Polysaccharide compositions and methods of use for the treatment and prevention of disorders associated with progenitor cell mobilization

A method of lessening, reducing, mitigating, ameliorating, or delaying pancreatic cancer in a subject, comprising administering to the subject a pharmaceutical composition comprising a low molecular weight heparin preparation produced by a process comprising:

• depolymerization of unfractionated heparin with nitrous acid to produce a depolymerized heparin preparation,
• oxidation of the depolymerized heparin preparation to produce an oxidized heparin preparation, and
• reduction of the oxidized heparin preparation to produce the low molecular weight heparin preparation, wherein the low molecular weight heparin preparation has the following characteristics
• (a) a weight average chain molecular weight between 5,000 and 8,000 Da as determined by high performance liquid chromatography coupled with a multi angle light scattering detector (MALS);
• (b) anti-Xa activity of less than 20 IU/mg and anti-IIa activity of 1 IU/mg or less;
• (c) greater than 5% and less than 25% glycol split uronic acid residues;
• and
• (d) wherein the preparation has a molecular weight distribution such that 10-30% of the polysaccharides of the preparation have a molecular weight <3000 Da;
• 55-65% of the polysaccharides have a molecular weight between 3000-8000 Da, and 15-30% of the polysaccharides have a molecular weight >8000 Da as determined by high performance liquid chromatography coupled with a multi angle light scattering detector (MALS);
• and
• wherein, the preparation comprises polysaccharides that comprise the structure:
• [Uw—Hx,y,z]m˜[UG—Hx,y,z]n, or a pharmaceutically acceptable salt thereof,
• wherein each occurrence of U indicates a uronic acid residue and each occurrence of H indicates a hexosamine residue;
• wherein m and n are integers such that
• m=4-16, and
• n=1-4;
• each of w, x, y and z can independently be the same or different for each occurrence of [Uw—Hx,y,z] and each of x, y and z can independently be the same or different for each occurrence of [UG—Hx,y,z], wherein
• w=-2OS or -2OH;
• x=—NS or —NAc;
• y=-3OS or -3OH;
• z=-6OS or -6OH;
• and
• wherein the symbol ˜ indicates that the units marked m and n are distributed along the polysaccharide chain and are not necessarily in sequence;
• and
• wherein the preparation is administered in combination with albumin-bound paclitaxel and gemcitabine.

A method of lessening, reducing, mitigating, ameliorating, or delaying locally advanced or metastatic pancreatic cancer in a subject, comprising administering to the subject a pharmaceutical composition comprising a low molecular weight heparin preparation produced by a process comprising:

• depolymerization of unfractionated heparin with nitrous acid to produce a depolymerized heparin preparation,
• oxidation of the depolymerized heparin preparation to produce an oxidized heparin preparation, and
• reduction of the oxidized heparin preparation to produce the low molecular weight heparin preparation, wherein the low molecular weight heparin preparation has the following characteristics
• (a) a weight average chain molecular weight between 5,000 and 8,000 Da as determined by high performance liquid chromatography coupled with a multi angle light scattering detector (MALS);
• (b) anti-Xa activity of less than 20 IU/mg and anti-IIa activity of 1 IU/mg or less;
• (c) greater than 5% and less than 25% glycol split uronic acid residues;
• and
• (d) wherein the preparation has a molecular weight distribution such that 10-30% of the polysaccharides of the preparation have a molecular weight <3000 Da;
• 55-65% of the polysaccharides have a molecular weight between 3000-8000 Da, and 15-30% of the polysaccharides have a molecular weight >8000 Da as determined by high performance liquid chromatography coupled with a multi angle light scattering detector (MALS);
• and
• wherein the preparation comprises polysaccharides that comprise the structure:
• [Uw—Hx,y,z]m˜[UG—Hx,y,z]n, or a pharmaceutically acceptable salt thereof,
• wherein each occurrence of U indicates a uronic acid residue and each occurrence of H indicates a hexosamine residue;
• wherein m and n are integers such that
• m=4-15, and
• n=1-3;
• each of w, x, y and z can, independently, be the same or different for each occurrence of [Uw—Hx,y,z] and each of x, y and z can, independently, be the same or different for each occurrence of [UG—Hx,y,z], wherein
• w=-2OS or -2OH;
• x=—NS or —NAc;
• y=-3OS or -3OH;
• z=-6OS or -6OH;
• and
• wherein the symbol ˜ indicates that the units marked m and n are distributed along the polysaccharide chain and are not necessarily in sequence;
• and
• wherein a plurality of the polysaccharides in the preparation have a 2,5-anhydromannitol residue at the reducing end and a non-native uronic acid at the non-reducing end;
• and
• wherein the subject receives multiple administrations of the preparation, the preparation is administered daily for at least one month, and the preparation is administered in combination with albumin-bound paclitaxel and gemcitabine.