The Scripps Research Institute

Emd Lexigen Research Center Corp.

Scripps Clinic and Research Foundation

Ralph A Reisfeld

Rong Xiang

Yunping Luo

Stephen D Gillies

Ze Liu

David A Cheresh

Dan Lu

Holger N Lode

Tingmei Chen

Si Chen

Andreas G Niethammer

Debbie Liao

He Zhou

Si Ruo Chen

Cyril J Honsik

Gregor Schulz

Markus Loeffler

Jörg A Krüger

An aqueous tumor-targeting liposome nanoparticle composition comprises an aqueous dispersion of liposome nanoparticles. The nanoparticles preferably encapsulate an anti-cancer chemotherapeutic agent, which can be added to a pre-formed liposome composition or can be incorporated in the liposomes during the formation of the liposomes. The liposome nanoparticles comprise a legumain-targeting lipid admixed with one or more other micelle or vesicle-forming lipid materials in the form of nanoparticulate liposomes dispersed in an aqueous carrier. A preferred tumor-targeting liposome nanoparticle composition comprises a legumain-targeting lipid component and polyethylene glycol-conjugated lipid component. The legumain-targeting lipid component comprising a hydrophobic lipid portion covalently attached to a legumain-binding moiety.

Nanoparticle-based tumor-targeted drug delivery

A DNA vaccine suitable for eliciting an immune response against cancer cells comprises a DNA construct operably encoding a cancer-associated Inhibitor of Apoptosis-family protein and an immunoactive gene product, such as a cytokine or a ligand for a natural killer cell surface receptor, in a pharmaceutically acceptable carrier. A preferred cytokine is CCL21. Preferred ligands for a natural killer cell surface receptor include human MICA, human MICB, human ULBP1, human ULBP2, and human ULBP3. The cancer-associated Inhibitor of Apoptosis (IAP)-family protein is preferably a survivin protein or livin protein. Method of inhibiting tumor growth by administering the vaccine of the invention to a mammal is also described.

DNA vaccines against tumor growth and methods of use thereof

The present invention provides an aqueous tumor-targeting liposome nanoparticle composition comprising an aqueous dispersion of liposome nanoparticles. The nanoparticles preferably encapsulate an anti-cancer chemotherapeutic agent, which can be added to a pre-formed liposome composition or can be incorporated in the liposomes during the formation of the liposomes. The liposome nanoparticles comprise a legumain-targeting lipid admixed with one or more other micelle or vesicle-forming lipid materials in the form of nanoparticulate liposomes dispersed in an aqueous carrier. A preferred tumor-targeting liposome nanoparticle composition comprises (a) a legumain-targeting lipid component, (b) a zwitterionic lipid component; (c) an amino-substituted lipid component; (d) a neutral lipid component; and (e) polyethylene glycol-conjugated lipid component. The legumain-targeting lipid component comprising a hydrophobic lipid portion covalenetly attached to a legumain-binding moiety.

The present invention provides an aqueous tumor-targeting liposome nanoparticle composition comprising an aqueous dispersion of liposome nanoparticles. The nanoparticles preferably encapsulate an anti-cancer chemotherapeutic agent, which can be added to a pre-formed liposome composition or can be incorporated in the liposomes during the formation of the liposomes. The liposome nanoparticles comprise a legumain-targeting lipid admixed with one or more other micelle or vesicle-forming lipid materials in the form of nanoparticulate liposomes dispersed in an aqueous carrier. A preferred tumor-targeting liposome nanoparticle composition comprises (a) a legumain-targeting lipid component, (b) a zwitterionic lipid component; (c) an amino-substituted lipid component; (d) a neutral lipid component; and (e) polyethylene glycol-conjugated lipid component. The legumain-targeting lipid component comprising a hydrophobic lipid portion covalently attached to a legumain-binding moiety.

A method of inhibiting endothelial cell proliferation in a mammal is provided. The method comprises the step of administering to the mammal an effective immunological response eliciting amount of a DNA composition comprising a DNA construct operably encoding a VEGF receptor polypeptide and a pharmaceutically acceptable carrier therefor, whereby said mammal exhibits an immune response elicited by vaccine and specific to proliferating endothelial cells. The methods of this invention inhibit vascular endothelial cell proliferation in the tumor micro-environment. Angiogenesis inhibition and subsequent decrease in tumor growth and dissemination is achieved.

DNA composition encoding an immunogenic VEGF receptor peptide and methods of use thereof

A DNA vaccine suitable for eliciting an immune response against cancer cells comprises a polynucleotide construct operably encoding an a Fra-1 protein, such as a polyubiquitinated human Fra-1 protein, and IL-18, such as human IL-18, in a pharmaceutically acceptable carrier. In a preferred embodiment, the polynucleotide construct is operably incorporated in an attenuated bacterial vector, such as an attenuated, particularly a doubly attenuated aroAdam. Transformed host cells, methods of inhibiting tumor growth, of vaccinating a patient against cancer, and of delivering genetic material to a mammalian cell in vivo are also described.

A DNA composition effective for inhibiting endothelial cell proliferation comprises a DNA construct operably encoding a vascular endothelial growth factor (VEGF) receptor polypeptide, which can be a full length VEGF receptor protein or an immunogenic fragment thereof. This invention provides DNA compositions that encode VEGF receptor-2 (KDR), VEGF receptor-1 (Flt-1), or Flk-1 (the murine homolog of KDR), as well as methods of using such a DNA composition to inhibit vascular endothelial cell proliferation in the tumor micro-environment. Angiogenesis inhibition and subsequent decrease in tumor growth and dissemination is achieved.

The invention provides methods for treating tumors and tumor metastases in a mammal comprising administering, to a mammal in need of treatment, a therapeutic amount of an antagonist sufficient to inhibit angiogenesis in combination with a therapeutic amount of anti-tumor immunotherapeutic agent, such as a anti-tumor antigen antibody/cytokine fusion protein having a cytokine and a recombinant immunoglobulin polypeptide chain sufficient to elicit a cytokine-specific biological response.

Methods for treatment of tumors and metastases using a combination of anti-angiogenic and immuno therapies

DNA vaccines against tumor growth and methods of use therof

A DNA vaccine effective for eliciting an immune response against cells that present a carcinoembryonic antigen (CEA) comprises a DNA operably encoding a CEA and a DNA operably encoding a CD40 ligand, SEQ ID NO:1 and SEQ ID NO: 2, respectively, or its homotrimer, CD40LT. The DNA vaccine can be incorporated in a delivery vector such as an attenuated live bacterium or virus, or a liposome carrier. In a method embodiment, the DNA vaccine is administered orally to a mammal, such as a human, to elicit an immune response against CEA presenting cells such as colon cancer cells. A preferred method embodiment includes the additional step of treating the mammal with recombinant antibody fusion protein huKS1/4-IL2 to enhance the immune response effectiveness of the vaccine.

DNA vaccines encoding CEA and a CD40 ligand and methods of use thereof

The invention teaches methods for treating tumors and tumor metastases in a mammal comprising administering, to a mammal in need of treatment, a therapeutic amount of an antagonist sufficient to inhibit angiogenesis in combination with a therapeutic amount of anti-tumor immunotherapeutic agent, such as a anti-tumor antigen antibody/cytokine fusion protein having a cytokine and a recombinant immunoglobulin polypeptide chain sufficient to elicit a cytokine-specific biological response.

A DNA vaccine effective for inhibiting endothelial cell proliferation comprises a DNA construct operably encoding a vascular endothelial growth factor (VEGF) receptor protein. This invention provides DNA vaccines that encode VEGF receptor-2 (KDR, SEQ ID NO: 2), VEGF receptor-1 (Flt-1, (SEQ ID NO: 4), or Flk-1 (the murine homolog of KDR, SEQ ID NO: 6), DNA sequences SEQ ID NOS: 1, 3, and 5 respectively, as well as methods of using such a DNA vaccine to inhibit vascular endothelial cell proliferation in the tumor micro-environment. Anti-angiogenesis and subsequent decrease in tumor growth and dissemination is achieved.

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La Jolla, CA, United States of America

Ralph A Reisfeld