Galactose-pronged polysaccharides in a formulation for antifibrotic therapies

• US 8,722,645 B2
• Filed: 07/17/2012
• Issued: 05/13/2014
• Est. Priority Date: 05/16/2006
• Status: Active Grant

• Current Assignee: Galectin Therapeutics Inc
• Original Assignee: Galectin Therapeutics Inc
• Inventors: Platt, David, Zomer, Eliezer, Klyosov, Anatole
• Primary Examiner(s): OLSON, ERIC
• Application Number:
  US13/550,962
• Publication Number:
  US 20120282220A1
• Time in Patent Office: 665 Days
• Field of Search: None
• US Class Current: 514/54
• CPC Class Codes: A61K 2300/00 Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00
• CPC Class Codes: A61K 31/715 Polysaccharides, i.e. having more than five saccharide radicals attached to each other by glycosidic linkages; Derivatives thereof, e.g. ethers, esters
• CPC Class Codes: A61K 31/732 Pectin
• CPC Class Codes: A61K 39/395 Antibodies agglutinins A61K38/36 ; as drug carriers A61K47/50; Immunoglobulins; Immune serum, e.g. antilymphocytic serum
• CPC Class Codes: A61K 45/06 Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• CPC Class Codes: A61P 1/16 for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
• CPC Class Codes: A61P 13/12 of the kidneys
• CPC Class Codes: A61P 17/00 Drugs for dermatological disorders
• CPC Class Codes: A61P 25/00 Drugs for disorders of the nervous system
• CPC Class Codes: A61P 9/12 Antihypertensives
• CPC Class Codes: C08B 37/0045 alpha-D-Galacturonans, e.g. methyl ester of (alpha-1,4)-linked D-galacturonic acid units, i.e. pectin, or hydrolysis product of methyl ester of alpha-1,4-linked D-galacturonic acid units, i.e. pectinic acid; Derivatives thereof
• CPC Class Codes: C08B 37/006 Heteroglycans, i.e. polysaccharides having more than one sugar residue in the main chain in either alternating or less regular sequence; Gellans; Succinoglycans; Arabinogalactans; Tragacanth or gum tragacanth or traganth from Astragalus; Gum Karaya from Sterculia urens; Gum Ghatti from Anogeissus latifolia; Derivatives thereof

Abstract

Methods and compositions for reducing fibrosis and cirrhosis are provided in which an effective dose of an admixture of a polysaccharide compound and, for example, a compound selected from the group consisting of antibodies specific to intracellular or cell-surface: (i) beta-PDGF receptors; (ii) synaptophysin; (iii) zvegf3; (iv) CCR1 receptors; (v) connective tissue growth factor; (vi) alpha 1-smooth muscle actin; (vii) matrix metalloproteinases MMP 2 and MMP9; (viii) matrix metalloproteinase inhibitors TIMP1 and TMP2; (ix) integrins; (x) TFG-β1; (xi) endothelin receptor antagonists; and (xii) collagen synthesis and degradation modulating compounds; (xiii) actin synthesis and degradation modulating compounds; and (xiv) tyrosine kinases is administered to an animal in order to treat fibrosis.

Claims

1. A composition comprising:

a. an effective amount of a galacto-rhamnogalacturonan compound and an acceptable pharmaceutical carrier, wherein the galacto-rhamnogalacturonan compound is a branched heteropolymer having a backbone of alternating α

-1,2 linked rhamnose and α

-1,4-linked GalA residues that carries neutral side-chains of predominantly 1,4-β

-D-galactose and/or 1,5-α

-L-arabinose residues attached to the rhamnose residues of the backbone,

wherein the galacto-rhamnogalacturonan compound is derived from USP pectin;

wherein the effective amount of the galacto-rhamnogalacturonan, when administered in a subject having at least one of the following;

chronic liver disease associated with the development of fibrosis, established liver fibrosis, or cirrhosis, is capable of inhibiting or slowing down of the progression of liver fibrosis or cirrhosis or reduction of established liver fibrosis or cirrhosis based on evidence comprising reduction of the level of biochemical markers of liver fibrosis, non invasive testing of liver fibrosis or cirrhosis or liver histologic grading of fibrosis or cirrhosis;

wherein, when the galacto-rhamnogalacturonan compound is utilized at a concentration of 0.1-0.5 mg/ml to treat LX2 immortalized human hepatic stellate cells in a MTT cell viability assay, the assay treatment results in substantially no decreased viability of activated hepatic stellate cells following administration of the compound, and wherein when the galacto-rhamnogalacturonan compound is utilized at a concentration of 0.1-0.5 mg/ml to treat LX2 immortalized human hepatic stellate cells in a proliferation assay, the assay results in substantially no effect on cell proliferation following administration of the compound; and

b. a therapeutic agent, wherein the therapeutic agent is a compound selected from the group consisting of antibodies specific to cell-surface and/or intracellular;

(i) β

-PDGF receptors;

(ii) synaptophysin;

(iii) zvegf3;

(iv) CCR1 receptors;

(v) connective tissue growth factor;

(vi) alpha 1-smooth muscle actin;

(vii) matrix metalloproteinases MMP 2 and MMP9;

(viii) matrix metalloproteinase inhibitors TIMP1 and TMP2;

(ix) integrins;

(x) TFG-β

1;

(xi) endothelin receptor antagonists;

(xii) collagen synthesis and degradation modulating compounds;

(xiii) actin synthesis and degradation modulating compounds; and

(xiv) tyrosine kinases.

2. The composition of claim 1 wherein the galacto-rhamnogalacturonan compound is derived from citrus pectin, apple pectin, soybean hull pectin or sugar beet pectin.

3. The composition of claim 1 wherein the galacto-rhamnogalacturonan compound has a molecular weight between 20 kDa and 400 kDa.

4. The composition of claim 1 wherein the galacto-rhamnogalacturonan compound has a molecular weight between 2 kDa and 200 kDa.

5. The composition of claim 1 wherein the ratio of galactose to rhamnose in the galacto-rhamnogalacturonan is 3.7 to 1.

6. The composition of claim 1 wherein the ratio of galactose to rhamnose in the galacto-rhamnogalacturonan is between 0.4 to 1 and 6.7 to 1.

7. The composition of claim 1 wherein the galacto-rhamnogalacturonan further comprises fucose, xylose, mannose or combinations thereof.

8. A method comprising the steps of:

Obtaining a galacto-rhamnogalacturonan compound;

wherein the galacto-rhamnogalacturonan compound is a branched heteropolymer having a backbone of alternating α

-1,2 linked rhamnose and α

-1,4-linked GalA residues that carries neutral side-chains of predominantly 1,4-β

D-galactose and/or 1,5-α

-L-arabinose residues attached to the rhamnose residues of the backbone and wherein the galacto-rhamnogalacturonan compound is obtained from USP pectin; and

Administering the galacto-rhamnogalacturonan compound in an admixture with a therapeutic agent parenterally to a subject having at least one of the following;

chronic liver disease associated with the development of fibrosis, established liver fibrosis, or cirrhosis an effective dose of the galacto-rhamnogalacturonan compound in an acceptable pharmaceutical carrier that results in at least one of the following;

Inhibition or slowing down of the progression of liver fibrosis or cirrhosis or reduction of established liver fibrosis or cirrhosis based on evidence comprising reduction of the level of biochemical markers of liver fibrosis, non invasive testing of liver fibrosis or cirrhosis or liver histologic grading of fibrosis or cirrhosis;

or reduction in the medical consequences of liver fibrosis or cirrhosis,

wherein, when the galacto-rhamnogalacturonan compound for parenteral administration is utilized to treat LX2 immortalized human hepatic stellate cells in a MTT cell viability assay, the assay treatment results in substantially no decreased viability of activated hepatic stellate cells following administration of the compound, and wherein when the galacto-rhamnogalacturonan compound is utilized at a concentration of 0.1-0.5 mg/ml to treat LX2 immortalized human hepatic stellate cells in a proliferation assay, the assay results in substantially no effect on cell proliferation following administration of the compound,

wherein the therapeutic agent is a compound selected from the group consisting of antibodies specific to cell-surface and/or intracellular;

(i) β

-PDGF receptors;

(ii) synaptophysin;

(iii) zvegf3;

(iv) CCR1 receptors;

(v) connective tissue growth factor;

(vi) alpha 1-smooth muscle actin;

(vii) matrix metalloproteinases MMP 2 and MMP9;

(viii) matrix metalloproteinase inhibitors TIMP1 and TMP2;

(ix) integrins;

(x) TFG-β

1;

(xi) endothelin receptor antagonists;

(xii) collagen synthesis and degradation modulating compounds;

(xiii) actin synthesis and degradation modulating compounds; and

(xiv) tyrosine kinases.

9. The method of claim 8 wherein in the step of obtaining the galacto-rhamnogalacturonan compound is obtained from citrus pectin, apple pectin, soybean hull pectin or sugar beet pectin.

10. The method of claim 8 wherein in the step of obtaining the galacto-rhamnogalacturonan compound has a molecular weight between 20 kDa and 400 kDa.

11. The method of claim 8 wherein in the step of obtaining the galacto-rhamnogalacturonan compound has a molecular weight between 2 kDa and 200 kDa.

12. The method of claim 8 wherein in the step of obtaining the ratio of galactose to rhamnose in the galacto-rhamnogalacturonan is 3.7 to 1.

13. The method of claim 8 wherein in the step of obtaining the ratio of galactose to rhamnose in the galacto-rhamnogalacturonan is between 0.4 to 1 and 6.7 to 1.

14. The method of claim 8 wherein in the step of obtaining the galacto-rhamnogalacturonan further comprises fucose, xylose, mannose or combinations thereof.