Oncogen

Bristol-myers Squibb Compnay

Oncogen Limited Partnership

Mcmaster University

Bristol Meyers Squibb Company

Mohammed Shoyab

Hans Marquardt

George J Todaro

Gregory D Plowman

Peter S Linsley

Joyce M Zarling

Marcia B Hanson

Thomas J Brown

Susan F Radka

Vicki Lynn McDonald

Ingegerd E Hellstrom

Karl E Hellstrom

Clay B Siegall

Anthony F Purchio

Timothy M Rose

Mario N Lioubin

Tatsuhiko Ikeda

Jack Gauldie

Najma Malik

James Garrett Bradley

Jean-Michel Culouscou

Carl D Richards

James G Bradley

A novel family of growth regulatory proteins termed 'epithelins' are described. The epithelins comprise several distinct members sharing significant structural homology. Two members of the epithelin family, epithelin 1 and epithelin 2, have been purified from natural sources. In addition, cDNA and PCR clones encoding mature and precursor epithelins from various chordate sources have been obtained and sequenced, including the complete human, mouse and rat epithelin precursors. The recombinant expression of rat epithelin precursor and mature forms is described. Purified epithelin 1 is a bifunctional growth regulator, capable of stimulating the growth of some cell types while inhibiting the growth of others. Purified epithelin 2 is functionally similar to epithelin 1 with respect to growth inhibitory bioactivity. In contrast, however, epithelin 2 is apparently not capable of eliciting the growth stimulatory activity characteristic of epithelin 1 and, in fact, antagonizes this epithelin 1 activity.

DNA encoding epithelins

The present invention relates to monoclonal antibodies that define Oncostatin M, a novel cytokine. The monoclonal antibodies of the invention are capable of binding to Oncostatin M, inhibiting Oncostatin M receptor binding, and/or inhibiting Oncostatin M bioactivity. Such antibodies may be used to detect the presence at Oncostatin M and/or to modulate Oncostatin M bioactivities in an in vivo or in vitro system.

Anti-oncostatin M monoclonal antibodies

A novel family of growth regulatory proteins termed 'epithelins' are described. The epithelins comprise several distinct members sharing significant structural homology. Two members of the epithelin family, epithelin 1 and epithelin 2, have been purified from natural sources. In addition, cDNA and PCR clones encoding mature and precursor epithelins from various chordate sources have been obtained and sequenced, including the complete human, mouse and rat epithelin precursors. The recombinant expression of rat epithelin precursor and mature forms is described. Purified epithelin 1 s a bifunctional growth regulator, capable of stimulating the growth of some cell types while inhibiting the growth of others. Purified epithelin 2 is functionally similar to epithelin 1 with respect to growth inhibitory bioactivity. In contrast, however, epithelin 2 is apparently not capable of eliciting the growth stimulatory activity characteristic of epithelin 1 and, in fact, antagonizes this epithelin 1 activity.

Methods of using epithelins to modulate cell proliferation

The present invention is directed to a family of heparin-binding epithelial cell growth factors termed amphiregulins (AR). In particular, it relates to the isolation of AR genes from different animal species, expression of the genes, identification of various forms of biologically active AR products, purification of the AR products, antibodies specific for AR, and uses of AR. AR is detectable in several normal human epithelial cells and in a high percentage of human colon cancers. In addition to stimulating the growth of these cultured epithelial cells, AR may have a wide range of applications including, but not limited to, accelerating the growth of normal epithelial cells. In some tumor cell lines, primarily of breast or ovarian carcinomas, AR serves as a direct growth inhibitor. On the other hand, AR may function as a growth stimulatory molecule in colorectal carcinomas and other pathologies of increased epithelial proliferation. In this regard AR may serve as a useful marker for disease staging and prognosis and reagents that specifically block AR may be of therapeutic use in controlling tumor cell growth and in disorders such as psoriasis.

Fanphiregulins: a family of heparin-binding epithelial cell growth

The molecular cloning, expression, and biological characteristics of a novel receptor tyrosine kinase related to the epidermal growth factor receptor, termed HER4/p180.sup.erbB4, are described. Antibodies to HER4 are disclosed. A HER4 ligand capable of inducing cellular differentiation of breast cancer cells is also disclosed. In view of the expression of HER4 in several human cancers and in certain tissues of neuronal and muscular origin, various diagnostic and therapeutic uses of HER4-derived and HER4-related biological compositions are provided.

Antibodies to HER4, human receptor tyrosine kinase

A method for decreasing metalloproteinase activity in a patient that comprises the step of administering to said patient a therapeutic composition comprising the cytokine oncostatin-M, or a biologically active fragment, mutant, analog or fusion construct thereof. Also, a method for increasing TIMP activity in a patient that comprises the step of administering to said patient a therapeutic composition comprising the cytokine oncostatin-M, or a biologically active fragment, mutant, analog or fusion construct thereof. In addition a method for inhibiting or treating progression of a tumor in a patient that comprises the step of administering to said patient a therapeutic composition comprising oncostatin-M, or a biologically active fragment, mutant, analog, or fusion construct thereof, said method being effective to inhibit invasion by a tumor cell through an extracellular space, extracellular matrix, basement membrane, interstitial tissue or connective tissue. Also methods effective to treat inflammatory or degenerative disease, methods effective to stimulate erythropoiesis, and methods effective to regulate tissue remodeling and to promote healing of injury.

Regulation of cellular invasiveness

Novel compositions comprising Oncostatin M and congeners thereof, as well as methods for their preparation and methods for their use are provided. The compositions may be prepared by isolation from natural sources, or by recombinant means in either prokaryotic or eukaryotic host cells. In addition, the DNA and polypeptide sequences for Oncostatin M are disclosed. The compositions find use in modulating growth of cells, in particular inhibition of tumor cell proliferation, and stimulation of normal cell growth, especially cells involved in hematopoiesis. Cell growth inhibition compositions may additionally include an adjunctive agent comprising at least one of a transforming growth factor, tumor necrosis factor, or an interferon. Receptors having high affinity for Oncostatin M may additionally be used to screen polypeptides for Oncostatin M-like activity. Methods for use of antibodies to the compositions and probes specific for Oncostatin M mRNA as a means for detecting tumor cells are also provided.

Oncostatin M and novel compositions having anti-neoplastic activity

Epithelins: novel cysteine-rich growth modulating proteins

Novel compositions are provided for modulating growth, particularly of tumor cells, which compositions are combinations of Oncostatin M, and one or both of transforming growth factors or .gamma.-interferons, or analogs thereof. In addition, a novel transforming growth factor is provided, designated TGF-.beta.2, as well as methods for its preparation.

A novel cell growth regulatory factor, named Amphiregulin, is described. This extremely hydrophilic glycoprotein, having a median molecular weight of 22,500 daltons, demonstrates unusual biological activity. Amphiregulin is a bifunctional cell growth regulatory factor which exhibits potent inhibitory activity on DNA synthesis in neoplastic cells, yet promotes the growth of certain normal cells. The invention is based, in part, on the discovery that MCF-7 cells, when treated with the tumor promoting agent, 12-O-tetradecanoyl-phorbol-13-acetate (TPA), express and secrete two distinct yet functionally equivalent forms of Amphiregulin. These two forms are structurally identical and perfectly homologous except that the truncated form lacks an amino-terminal hexapeptide found in the larger form. The Amphiregulin gene has been cloned and used to construct plasmids which direct the expression of bioactive Amphiregulin in transformed Escherichia coli cells. A wide variety of uses for Amphiregulin are encompassed by the present invention, including the treatment of wounds and cancers.

Amphiregulin: a bifunctional growth modulating glycoprotein

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.

Growing community of inventors

Seattle, WA, United States of America

Mohammed Shoyab