Polyketal particles including a CpG oligodeoxynucleotide for the treatment of lung cancer
Inventors
KLINMAN, DENNIS M. • Sato, Takashi
Assignees
US Department of Health and Human Services
Publication Number
US-9919058-B2
Publication Date
2018-03-20
Expiration Date
2035-07-08
Interested in licensing this patent?
MTEC can help explore whether this patent might be available for licensing for your application.
Abstract
Methods are disclosed herein for treating a subject with a lung cancer. The lung cancer can be small cell carcinoma of the lung or non-small cell carcinoma of the lung.The methods include locally administering to the subject a therapeutically effective amount of the polyketal particle comprising a CpG oligodexoynucleotide. Optionally, the polyketal particle can include an imidazoquinoline compound.
Core Innovation
Lung cancer is a leading cause of cancer-related death with a low five-year survival rate, particularly for non-small cell lung cancer (NSCLC). Current therapies, including systemic administration of CpG oligodeoxynucleotides (CpG ODN), have limited efficacy due to the rapid clearance of free CpG ODN from the lungs and poor accumulation in tumor sites. Lung tumors are poorly immunogenic and resistant to immune surveillance, necessitating new compositions that activate the pulmonary immune system to promote tumor regression.
This invention discloses methods for treating subjects with lung cancer, including small cell and non-small cell carcinoma types, by locally administering polyketal particles comprising CpG oligodeoxynucleotides. The CpG ODN may be K-type or D-type with specified nucleotide sequences. Polyketal nanoparticles, sized about 150-500 nm, can include imidazoquinoline compounds, such as lipophilic derivatives like 3M-052. These particles degrade via acid-catalyzed hydrolysis into non-inflammatory compounds and can form microparticles (1-5 µm) optimized for delivery to the distal lung regions.
The polyketal particle delivery system enhances localization and persistence of CpG ODN within pulmonary tumor nodules, eliciting a robust Th1 immune response. This is accompanied by decreased immunosuppressive regulatory T cells and M2 macrophages in the tumor microenvironment, leading to significant tumor cell apoptosis and reduced tumor burden. The methods have demonstrated efficacy in both primary lung cancer and metastatic lung cancer models, offering increased survival for subjects with lung cancer through local pulmonary delivery of immunostimulatory polyketal particles.
Claims Coverage
The patent includes a number of inventive features centered on a method of treating lung cancer by locally administering polyketal particles comprising CpG oligodeoxynucleotides, with optional inclusion of imidazoquinoline compounds.
Local administration of polyketal particles with CpG oligodeoxynucleotides
A method of treating lung cancer by locally administering a therapeutically effective amount of a polyketal delivery particle comprising a CpG oligodeoxynucleotide, which can be K-type or D-type with specified nucleotide sequences, to the subject.
CpG oligodeoxynucleotide attachment and modification
The CpG oligodeoxynucleotide is conjugated to or adsorbed on the surface of the polyketal particle and can be modified to prevent degradation, including by incorporation of phosphorothioate bonds.
Specific lengths and sequences of CpG oligodeoxynucleotides
The CpG oligodeoxynucleotide is at most 30 nucleotides in length, with K-type CpG ODN corresponding to SEQ ID NOs: 3-34 and D-type CpG ODN corresponding to SEQ ID NOs: 37-63.
Inclusion of imidazoquinoline compounds in particles
The polyketal delivery particle optionally includes an imidazoquinoline compound, specifically a lipophilic variant such as 3M-052.
Types of lung cancer treated
The method applies to treating non-small cell and small cell lung cancers, aiming to reduce tumor volume and metastasis.
Particle size and formulation for pulmonary delivery
The polyketal nanoparticles have a diameter of about 200 nm to about 400 nm and can be administered as microparticles about 1 µm to about 5 µm in diameter, consisting of polyketal nanoparticles such as PPADK, PCADK, or PK1-PK6 copolymers.
Specific combination for treatment
A method combining administration of a K-type CpG oligodeoxynucleotide of SEQ ID NO: 33 within PPADK polyketal nanoparticles assembled into microparticles of about 1 µm to 5 µm diameter, delivered intratracheally or by pulmonary inhalation to treat non-small cell lung cancer.
The claims cover a local administration method using polyketal particles carrying specific CpG oligodeoxynucleotides, optionally with imidazoquinoline compounds, targeted to treat both major types of lung cancer with defined particle sizes and sequences, enhancing efficacy through pulmonary delivery.
Stated Advantages
Local delivery of CpG oligodeoxynucleotides via polyketal particles achieves superior tumor targeting and increased pulmonary retention compared to systemic administration.
The method induces a robust Th1 immune response, significantly reducing immunosuppressive regulatory T cells and M2 macrophages in the tumor microenvironment.
Treatment with the particles results in significant reduction of tumor burden and improved long-term survival in lung cancer models.
Polyketal particles degrade into non-inflammatory low molecular weight compounds, minimizing adverse inflammatory effects.
Documented Applications
Treatment of subjects with lung cancer, including small cell carcinoma and non-small cell carcinoma of the lung.
Use in increasing survival of subjects by reducing tumor volume and metastasis.
Local pulmonary delivery, including intratracheal administration or inhalation, of polyketal particle formulations to target lung tumors.
Use in both primary lung cancer and metastatic lung cancer disease models.
Interested in licensing this patent?