Cancer Therapeutics

Plasma Cell Disorders

Use of NOTCH Pathway Interfering Agents for Treatment of Plasma Cell Disorders

U.S. Patent Number: 7,282,203
Issue Date: October 16, 2007

Summary: The invention provides a method for reducing the severity of, or treatment of, plasma cell disorders. The method comprises the step of administering to an individual afflicted with a plasma cell disorder, a composition comprising an antibody directed to the extracellular portion of NOTCH or to JAG2.

Detail: The invention provides a method for novel therapeutic approaches to the treatment of plasma cell disorders. The method comprises the use of agents which interfere with the NOTCH pathway.

In one embodiment, the invention provides a method for reducing the severity of plasma cell disorders or treatment of plasma cell disorders comprising the steps of administering antibodies to NOTCH protein, particularly the extracellular portion of the NOTCH1 protein. In another embodiment, the invention provides a method for reducing the severity of plasma cell disorders or treatment of plasma cell disorders comprising the steps of administering antibodies to JAG2 protein. The JAG2 protein is a surface protein considered to be on malignant plasma cells.

In another embodiment, the invention provides a method for reducing the severity of plasma cell disorders or treating plasma cell disorders comprising the steps of administering antibodies to NOTCH protein and/or antibodies to the JAG2 protein in combination with a cytotoxic agent. An example of a useful chemotherapeutic agent is doxorubicin.

Solid Tumors

Method of Enhancing the Efficacy of Anti-Tumor Agents

Patent(s): Issued U.S. Patent Number: 6,171,620; 6,426,094 (CON); 6,620,779 (DIV)
Issue Date: January 9, 2001; July 30, 2002 (CON); September 16, 2003 (DIV)
International Issued Patents: KR, AZA, SG, RU, NZ, MX, IN, CN, BG, AU
International Pending Applications: PL, NO, JA, IL, ID, CA, BR

Summary: A method for enhancing the effect of anti-tumor agents on solid tumors is provided. The method comprises administering to an individual an anti-tumor agent and a hematocrit elevator. The hematocrit elevator may be administered before or concurrently with the anti-tumor agent.

Detail: The present invention discloses a method for enhancing the efficacy of anti-tumor agents. The method comprises administering to an individual, in need of such a treatment, an anti-tumor agent under conditions of elevated hematocrit. Thus, an object of the present invention is to provide a method for the treatment of solid tumors by administration of a combination of an anti-tumor agent and a hematocrit elevator. In a preferred embodiment, the hematocrit elevator is administered prior to the anti-tumor agent. Another object of the present invention is to provide a method for the treatment of solid tumors by administration of an anti-tumor platinum compound and erythro- poietin or an erythropoietin like compound.

Method of Augmenting the Antitumor Activity of Anticancer Agents

Patent(s): Pending
U.S. Patent Application Number: 11/405,377
International Issued Patents: GB, CN
International Pending Applications: CA

Summary: A method for augmenting the antitumor activity of anti-cancer agents is provided. The method comprises administering to an individual an anti-cancer and a selenium compound. A method is also provided for inhibiting the growth of a tumor which-has proven to be refractory to anticancer agents. The methods comprises administration of selenium compound followed by administration of the anticancer agent.

Detail: In the present invention it was observed that administration of selenium compounds augments the antitumor activity of anticancer agents. Data is presented for in vivo studies in xenograft bearing animals. Additionally, clinical studies have been carried out which further confirm augmentation of antitumor activity of anticancer agents by administration of selenium. While tumor shrinkage was observed for several chemotherapeutic agents, the effect was not durable with all chemotherapeutic agents and complete tumor regression (cure) was observed only with irinotecan and taxotere. Further, it was observed that the augmentation of activity was provided by the administration of seleno-L-methionine (SLM) and methylseleno cysteine (MSC), but not sodium selenite (SS) or methylseleninic acid (MSA). The selenium compound is preferably administered at least three days prior to the administration of the anti-tumor agent. Accordingly, the present invention discloses a method for augmenting the antitumor activity of anticancer agents selected from the group consisting of irinotecan and taxotere. The method comprises administering to an individual having a tumor, the anti-tumor agent and a selenium compound selected from the group consisting of SLM and MSC. In one embodiment, the selenium compound is administered at least 3 days prior to chemotherapy and may be continued during and after the chemotherapy.

Method for Treating Hyperproliferative Tissue in a Mammal

U.S. Patent Number: 6,495,585
Issue Date: December 17, 2002

Summary: A novel method for treating undesired hyperproliferative tissue in a mammal. The method includes the steps of: injecting the mammal with a photodynamic compound having a selective uptake in the hyperproliferative tissue and which is activated at a particular light frequency; injecting the mammal with a xanthenone-4-acetic acid or a Group I metal, Group II metal or quaternary salt thereof near the time of maximum uptake of the photodynamic compound in the hyperproliferative tissue; and exposing the hyperproliferative tissue to light at the particular frequency that activates the photodynamic compound. The method of the invention causes necrosis of the hyperproliferative tissue to an extent greater than can be obtained by either the photodynamic compound or xanthenone-4-acetic acid alone. Further and surprisingly the method enhances immune response of the mammal to the hyperproliferative tissue even after the photodynamic compound and xanthenone-4-acetic acid are no longer present in the mammal.

Detail: In accordance with the invention a novel method is provided for treating undesired hyperproliferative tissue in a mammal. The method includes the steps of: injecting the mammal with a photodynamic compound having a selective uptake in the hyperproliferative tissue and which is activated at a particular light frequency; injecting the mammal with a xanthenone-4-acetic acid or a Group I metal, Group II metal or quaternary salt thereof near the time of maximum uptake of the photodynamic compound in the hyperproliferative tissue; and exposing the hyperproliferative tissue to light at the particular frequency that activates the photodynamic compound. The method of the invention causes necrosis of the hyperproliferative tissue to an extent greater than can be obtained by either the photodynamic compound or xanthenone-4-acetic acid alone. Further and surprisingly the method enhances immune response of the mammal to the hyperproliferative tissue even after the photodynamic compound and xanthenone-4-acetic acid are no longer present in the mammal.

p53 as Protein and Antibody Therefor

U.S. Patent Number: 7,238,523 (CIP); 6,965,009 (DIV)
Issue Date: July 3, 2007 (CIP); November 15, 2005 (DIV)

Summary: The invention comprises plasmids and viral vectors containing an animal p53as cDNA sequence. A portion of the p53as sequence may be identified to a position of wild type p53 gene from the same animal. In preferred embodiments, the p53as is mouse or human p53as. A preferred viral vector is baculovirus vector. The invention further includes antibodies both polyclonal and monoclonal, to p53as and to at least a portion of human p53 intron 10 sequence encoding SLRPFKALVREKGHRPSSHSC (SEQ. I.D. NO. 1) which is related to p53as sequences and plasmids and viral vectors containing such sequences. All of the above find utility in studying p53 and p53as and their relative expressions which is believed important for detection and control of malignant cells and their susceptibility to treatment agents. The antibodies can detect the presence of p53as and related sequences and when injected into cells could cause cell cycle arrest and the plasmids and viral vectors, with appropriate promoters, can cause expression of the p53as and p53 intron 10 sequences which can affect cell growth and perhaps arrest certain malignancies.

Detail: p53as protein exhibited the antibody binding properties of wild type p53 protein, PAb246+, PAb240-, but lacked the C-terminal epitope reactive with PAb421. p53as protein translated in vitro was activated for binding to a p53 DNA binding sequence. The major p53 protein, in contrast, required activation for DNA binding (by monoclonal antibody PAb421). There appears to be a direct interaction between p53as and p53 proteins which influenced the composition of the DNA binding complex and the magnitude of DNA binding. Because cotranslated p53 protein inactivated p53as protein for DNA binding, and because two bands were super-shifted by PAb421 in lysates containing p53as and p53 cotranslated proteins, compared to one band in lysate containing p53 alone. These results could be explained by binding to DNA of p53as and p53/p53as heterooligomers, in addition to the binding of p53. The significance of these findings is that they are consistent with a functional role for p53as protein in cells, which may, at least in part, be distinct from the function(s) of the major p53 protein form. Considering that vectors and plasmids containing the p53 gene are being tested for applications in gene therapy, and considering the results herein that p53as is active for binding to a p53 binding sequence and that p53as interacts with p53, resulting in altered DNA binding, plasmids and vectors for the expression of mouse and human p53as in cells and for uses in gene therapy in humans are claimed herein.

GD2 Peptide Mimics

U.S. Patent Number: 6,939,948
Issue Date: September 6, 2005

Summary: The invention provides peptide mimics for GD2 ganglioside. The peptide mimics were identified by panning phage display peptide libraries with an anti-GD2 monoclonal antibody. The identified peptide mimics can be used as immunogens for cancer therapy such as for melanoma and neuroblastoma.

Detail: The invention provides methods of using compositions which elicit an immune response against a tumor associated antigen that is not normally immunogenic. The method comprises using peptide mimics to a ganglioside, GD2, to elicit an immune response. Accordingly, in one aspect, the invention provides methods for identifying peptide mimics. The method comprises the steps of screening phage display peptide libraries with antibodies to GD2. The identified peptides are then tested for their ability to elicit an immure response and the ability of those antibodies to against GD2 bearing cells. In another embodiment, the invention provides a method for eliciting an immune response in patients with GD2 positive tumors. The method comprises administering a composition effective in stimulating a specific immunological response against the GD2 antigen. These composition(s) comprise a peptide that shares immunological characteristics of GD2. While a detectable immunological response is likely to be beneficial, efficacy can also be deduced by an improvement in symptoms or control of growth of the tumor.

Other embodiments include include methods for treating GD2 bearing tumors in an individual by eliciting an antiGD2 immunological response in the subject. The immunological response can be elicited using any of the peptide mimics to the GD2. Still other embodiment include preparing a composition for use in the generation of an immune response and in the treatment of tumors bearing GD2. The composition comprises the peptide mimics disclosed herein.

GD3 Peptide Mimics

U.S. Patent Number: 6,998,237
Issue Date: February 14, 2006

Summary: The invention provides peptide mimics for GD3 ganglioside. The peptide mimics were identified by panning phage display peptide libraries with an anti-GD3 monoclonal antibody. The peptide mimics inhibit the binding of an anti-GD3 antibody to GD3 positive cells and also elicit antibodies which can bind to GD3 positive cells. The identified peptide mimics can be used as immunogens for cancer therapy.

Detail: The invention provides peptide mimics of the ganglioside GD3 and a method for producing same. This invention also provides a method of using the peptides to elicit an immune response against a tumor associated antigen that is not normally immunogenic. Accordingly, in one aspect, the invention provides methods for identifying peptide mimics. The method comprises the steps of screening phage display peptide libraries with antibodies to GD3. The identified peptides are then tested for their ability to elicit an immure response and the reactivity of those antibodies against GD3 bearing cells. In another aspect, the invention provides a method for eliciting an immune response in patients with GD3 positive tumors. The method comprises administering a composition effective in stimulating a specific immunological response against the GD3 antigen. These composition(s) comprise a peptide that shares immunological characteristics of GD3. While a detectable immunological response is likely to be beneficial, efficacy can also be deduced by an improvement in symptoms or control of growth of the tumor.

Other aspects include methods for treating GD3 bearing tumors in an individual by eliciting an anti GD3 immunological response in the subject. The immunological response can be elicited using any of the peptide mimics to the GD3. Still other embodiment include preparing a composition for use in the generation of an immune response and in the treatment of tumors bearing GD3. The composition comprises the peptide mimics disclosed herein.

Anti-Idiotypic Peptide Sequences

Patent(s): Issued
U.S. Patent Number: 7,348,153
Issue Date: December 20, 2005

Summary: The invention provides a method for identifying peptides for use in increasing a cytotoxic T lymphocytes (CTL) response to an antigen. The method comprises the steps of comparing the amino acid sequence of the VH and/or VL portions of an anti-idiotypic monoclonal antibody to the amino acid sequence of an antigen to identify regions of homology between the Ab2 and the antigen, and to further identify an HLA binding motif in a homologous region. The identified homologous region which comprises an HLA binding motif defines a peptide sequence that is useful for stimulating a CTL response. Also provided are peptides identified by the method, and a method of using the peptides to stimulate a CTL response in an individual.

Detail: The invention provides a method for identifying peptides for use in immunotherapeutic approaches. The peptides are identified as short regions (8-20 amino acid) of an anti- idiotypic antibody having homology with a region of the corresponding antigen and further comprising one or more HLA binding motif(s). These peptides have the ability to stimulate a cytotoxic T lymphocyte (CTL) response. The peptide regions of the antid antibodies may be modified to further enhance the immunogenic response. In one embodiment, the method comprises obtaining the amino acid sequences of the VH and/or VL portions of the anti-idiotypic antibody (Ab2), obtaining the sequence of the antigen, comparing the sequences to identify candidate homologous regions within the Ab2 (i.e., regions that show homology to regions of the corresponding antigen), and further identifying those candidate homologous regions of Ab2 which also comprise HLA binding motifs. These peptides are then tested for their ability to stimulate a CTL response. Preferred peptides are those which stimulate a greater CTL response than the corresponding antigen or a peptide derived from the antigen. In another embodiment, the invention also provides peptides identified by the method. In this regard, the peptide sequences are homologous to a portion of Ab2 and a portion of the antigen, and further comprise an HLA binding motif. In another embodiment, the method further comprises modifying the peptide sequences identified as homologous regions of Ab2 to further enhance their ability to stimulate a CTL response. This invention also provides a method for using the peptides identified by the method in generating an increased immunogenic response in an individual against the tumor antigen. The method comprises administering to the individual an amount of peptide which has homology to a portion of the antigen and to a portion of an Ab2 which mimics an epitope on the antigen, and wherein the peptide comprises an HLA binding motif, effective to stimulate a CTL mediated immune response against the antigen.

5-Amino-4-Imidazolecarboxamide Riboside and Its Nucleobase as Potentiators of Antifolate Transport and Metabolism

U.S. Patent: Pending
Application Number: 11/327,872

Summary: The invention provides a method for increasing the efficacy of antifolates which act via inhibition of dihydrofolate reductase (DHFR). The method comprises the steps of administration of 5-amino-4-imidazolecarboxamide riboside (Z) or its base with the antifolate such that the targeted cells are exposed to both the antifolate and Z simultaneously. This results in increased influx of the antifolate. For MTX, accumulation of the more biologically active polyglutamate forms is also potentiated. This potentiation appears to be mediated by an effect on the RFC.

Detail: The invention provides a method for enhancing the uptake and efficacy of antifolates which act via inhibition of DHFR such as the 2,4 diaminopteridine antifolates methotrexate and aminopterin. The method is based on the unexpected observation that exogenous 5-amino-4-imidazolecarboxamide riboside (Z), a nucleoside precursor of (among others) the triphosphate ZTP, potentiates uptake of MTX and synthesis of MTX polyglutamate in cancer cells. Based on the data presented herein, it is considered that Z potentiates transport of antifolates via the RFC and the increased transport leads to increased synthesis of antifolate polyglutamates and consequently increased drug accumulation. Z was observed to enhance the growth inhibitory potency of MTX against cancer cells. Thus in one embodiment, this invention provides a method comprising the administration of Z or its base (i.e., 5-amino-4-imidazolecarboxamide) with an antifolate which acts via inhibition of the DHFR at concentrations at which the antifolate inhibits DHFR. The administration of Z or its base can be accomplished by any standard method, although systemic administration is preferred. Z has already been tested in clinical trials as a treatment for cardiac ischemia and is known to be nontoxic. In another embodiment, Z or its base and an antifolate which acts via inhibition of DHFR can be administered with a second antifolate(s) which primarily act via another mechanism such as inhibition of thymidylate synthase, inhibition of purine synthesis or other multi-targeted inhibition pathways. Administration of Z or its base with folate(s) which inhibit DHFR (with or without other folates) to enhance the efficacy of the folate(s) can be carried out for inhibiting the growth of cells as in various cancers as well as in other pathological conditions such as rheumatoid arthritis and psoriasis.

Peptides for Stimulating an Immune Response Against Melanoma

U.S. Patent : Pending
Application Number: 11/487,877

Summary: Provided in the invention are recombinant peptides and a method for using the peptides in stimulating an immune response against human high molecular weight-melanoma associated antigen (HMW-MAA). The peptides were designed from the identification of regions of structural and amino acid sequence homology between HMW-MAA and the mouse anti-idiotypic monoclonal antibody MK2-23. The method comprises the step of administering to an individual a peptide of the invention in an amount effective to elicit an immune response against HMW-MAA.

Detail: The invention provides recombinant peptides for use in stimulating an immune response against melanoma. The peptides were designed from regions of structural and amino acid sequence homology identified herein between HMW-MAA and the mouse anti-idiotypic monoclonal antibody (anti-id mAb) MK2-23, which mimics an HMW-MAA epitope. In particular, X-ray crystallography analysis of the Fab' portion of MK2-23 was used to identify regions of the heavy and light chains of the MK2-23 anti-idiotypic antibody which displayed similar folding patterns as the region of the HMW-MAA comprising the epitope mimicked by MK2-23. These studies indicated that the complementarity determining region 3 (CDR3) of its heavy chain (also referred to herein as "H3") and the complimentarity determining region 1 (CDR1) of its light chain (also referred to herein as "L1") display partial amino acid sequence homology and a similar structural folding as a portion of the HMW-MAA protein that comprises the epitope which is mimicked by MK2-23. Based on these data, three peptides are provided--one each from the H3 and the L1 region of MK2-23 and one from the HMW-MAA. The invention also provides a method for using the peptides identified herein for stimulating an immune response in an individual against melanoma. The method comprises administering to the individual an amount of a composition comprising one or more peptides of the invention in an amount effective to stimulate an immune response against HMW-MAA.

Inhibition of Breast Carcinoma Stem Cell Growth and Metastasis

U.S. Patent: Pending
Application Number: 11/724,884

Summary: Disclosed is a method for inhibiting the growth of breast carcinoma stem cells that express High Molecular Weight -Melanoma Associated Antigen (HMW-MAA). The method comprises administering to an individual a composition comprising an antibody reactive with HMW-MAA or a fragment of such an antibody in an amount effective to inhibit the growth of the breast carcinoma cells. Also provided are methods for inhibiting metastasis of breast carcinomas and methods for identifying HMW-MAA+ breast cancer stem cells.

Detail: The invention provides a method for inhibiting the growth of breast carcinoma stem cells. The breast carcinoma stem cells express High Molecular Weight--Melanoma Associated Antigen (HMW-MAA). The method comprises administering to an individual a composition comprising an antibody reactive with HMW-MAA in an amount effective to inhibit the growth of the breast carcinoma stem cells. In another embodiment, a method is provided for inhibiting metastasis of a breast carcinoma where the breast carcinoma comprises HMW-MAA+ breast carcinoma stem cells. The method comprises administering to the individual a composition comprising an amount of an antibody reactive with HMW-MAA effective to inhibit metastasis of the breast carcinoma. In another embodiment, a method is provided for detection of HMW-MAA+ breast carcinoma stem cells. The method comprises administering to an individual, or contacting a biological sample obtained from the individual with, a combination of antibodies, where the combination of antibodies comprises an antibody directed HMW-MAA and at least one antibody directed to a breast cancer stem cell marker. Detecting the binding of both the HMWMAA antibody and the at least one breast cancer stem cell marker determines the presence of an HMA-MAA+ breast carcinoma stem cell. In particular embodiments, the antibody employed in practicing the invention can be the monoclonal antibody designated 225.28 and/or the monoclonal antibody designated 763.74.

Methods of Therapy for Cancers Characterized by Overexpression of the HER2 Receptor Protein

Patent(s): Issued
U.S. Patent Number: 7,306,801
Issue Date: December 11, 2007

Summary: Methods for treating a subject with a cancer that is characterized by overexpression of HER2 receptor protein using a combination of interleukin-2 (IL-2) or variant thereof and at least one anti-HER2 antibody or fragment thereof are provided. These anti- tumor agents are administered as two separate pharmaceutical compositions, one containing IL-2 (or variant thereof), the other containing at least one anti-HER2 antibody (or fragment thereof), according to a dosing regimen. Administering of these two agents together potentiates the effectiveness of the anti-HER2 antibody alone, resulting in a positive therapeutic response that is improved with respect to that observed with this anti-tumor agent.

Detail: Methods for providing treatment to a subject with a cancer characterized by overex- pression of the p185HER2 growth factor receptor using a combination of interleukin-2 (IL-2) or variant thereof and at least one anti-HER2 antibody or fragment thereof are provided. The combination of IL-2 (or variant thereof) and at least one anti-HER2 antibody (or fragment thereof) promotes a positive therapeutic response. The methods comprise concurrent therapy with IL-2 (or variant thereof) and at least one anti-HER2 antibody (or fragment thereof). These anti-tumor agents are administered as two separate pharmaceutical compositions, one containing IL-2 (or variant thereof), the other containing at least one anti-HER2 antibody (or fragment thereof), according to a dosing regimen. Administering of these two agents together potentiates the effectiveness of the anti-HER2 antibody, resulting in a positive therapeutic response that is improved with respect to that observed with the antibody alone.

HLA Class II Peptide Mimics

Patent(s): Issued
U.S. Patent Number: 7,592,421
Issue Date: September 22, 2009

Summary: The present invention provides peptide mimics for HLA class II antigens. The peptide mimics were identified by panning phage display peptide libraries with anti-HLA class II monoclonal antibodies. The peptide mimics inhibit the binding of an anti-HLA class II antigen antibody to HLA class II antigen positive cells and also elicit antibodies which can bind to HLA class II antigen positive cells. The identified peptide mimics can be used as immunogens for therapy of diseases related to cells expressing the HLA class II antigen, such as Non-Hodgkins Lymphoma.

Detail: The present invention provides compositions in the form of peptide mimics of the HLA class II antigen and a method for producing same. This invention also provides a method of using the peptides to elicit an immune response against HLA class II antigen that is not normally immunogenic in hosts with HLA class II antigen expression. Still other embodiments include preparing a composition for use in the generation of an immune response and in the treatment of cells bearing HLA class II antigen. The composition comprises the peptide mimics disclosed herein. In another aspect, the present invention provides a method for eliciting an immune response in patients with NHL. The method comprises administering a composition effective in stimulating a specific immunological response against the HLA class II antigen. These composition(s) comprise a peptide that shares immunological characteristics of HLA class II antigen. While a detectable immunological response is likely to be beneficial, efficacy can also be deduced by an improvement in symptoms or control of the disease. Accordingly, in one aspect, the invention provides methods for identifying peptide mimics. The method comprises the steps of screening phage display peptide libraries with antibodies to HLA class II antigen. The identified peptides are then tested for their ability to elicit an immune response to HLA class II antigen and for reactivity of the elicited antibodies against HLA class II antigen bearing cells.

Iridoid-saccharide Compound and Method of Using Same

Patent(s): Pending
U.S. Patent Application Number: 11/901,113
International Pending Applications: GB, FR, DE

Summary: A method for treatment of hyperproliferative tissue which by exposing the hyperprolif- erative tissue to a sufficient quantity of a purified iridoid compound to inhibit its growth, where the iridoid compound includes a polysubstituted cyclopenta(c)dihydropyran where the cyclopenta ring is substituted at its 2' position with a ketofuryl group, where the numbering of the fused cyclopenta(c)dihydropyran ring structure includes heterocyclic oxygen, is counterclockwise and begins at the first carbon atom counterclockwise from the cyclopenta ring so that oxygen is in the 2 position in the pyran ring. The invention also includes the mouse iridoid compounds.

Detail: In accordance with the invention a method is provided for treatment of hyperproliferative tissue which comprises exposing the hyperproliferative tissue to a sufficient quanti- ty of a purified iridoid compound to inhibit its growth. The iridoid compounds for use in accordance with the invention may be purified from natural sources or may be made synthetically. The iridoid compounds suitable for use in accordance with the invention comprise polysubstituted cyclopenta(c)dihydropyrans where the cyclopenta ring is sub- stituted at its 2' position with a ketofuryl group where the numbering of the fused cyclopenta(c)dihydropyran ring structure including heterocyclic oxygen, is counter-clockwise and begins at the first carbon atom counter-clockwise from the cyclopenta ring so that oxygen is in the 2 position in the pyran ring. Within this group of compounds, the invention also includes such compounds substituted with a mono or polysaccharide moiety especially those compounds where the pyran ring is substituted at its 1 position by an --O-saccharide substituent, i.e. where the --O-saccharide substituent is an --O-polysaccharide or an --O-monosaccharide. The most common saccharide substituent is a glucoside moiety. More specifically the invention includes compounds of the formula: where R.sup.1 and R.sup.2 are independently lower alkenyl of 1-8 carbon atoms, lower alkyl of 1-8 carbon atoms, carboxy, carboxy C1-C8 lower alkyl (includ- ing salts and esters thereof), C1-C8 lower alkyl carboxy (including salts and esters thereof), hydroxy, C1-C8 hydroxy lower alkyl, lower alkylene-lower alkyl ether, lower alkyl amino, lower alkylene alkyl amine or C1-C8 alkylene alkyl ketone and n is an integer of 0 through 3, and their use for treating hyperproliferative tissue.

Glycosylation and Carbohydrate Therapeutics

Synthetic Core 2-like Branched Structures Containing GalNAc-lewis.sup.x and Neu5Ac.alpha.2-2Gal.beta.1- 3GalNAc Sequences as Novel Ligands for Selectins

U.S. Patent Number: 5,972,907
Issue Date: October 26, 1999

Summary: Compounds which bind to selectin receptors and thus may modulate the course of inflammation, cancer and related processes by intervening with cell-cell adhesion events. Further, such compounds can be used for identification and analysis of such receptors. In this regard the invention is directed to compounds of formula (I). ##STR1## wherein R.sup.1 is independently H, alkyl, aryl, an aryl alkyl, alkenyl or one or more additional saccharide residues; R.sup.2 =H or OH provided that when R.sup.2 is H, R.sup.3 is OH; R.sup.3 =H or OH provided that when R.sup.3 is H, R.sup.2 is OH; X=H, SO.sub.3.sup.- or PO.sub.4.sup.- ; Y is independently H, OH, OR.sup.4 or NHCOR.sup.4, wherein R.sup.4 is alkyl, and Z is an organic acid residue. .alpha.-L-Fucose residue can be modified or replaced with suitable bioisosters or a different saccharide residue such as D-mannose. Modification of L-fucose may include replacement of each or all of the hydroxyl groups with H or OR' wherein R' can be methyl, ethyl or allyl groups.

Detail: The invention relates to compounds useful in the treatment of inflammation, allergic reactions, autoimmune diseases, cancer, and similar other conditions that are cell adhesiondependent. More specifically, the invention concerns compounds, containing GalNAc lewis.sup.x as a mucin Core 2 branched structure, which have the ability to bind selectin receptors. Such structures have not been reported to be part of any O-linked glycoproteins. The invention is also concerned with pharmaceutical compositions containing such compounds. It is also directed to methods useful for the synthesis of such compounds and analogs derived therefrom.

Fluorinated Glucosamine Analogs Useful for Modulating Post-Translational Glycosylation of Cells

U.S. Patent Number: 7,098,195
Issue Date: August 29, 2006

Summary: The invention provides compositions and methods for inhibiting cell migration, e.g., lymphocytes and inflammation. The invention also provides an improved process for preparing fluorinated N-acetylglucosamines.

Detail: The invention features methods of inhibiting cell migration, cell proliferation or cell differentiation by contacting a cell with a fluorinated N-acetylglucosamine (F-GlcNAc), e.g., 2-acetamido-2-deoxy-1,3,6-tri-O-acetyl-4-deoxy-4-fluoro-D-glucopyranose or 2-acetamido- 2-deoxy-1,4,6-tri-O-acetyl-3-deoxy-3-fluoro-D-glucopyranos- e in an amount sufficient to inhibit cell migration, proliferation or differentiation.

Also provide by the invention is a method of decreasing an amount of HECA-452 epitope on a glycoprotein, e.g., PSGL-1 or CD44 on a cell, by contacting the cell with a fluorinated N-acetylglucosamine. The amount of the glycoprotein on the cell in the presence of the fluorinated N-acetylglucosamine as compared to in the absence of the fluorinated Nacetylglucosamine differs by less than 10%, 5% or 1%.

In another aspect the invention features a method of inhibiting inflammation in a tissue, e.g., dermal tissue of a subject by administering to the subject a fluorinated N-acetylglucosamine. The inflammation is for example, chronic inflammation, e.g., DTH, acute inflammation, cutaneous inflammation, psoriasis, inflammatory bowel disease, colitis or Crohn's disease. The fluorinated N-acetylglucosamine is administered prior to an inflammatory event. Alternatively, the fluorinated N-acetylglucosamine is administered after an inflammatory event. Administration is, intraperitoneal, subcutaneous, nasal, intravenous, oral, topical and transdermal delivery.

The cell is a leukocyte such as a lymphoid cell, e.g., T-cell or a hematopoietic cell. Alternatively, the cell is a cancerous cell such a leukemic cell or a lymphoma, e.g., cutaneneous lymphoma. The cell is further contacted with a chemotherapeutic agent such as daunorubicin (DNR), cytarabine (ara-C), idarubicin, thioguanine, etoposide, and mitoxantrone or an anti-inflammatory agent such as aspirin, ibuprofen, naproxen sodium, celecoxib, prednisone, prednisolone, and dexamethasone.

The invention provides an improved method for preparing fluorinated N-acetylglucosamine which comprises the intermediate step of preparing benzyl 2-acetamido-2- deoxy-3,6-di-O-benzyl-D-glucopyranoside from benzyl 2-acetamido-3-O-benzyl-4,6-benzylidene- 2-deoxy-D-glucopyranoside, the improvement comprising (i) hydrolyzing benzyl 2-acetamido-3-O-benzyl-4,6-benzylidene-2-deoxy-D-glucopyranoside under appropriate conditions to form benzyl 2-acetamido-3-O-benzyl-2-deoxy-D-glucopyranoside; (ii) reacting benzyl 2-acetamido-3-O-benzyl-2-deoxy-D-glucopyranoside with a tin compound to form a tin complex comprising benzyl 2-acetamido-3-O-benzyl-2-deoxy-D-glucopyranoside; and (iii) reacting the tin complex with a benzylating agent under appropriate conditions to form benzyl 2-acetamido-3,6-benzyl-2-deoxy-D-glucopyranoside.

Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. Although methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present invention, suitable methods and materials are described below. All publications, patent applications, patents, and other references mentioned herein are hereby incorporated by reference in their entirety. In case of conflict, the present specification, including definitions, will control. In addition, the materials, methods, and examples are illustrative only and not intended to be limiting.