Research Development Foundation

University of California

Depotech Corporation

Chemex Pharmaceuticals, Inc.

Skye Pharma, Inc.

Stephen B Howell

Sinil Kim

Xinjian Lin

Dennis P Gately

Charles G Smith

Atul Khandwala

Xiying Shang

Randolph D Christen

Seiji Isonishi

Paul A Andrews

Robert E Enns

Jerry Yang

Alice Luong

Seong Kong

Gerrit Los

Om P Sachdey

Edward F McClay

Peter Naredi

Edward F Mc Clay

Buran Kurdi-Haidar

Om P Sachdev

The invention is directed to cell-targeted cytotoxic agents, including sortase serine protease constructs. Methods for targeted cell killing for treatment of proliferative diseases, for example, cancer, are provided. Exemplary embodiments comprise an R-spondin ligand for targeting the cytotoxic agents to effect the cell killing.

Cell-targeted cytotoxic constructs

The present invention is directed generally to cell-targeted cytotoxic constructs comprising a targeting polypeptide, a linking polypeptide and a cytotoxic polypeptide. Preferably, (a) the targeting polypeptide is a R-spondin1 (RSPO1), R-spondin2 (RSPO2) or yoked chorionic gonadotropin (YCG), the linking polypeptide comprises LPXT (SEQ ID NO: 56) or NPXT (SEQ ID NO: 60) as well as others, where X is any amino acid, the linking polypeptide being positioned between the targeting ligand and (c) the cytotoxic moiety is an auristatin or a truncated serine protease, the serine protease having an IIGG (SEQ ID NO: 91), IVGG (SEQ ID NO: 92) or ILGG (SEQ ID NO: 93) at its N-terminus. Such constructs can be used in methods for targeted cell killing such as for treatment cell of proliferative diseases (e.g., cancer).

The invention is in general directed to acid-sensitive linkers, and methods of use thereof, such as, for example, in drug delivery methods.

Acid-sensitive linkers for drug delivery

The present invention features a novel cellular injury reporter system in which a chimeric gene containing the GADD153 promoter linked to the coding region of an enhanced green fluorescent protein (EGFP) gene was stably integrated into the genome of carcinoma cells. Activation of the GADD153 promoter was quantified using flow cytometric measurement of EGFP expression following drug exposure. This reporter system is suitable for high. throughput in vitro and in vivo screening for agents capable of producing cytotoxicity via a wide variety of different mechanisms, and can be utilized to investigate the relative potency of structurally related DNA adducts.

Quantification of cellular injury using expression of a fluorescent protein under the control of the GADD153 promoter

The present invention provides a novel composition of matter useful for the treatment of a wide variety of human cancers. The novel composition is synergistic and cytotoxic and comprised of platinum containing antineoplastic agent and tamoxifen. The present invention also provides for methods of treating cancer. That is, the present invention provides a novel method of treating non-melanoma cancers used the novel pharmacologic combination of the present invention. Other embodiments of the invention provide novel methods of reducing or overcoming resistance that develops to platinum containing antineoplastic agents, such as, cisplatin.

Combination cisplatin/tamoxifen therapy for human cancers

Disclosed are multivesicular liposomes containing biologically active substances, and having defined size distribution, adjustable average size, adjustable internal chamber size and number, and a modulated release of the biologically active substance. The liposomes are made by a process comprising dissolving a lipid component in volatile organic solvents, adding an immiscible aqueous component containing at least one biologically active substance to be encapsulated, and adding to either or both the organic solvents and the lipid component, a hydrochloride effective to control the release rate of the biologically active substance from the multivesicular liposome. A water-in-oil emulsion is made from the two components, the emulsion is immersed into a second aqueous component, and then divided into small solvent spherules which contain even smaller aqueous chambers. The solvents arc finally removed to give an aqueous suspension of multivesicular liposomes encapsulating biologically active substances.

Multivesicular liposomes with controlled release of active agents

The present invention provides DNA encoding a human ARSA-I protein selected from the group consisting of: (a) isolated DNA which encodes a human ARSA-I protein; (b) isolated DNA which hybridizes to isolated DNA of (a) above and which encodes a human ARSA-I protein; and (c) isolated DNA differing from the isolated DNAs of (a) and (b) above in codon sequence due to the degeneracy of the genetic code, and which encodes a human ARSA-I protein. Also provided are pharmaceutical compositions comprising human human ARSA-I protein and a pharmaceutically acceptable carrier and host cells transfected with the vector of the present invention said vector expressing a human ARSA-I protein.

Isolation and cloning of the human ARSA-I gene and uses thereof

The present invention provides a composition of matter for the treatment of non-melanoma cancers, wherein said composition comprises a platinum anti-neoplastic compound and tamoxifen, wherein said platinum anti-neoplastic compound and tamoxifen exert a synergistic anti-tumor effect on said non-melanoma cancer. Also provided are various methods of treating non-melanoma cancers and methods of preventing or overcoming resistance to platinum-containing anti-neoplastic compounds.

Combination platinum chemotherapeutic/antiestrogen therapy for human

Disclosed are multivesicular liposomes containing biologically active substances, the multivesicular liposomes having defined size distribution, adjustable average size, adjustable internal chamber size and number, and a modulated rate of the biologically active substance in contrast to the previous art. The process comprises dissolving a lipid component in volatile organic solvents, adding an immiscible aqueous component containing at least one biologically active substance to be encapsulated, and adding to either or both the organic solvents and the lipid component, a hydrochloride effective to control the release rate of the biologically active substance from the multivesicular liposome, making a water-in-oil emulsion from the two components, immersing the emulsion into a second aqueous component, dividing the emulsion into small solvent spherules which contain even smaller aqueous chambers, and then removing the solvents to give an aqueous suspension of multivesicular liposomes encapsulating biologically active substances.

Multivesicular liposomes having a biologically active substance

The present invention provides a vector with a DNA sequence coding for a cellular injury element promoter from nucleotides -74 to -35 of the GADD153 promoter, relative to the start of transcription. The vector includes an origin of replication in operable linkage with a DNA sequence coding for the promoter. Also, a host cell is transfected with the vector and expresses the cellular injury response element promoter.

Cellular injury response element and uses thereof

The present invention comprises a method of sensitizing various types of cancer cells derived from different tissues of origin to various cytotoxic agents and augmenting the sensitivity of cancer cells to these cytotoxic agents. The invention provides a method to treat cancer and other cell proliferative diseases by the administration of a sensitizing agent prior to or concurrently with the administration of a cytotoxic agent.

Taxol and epidermal growth factor used to enhance treatment of ovarian

A method for ameliorating a neurological disorder in a human by administration to the cerebrospinal fluid (CSF) of a therapeutic agent in a dispersion system which allows the therapeutic agent to persist in the cerebro-ventricular space.

Method for treating neurological disorders

A method and composition for treating multidrug resistance in a mammal, in which the composition includes NDGA or an analog of NDGA in accordance with the following formula: ##STR1## wherein R.sub.1 and R.sub.2 are independently H, lower alkyl or lower acyl;

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Del Mar, CA, United States of America

Stephen B Howell