with HMGN1 protein and the TLR7 or TLR8 ligand. The nanoparticle can be a PEGylated gold nanoparticle with defined size (about 10-100 nm) and zeta potential (−40 mV to +40 mV).
Nanoparticle composition specifics
The composition comprises percentages of gold (approx. 70-96%), polyethylene glycol (PEG) (approx. 2-22%), HMGN1 (approx. 0.5-10%), and TLR7 or TLR8 ligand (approx. 0.5-10%).
Composition with immune checkpoint inhibitor and nanoparticle delivery
A composition comprising HMGN1 protein, a TLR7 or TLR8 ligand adsorbed to a nanoparticle, and an immune checkpoint inhibitor as described, including cyclophosphamide or specific checkpoint antibodies.
The independent claims cover innovative methods and compositions for cancer therapy based on synergistic co-administration of HMGN1, TLR7 or TLR8 ligands, immune checkpoint inhibitors, and their delivery via specific nanoparticle compositions with defined physicochemical properties.
Stated Advantages
The co-administration of HMGN1 with TLR7 or TLR8 ligands and immune checkpoint inhibitors synergistically enhances antitumor immune responses.
The treatment can eradicate large, established solid tumors and promote tumor-specific immune protection.
Nanoparticle delivery platforms provide stable and effective co-delivery, enabling systemic administration and tumor accumulation.
The method works in the absence of tumor antigens, simplifying treatment and enhancing effectiveness.
Documented Applications
Treatment of various cancers including solid tumors, thymoma, colon cancer, kidney cancer, liver cancer, and others.
Use in prophylaxis to reduce the incidence of tumor relapse after treatment.
Intratumoral, intravenous, intraperitoneal, or intramuscular administration of therapeutic compositions for cancer therapy.
Use of nanoparticle compositions for systemic delivery of TLR4 and TLR7/8 ligands in combination with immune checkpoint inhibitors.
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