Oncogen

Other

Fred Hutchinson Cancer Center

University of Washington

The United States of America As Represented by the Department of Health

Kollmorgen Corporation

Collagen Corporation

George J Todaro

Mohammed Shoyab

Daniel R Twardzik

Hans Marquardt

Timothy M Rose

David W Leung

Neville Robert Kallenbach

Harvey Rubin

John M McPherson

Kenneth K Iwata

Karl A Piez

Kurt Strand

Marnix L Bosch

Danile R Twardzik

Jane E Ranchalis

Charlotte M Fryling

Robin M Hochstrasser

Paul A Cornelius

Karl Erik Hellstrom

Ingegerd Hellstrom

The invention provides a method of treating a disease or disorder in a subject by inducing a TGF alpha immune response or by administering an anti-TGF-alpha antibody or a biologically active fragment thereof. The TGF-alpha immune response is induced using a TGF-alpha polypeptide or biologically active fragment, a vaccine, a genetic construct or a transformed cell, for example.

Use of TGF-alpha polypeptide or anti-TGF-alpha antibodies for the treatment of diseases and disorders

Hybrid cytokines containing four helical regions, each of which is derived from a corresponding &agr;-helical region in leukemia inhibitory factor (LIF), granulocyte colony stimulating factor (G-CSF), interleukin-6 (IL-6) or oncostatin-M (OSM) are disclosed. These hybrid cytokines may further contain linking regions also derived from corresponding linking regions in these factors. The hybrid cytokines offer a unique spectrum of activities useful in treating conditions for which the native cytokines are useful or in treating conditions characterized by an excess of the native cytokines.

Hybrid cytokines

Therapeutic hybrid cytokines, having a size ranging from about 10 to about 30 kDa, comprise portions of cytokines: leukemia inhibitory factor (LIF), granulocyte-colony stimulating factor (G-CSF), interleukin-6 (IL-6), interleukin-11 (IL-11), oncostatin-M (OSM), and ciliaryneurotrophic factor (CNTF). Hybrid cytokines comprise three or four &agr;-helical sequences selected from &agr;-helical sequences of IL-6, G-CSF, LIF, IL-11, CNTF and OSM and linking sequences of 5-40 amino acids in length, selected from the linking sequences of IL-6, G-CSF, LIF, IL-11, CNTF and OSM or other, desirable linking sequences. In the hybrid cytokines, at least one &agr;-helical sequence is derived from a different cytokine than at least one other &agr;-helical sequence; or, at least one linking sequence of a cytokine differentiates the hybrid cytokine from a corresponding cytokine. In hybrid cytokines having three &agr;-helical sequences selected from the group of cytokines listed, a possible fourth sequence may not correspond to any &agr;-helical sequence in any of the cytokines. Hybrid cytokines, radically different from any corresponding cytokines, have unexpected advantages in selective biological mechanisms over a much broader range of biological activities than exhibited by cytokines.

This invention provides isolated polynucleotides encoding DNA polymerases of three members of a subfamily of gamma herpes viruses. Two were obtained from macaque monkeys affected with retroperitoneal fibromatosis, the other from human AIDS patients affected with Kaposi's sarcoma. A 454-base pair fragment encoding a region near the active site of the DNA polymerase is 69-83% identical amongst the three viruses, but only 54-68% identical with other known gamma herpes sequences and &lt;55% identical with alpha and beta herpes sequences. Also provided are polynucleotides encoding DNA polymerase from related viruses in the RFHV/KSHV subfamily. Polynucleotides prepared according to the sequence data can be used as reagents to detect and characterize related sequences. Such reagents may be used to detect members of the RFHV/KSHV subfamily, including but not limited to RFHV, RFHV2, and KSHV. Corresponding polypeptides and peptide fragments may be obtained by expressing the polynucleotide or by chemical synthesis. They may be used for detecting specific antibody potentially present in the serum of infected subjects. They may also be used for designing or screening pharmaceutical compounds that limit viral replication by inhibiting DNA polymerase activity.

DNA polymerase of gamma herpes viruses associated with Kaposi's sarcoma

Novel polypeptide compositions are provided which inhibit human tumor cell growth, which may or may not stimulate autophosphorylation of pp6src and induce the release of a 52 kD polypeptide from neoplastic cells. Individual polypeptides may be isolated from mammalian blood platelets by selected extraction and purification procedures, may be synthesized or produced by hybrid DNA technology.

Methods for inhibiting neoplastic cell proliferation using platelet

Novel biologically active polypeptides, including a new class of transforming growth factor (TGF) polypeptides, which exhibit cell growth promoting properties are disclosed, as well as a process for isolating the TGF polypeptides from both human and murine cell lines in homogeneous form. Also disclosed are antigenic oligopeptides derived from the TGF polypeptides and antibodies raised therefrom which have application in the detection and treatment of malignancies and oligopeptides have the ability to bind with cellular growth factor receptors and thus to interfere with transformation of certain cell lines into a cancerous state. Compositions and methods based on the disclosed peptides for detection and treatment of cancer and other proliferative diseases and for cell or tissue growth associated treatment, e.g., wound healing, ulcer therapy and bone loss are also described.

Transforming growth factor (TGF) peptides

Neutral lipids are provided characterized by binding to phorboid and ingenoid receptors. These lipids are found in a wide variety of cellular sources as well as milk and may be isolated by specific extraction and chromatographic procedures. Depending upon the source, the glycerides may be mono- or di-glycerides, wherein the total number of carbon atoms of the fatty acis is in the range of 18 to 26, so that the monoglyceride has a fatty acid of at least 18 carbon atoms, while the di-glyceride has a fatty acid of at least 14 carbon atoms. The long chain fatty acids have at least one site of olefinic unsaturation.

Biologically active lipids binding membrane receptors

Neutral lipids are provided characterized by binding to phorboid and ingenoid receptors. These lipids are found in a wide variety of cellular sources as well as milk and may be isolated by specific extraction and chromatographic procedures. Depending upon the source, the glycerides may be mono- or di-glycerides, wherein the total number of carbon atoms of the fatty acids is in the range of 18 to 26, so that the monoglyceride has a fatty acid of at least 18 carbon atoms, while the di-glyceride has a fatty acid of at least 14 carbon atoms.

Novel polypeptides, polynucleotide sequences, DNA constructs and compositions are provided for the preparation and use of polypeptides associated with naturally occurring polypeptides found in brains. The low molecular weight polypeptides either are growth inhibitors for neoplastic cells without inhibiting normal cells or affect GABA-ergic transmission. The polypeptides find use in inhibiting neoplastic growth, modulating diazepam receptor response, and detecting receptors for the polypeptides. Antibodies are provided in conjunction with the polypeptides, which may be used together or separately for detecting the presence of the polypeptides.

Vectors encoding brain derivable polypeptide factors

Neutral lipids are provided characterized by binding to phorboid and ingenoid receptors. These lipids are found in a wide variety of cellular sources as well as milk and may be isolated by specific extraction and chromatographic procedures. Depending upon the source, the glycerides may be mono-or di-glycerides, wherein the total number of carbon atoms of the fatty acids is in the range of 18 to 26, so that the monoglyceride has a fatty acid of at least 18 carbon atoms, while the di-glyceride has a fatty acid of at least 14 carbon atoms.

Brain derivable polypeptide factors and antibodies thereto

A novel irradiation process and products made thereby. The process treats biological media such as blood fractions, genetically engineered protein products and vaccine preparations. The process photolyzes nucleic acids in preference to proteins in the media, e.g., it inactivates DNA- or RNA-containing pathogens while leaving the proteins substantially intact or functional. In general, the process comprises irradiating the medium with pulsed light of wavelength and flux selected so that (1) the nucleic acids in their ground state absorb radiation and thereby rise to an excited state or states, (2) the nucleic acids in their excited states absorb radiation and thereby rise to higher energy states and undergo photolysis, and (3) the proteins in their ground or their excited states do not absorb sufficient radiation to undergo substantial photolysis. It is surprising and unexpected that nucleic acids in their excited states undergo efficient photolysis whereas proteins under the same conditions in the same medium are kept substantially intact.

Pulsed light selective photolysis process for treatment of biological

Novel biologically active polypeptides, including a new class of transforming growth factor (TGF) polypeptides, which exhibit cell growth promoting properties are disclosed, as well as a process for isolating the TGF polypeptides from both human and murine cell lines in homogeneous form. Also disclosed are antigenic oligopeptides derived from the TGF polypeptides and antibodies raised therefrom which have application in the detection and treatment of malignancies and oligipeptides which have the ability to bind with cellular growth factor receptors and thus to interfere with transformation of certain cell lines into a cancerous state. Compositions and methods based on the disclosed peptides for detection and treatment of cancer and other proliferative diseases and for cell or tissue growth associated treatment, e.g., wound healing, ulcer therapy and bone loss are also described.

Growing community of inventors

Seattle, WA, United States of America

George J Todaro