Georgetown University

Synergene Therapeutics, Inc.

Other

Aventis Pharma Deutschland, Gmbh

Esther H Chang

Kathleen F Pirollo

Liang Xin Xu

William Alexander

WenHua Tang

Cheng-Cheng Huang

Kathleen Pirollo

Eugen Uhlmann

Anuschirwan Peyman

David William Will

SangSoo Kim

Antonina Rait

Joe B Harford

Sang Soo Kim

Wenhua Tang

Antonia Rait

Liang Xu

Sangsoo Kim

This invention provides methods to overcome the current limitations of immune checkpoint immunotherapy to provide more effective methods of treating cancer. In embodiments this invention provides a means of using of p53 gene therapy to augment immune checkpoint inhibition by combining antibodies targeting immune checkpoint molecules with SGT-53, a nanomedicine carrying a plasmid encoding human wild-type p53. This invention provides means of increasing tumor immunogenicity, enhancing both innate and adaptive immune responses, and reducing tumor-induced immunosuppression, sensitizing otherwise refractory tumors to anti-immune checkpoint antibodies. In other embodiments this invention also unexpectedly reduces immune-related toxicities that are seen with immunotherapies.

Methods for reducing side effects of immunotherapy

The present invention is in the field of drug delivery, and specifically, cationic liposome-based drug delivery. In embodiments, this invention provides methods of making ligand-targeted (e.g., antibody- or antibody fragment-targeted) liposomes useful for the delivery of liposomes to tumors, including brain tumors. In embodiments, the liposomes deliver temozolomide across the blood-brain barrier for treatment of primary or metastatic brain tumors. Additional cancers that can be treated with the liposomes include neuroendocrine tumors, melanoma, prostate, head and neck, ovarian, lung, liver, kidney, breast, urogenital, gastric, colorectal, cervical, vaginal, angiosarcoma, liposarcoma, rhabdomyosarcoma, choriocarcinoma, pancreatic, retinoblastoma and other types of cancer. In another embodiment the liposomes deliver melphalan for the treatment of multiple myeloma, other tumors of the blood or other solid tumors. In still other embodiments the liposomes can deliver other drugs such as pemetrexed or irinotecan for treatment of cancer or drugs including atropine for treatment of organophosphate poisoning.

Targeted liposomes

The present application provides methods of preventing and treating the toxic effects of exposure to organophosphate agents. In embodiments, targeted cationic liposome complexes delivering nucleic acid molecules encoding butyrylcholinesterase and a polyproline rich peptide are administered. Suitably, the administration is via inhalation or via aerosol. Also provided are cationic liposome complexes and methods of making the complexes for such administration.

Treatment for exposure to nerve agent

A method of preparing an antibody- or antibody fragment-targeted cationic immunoliposome or polymer complex comprises the steps of (a) preparing an antibody or antibody fragment; (b) mixing said antibody or antibody fragment with a cationic liposome to form a cationic immunoliposome or with a cationic polymer to form a polyplex; and (c) mixing said cationic immunoliposome or said polyplex with a therapeutic or diagnostic agent to form said antibody- or antibody fragment-targeted cationic immunoliposome or polymer complex.

Preparation of antibody or an antibody fragment targeted immunoliposomes for systemic administration of therapeutic or diagnostic agents and uses thereof

The present invention provides methods of preparing an antibody- or antibody fragment-targeted cationic immunoliposome or polymer complex comprising (a) preparing an antibody or antibody fragment; (b) mixing said antibody or antibody fragment with a cationic liposome to form a cationic immunoliposome or with a cationic polymer to form a polyplex; and (c) mixing said cationic immunoliposome or said polyplex with a therapeutic or diagnostic agent to form said antibody- or antibody fragment-targeted cationic immunoliposome or polymer complex. The present invention also provides cationic immunoliposome or polymer complexes produced by such methods and compositions comprising such complexes. The present invention also provides methods for treating various diseases and disorders, including cancers, by administering the complexes and compositions of the invention to a patient.

Preparation of antibody or an antibody fragment-targeted immunoliposomes for systemic administration of therapeutic or diagnostic agents and uses thereof

Provided herein is an antibody- or antibody fragment-targeted cationic immunoliposome complex prepared by a method comprising the steps of (a) preparing an antibody or antibody fragment; (b) mixing the antibody or antibody fragment with a cationic liposome and to form a cationic immunoliposome wherein the antibody or antibody fragment is complexed with the cationic liposome, but is not chemically conjugated to the cationic liposome and wherein said antibody or antibody fragment does not comprise a lipid tag; and (c) mixing the cationic immunoliposome with a therapeutic or diagnostic agent to form the antibody- or antibody fragment-targeted cationic immunoliposome. Also provided is an antibody- or antibody fragment-targeted cationic immunoliposome comprising an antibody or antibody fragment; a cationic liposome, wherein the antibody or antibody fragment is complexed with the cationic liposome, but is not chemically conjugated to the cationic liposome and wherein said antibody or antibody fragment does not comprise a lipid tag and a therapeutic or diagnostic agent.

Simplified and improved method for preparing an antibody or an antibody fragment targeted immunoliposome for systemic administration of a therapeutic or diagnostic agent

A targeted vector allowing enhanced gene transfer to human hepato-cellular carcinoma (HCC) cells in vitro was developed using cationic liposomes covalently conjugated with the mAb AF-20. This high affinity antibody recognizes a rapidly internalized 180 kDa cell surface glycoprotein which is abundantly expressed on the surface of human HCC and other cancer cells. Quantitative binding analysis of liposomes with target cells by flow cytometry showed specific association of mAb-targeted liposomes with human HCC cells. Using mAb-targeted cationic liposomes containing 20% DOTAP, in the presence or absence of serum, gene expression in HuH-7 cells was enhanced up to 40-fold as compared to liposomes conjugated with an isotype-matched non-relevant control antibody. Transfection specificity was not observed in a control cell line that does not express the antigen recognized by mAb AF-20. This study demonstrates that cationic liposome formulations can be targeted with monoclonal antibodies (mAbs) to enhance specific in vitro gene delivery and expression in the presence or absence of serum.

Antibody fragment-targeted immunoliposomes for systemic gene delivery

The present invention is in the fields of drug delivery, cancer treatment and diagnosis and pharmaceuticals. This invention provides a method of making antibody- or antibody fragment-targeted immunoliposomes for the systemic delivery of molecules to treat and image diseases, including cancerous tumors. The invention also provides immunoliposomes and compositions, as well as methods of imaging various tissues. The liposome complexes are useful for encapsulation of imaging agents, for example, for use in magnetic resonance imaging. The specificity of the delivery system is derived from the targeting antibodies or antibody fragments.

Tumor-targeted nanodelivery systems to improve early MRI detection of cancer

Nucleic acid-immunoliposome compositions useful as therapeutic agents are disclosed. These compositions preferably comprise (i) cationic liposomes, (ii) a single chain antibody fragment which binds to a transferrin receptor, and (iii) a nucleic acid encoding a wild type p53. These compositions target cells which express transferrin receptors, e.g., cancer cells. These compositions can be used therapeutically to treat persons or animals who have cancer, e.g., head and neck cancer, breast cancer or prostate cancer.

Provided are antisense oligonucleotides directed against the raf-1 gene, Ha-ras gene and HER-2 gene, components of a signal transduction pathway involving oncogenes and their normal counterparts and leading to the phenotype of cellular radioresistance. Administration of these antisense oligonucleotides is shown to reverse the radioresistance phenotype in cells overexpressing HER-2 or a mutant form of Ha-ras. Methods and compositions for reversing radiation resisting among other conditions involving these genes are disclosed.

Compositions and methods for reducing radiation and drug resistance in cells

Targeted ligand-liposome-therapeutic molecule complexes (vectors) for the systemic delivery of the therapeutic molecule to various target cell types including cancer cells such as squamous cell carcinoma of the head and neck, breast and prostate tumors. The preferred ligands, folate and transferrin, target the liposome complex and facilitate transient gene transfection. The systemic delivery of complexes containing DNA encoding wild-type p53 to established mouse xenografts markedly sensitized the tumors to radiotherapy and chemotherapy. The combination of systemic p53 gene therapy and conventional radiotherapy or chemotherapy resulted in total tumor regression and long tern inhibition of recurrence. This cell-specific delivery system was also used in vivo to successfully deliver, via intravenous administration, small DNA molecules (oligonucleotides) resulting in chemosensitivity and xenograft growth inhibition. Other therapeutic molecules, including intact viruses, can be encapsulated in a complex and targeted in accordance with the invention.

Targeted liposome gene delivery

The invention relates to a specific modified oligonucleotide complementary to a section of the human Ha-ras gene and mRNA, and its use to specifically regulate, modulate or inhibit expression of the HA-ras gene, and its use as a pharmaceutical for the treatment of conditions arising from the abnormal expression of the Ha-Ras gene, in particular in combination with chemotherapy and radiotherapy. The modified oligodeoxynucleotide according to the invention has the sequence 5&prime;-TxAxTxTxCxCxGxTxCxAxT-3&prime;-O&mdash;PO &mdash;O&mdash;R (SEQ ID NO:1), wherein X is an internucleotide linkage of type o or s, with the proviso that x is an s linkage at least 4 times and at most 9 times, and o means a phosphodiester internucleoside linkage, s means a phosphorothioate internucleoside linkage, R means a C -C alkyl group, &mdash;(CH &mdash;CH O)n-(CH ) &mdash;CH , or &mdash;CH &mdash;CH(OH)CH O&mdash;(CH ) &mdash;CH wherein n is an integer from 1 to 6, m is an integer from 0 to 20 and q is an integer from 7 to 20 and A is 2&prime;-deoxyadenosine, G is 2&prime;-deoxyguanosine, C is 2&prime;-deoxycytidine and T is thymidine.

Growing community of inventors

Potomac, MD, United States of America

Esther H Chang