Sterically stabilized cationic liposomes (SSCL) encapsulating K type oligodeoxynucleotide (ODN) including CpG motif; interleukins; fusion proteins; immunology; antitumor agents
Inventors
KLINMAN, DENNIS M. • Gursel, Ihsan • Ishii, Ken J.
Assignees
SOCIETY FOR RESEARCH AND INITIATIVES (SRISTI) • US Department of Health and Human Services
Publication Number
US-7666674-B2
Publication Date
2010-02-23
Expiration Date
2022-07-29
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Abstract
Sterically stabilized cationic liposomes (SSCL) encapsulating a K type oligodeoxynucleotide (ODN) including a CpG motif are disclosed. These SSCL encapuslating a K type ODN can be used to effectively deliver the ODN to a cell. A novel method is also disclosed for producing the SSCL encapsulating the K type ODN. Administration of the SSCL encapsulating a K type ODN and a chemotherapeutic agent, such as a chimeric molecule comprising a targeting molecule selected from the group consisting of an IL-13, and an anti-IL-13 receptor antibody; and an effector molecule selected from the group consisting of a Pseudomonas exotoxin, a Diphtheria toxin, and a radionuclide, can be used to dramatically reduce the growth of solid tumors.
Core Innovation
The invention disclosed concerns sterically stabilized cationic liposomes (SSCL) that encapsulate a K type oligodeoxynucleotide (ODN) including a CpG motif. These SSCL encapsulating K type ODNs enable effective delivery of the ODN to cells, particularly cells of the immune system. A novel method of producing such SSCL encapsulating K type ODNs is also provided. The composition of the SSCL includes a cationic lipid, a co-lipid, and a stabilizing agent in specified molar ratios, encapsulating an oligodeoxynucleotide of at least ten nucleotides in length that contains a CpG motif represented by the formula 5′ N1N2N3Q-CpG-WN4N5N6 3′ (SEQ ID NO: 97).
The problem being addressed is that synthetic CpG ODNs have rapid elimination in vivo due to degradation and adsorption onto serum proteins, limiting their therapeutic efficacy. Prolonging the bioavailability and enhancing the delivery of CpG ODNs would improve their immunostimulatory and therapeutic effects. Prior methods for protecting CpG ODNs include liposome encapsulation; however, previous liposomes were less efficient in encapsulation and cell uptake. The disclosed SSCLs offer improved encapsulation and delivery of K type CpG ODNs, leading to enhanced immune stimulation.
Furthermore, the SSCL encapsulating K type ODNs, when administered in conjunction with targeted biological agents such as chimeric molecules combining a targeting molecule like interleukin-13 or an anti-IL-13 receptor antibody and an effector molecule such as Pseudomonas exotoxin, Diphtheria toxin, chemotherapeutic agents, or radionuclides, synergistically reduce the growth of solid tumors. Thus, the invention addresses effective delivery and enhanced therapeutic efficacy of CpG ODNs alone and in combination with other agents, particularly for immune stimulation and cancer treatment.
Claims Coverage
The patent contains multiple independent claims covering the composition of SSCL encapsulating K type oligodeoxynucleotides, methods of stimulating immune responses using these compositions, and methods for producing SSCL encapsulating agents of interest.
Sterically stabilized cationic liposome encapsulating K type CpG oligodeoxynucleotide
A composition comprising a cationic lipid, a co-lipid, and a stabilizing agent encapsulating a K type oligodeoxynucleotide of at least ten nucleotides containing a CpG motif with a specified sequence formula, wherein the lipid, co-lipid and stabilizing agent are present at a specified molar ratio, specifically including DC-CHOL as the lipid, DOPE as the co-lipid, and polyethylene glycol-phosphatidyl ethanolamine (PEG-PE) as the stabilizing agent.
Sterically stabilized cationic liposome composition with an antigen
The SSCL composition further including an antigen that can be a protein, polypeptide, or polysaccharide.
Sterically stabilized cationic liposome further comprising a targeting molecule
The SSCL composition including a targeting molecule for specific delivery to target cells.
Method of stimulating immune response in subjects using SSCL encapsulating K type CpG ODN
Administration of therapeutically effective amounts of the sterically stabilized cationic liposome composition encapsulating K type CpG ODN to stimulate an immune response including cytokine expression, antigen-specific immune responses, or immunotherapeutic responses against tumors.
Method for stimulating immune cells in vitro or in vivo
Contacting immune cells with SSCL encapsulating K type CpG ODN thereby stimulating the immune cells, either in vitro or in vivo.
Method for producing SSCL encapsulating an agent of interest
A process involving contacting a unilamellar vesicle with the agent, dehydrating the mixture, then rehydrating to produce SSCL encapsulating the agent.
The claims broadly cover the composition of the SSCL encapsulating K type CpG ODNs, variants including antigens and targeting molecules, pharmaceutical compositions, methods for immune stimulation both in vitro and in vivo, and a novel method for producing these liposomes encapsulating agents of interest. The inventive aspects focus on the specific combination of lipids at defined molar ratios, the encapsulation of the defined K type CpG ODNs, and their use to stimulate immune responses and treat tumors.
Stated Advantages
Increased efficiency of K type CpG ODN encapsulation compared to other liposome types.
Enhanced uptake of CpG ODN by immune cells in vitro and in vivo.
Increased and prolonged immune stimulation, including cytokine production and activation of immune cells.
Improved immune adjuvant activity and enhanced antigen-specific immune responses when CpG ODN and antigen are co-encapsulated.
Increased duration of protection against lethal pathogen challenge following treatment with SSCL-encapsulated CpG ODN.
Synergistic reduction in solid tumor growth when SSCL-encapsulated CpG ODN are administered with targeted biological agents such as IL-13 receptor-directed cytotoxins.
Documented Applications
Use of SSCL encapsulating K type CpG ODN to stimulate immune cells in vitro and in vivo for immunotherapy.
Use as immune adjuvants to enhance immune responses to co-administered antigens or vaccines.
Treatment or prevention of infectious diseases by inducing immune responses against pathogens.
Treatment or amelioration of allergic reactions and allergic conditions such as allergic asthma.
Treatment or prevention of neoplasms, including solid tumors, by immune stimulation alone or combined with chemotherapeutic or biological agents.
Combination therapy with chimeric molecules targeting IL-13 receptor-expressing tumors to synergistically reduce tumor growth.
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