CA2478700A1 - Analysis of sulfated polysaccharides - Google Patents

Analysis of sulfated polysaccharides Download PDF

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Publication number
CA2478700A1
CA2478700A1 CA002478700A CA2478700A CA2478700A1 CA 2478700 A1 CA2478700 A1 CA 2478700A1 CA 002478700 A CA002478700 A CA 002478700A CA 2478700 A CA2478700 A CA 2478700A CA 2478700 A1 CA2478700 A1 CA 2478700A1
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delta
mole
lmwh
subject
sample
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CA2478700C (en
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Ganesh Venkataraman
Ram Sasisekharan
Mallikarjun Sundaram
Zachary Shriver
Yi-Wei Qi
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Momenta Pharmaceuticals Inc
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    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
    • G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
    • G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
    • G01N33/66—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving blood sugars, e.g. galactose
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A61P11/06—Antiasthmatics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A61P11/16—Central respiratory analeptics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/02—Drugs for dermatological disorders for treating wounds, ulcers, burns, scars, keloids, or the like
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/06—Antipsoriatics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/08—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/08—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease
    • A61P19/10—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease for osteoporosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/06—Antimigraine agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/02—Ophthalmic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/04—Antineoplastic agents specific for metastasis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/08—Antiallergic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A61P7/02—Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A61P7/04—Antihaemorrhagics; Procoagulants; Haemostatic agents; Antifibrinolytic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/06—Antiarrhythmics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/14—Vasoprotectives; Antihaemorrhoidals; Drugs for varicose therapy; Capillary stabilisers
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
    • G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
    • G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
    • G01N33/86—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving blood coagulating time or factors, or their receptors
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N2400/00—Assays, e.g. immunoassays or enzyme assays, involving carbohydrates
    • G01N2400/10—Polysaccharides, i.e. having more than five saccharide radicals attached to each other by glycosidic linkages; Derivatives thereof, e.g. ethers, esters
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N2400/00—Assays, e.g. immunoassays or enzyme assays, involving carbohydrates
    • G01N2400/10—Polysaccharides, i.e. having more than five saccharide radicals attached to each other by glycosidic linkages; Derivatives thereof, e.g. ethers, esters
    • G01N2400/38—Heteroglycans, i.e. polysaccharides having more than one sugar residue in the main chain in either alternating or less regular sequence, e.g. gluco- or galactomannans, e.g. Konjac gum, Locust bean gum, Guar gum
    • G01N2400/40—Glycosaminoglycans, i.e. GAG or mucopolysaccharides, e.g. chondroitin sulfate, dermatan sulfate, hyaluronic acid, heparin, heparan sulfate, and related sulfated polysaccharides
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y10—TECHNICAL SUBJECTS COVERED BY FORMER USPC
    • Y10T—TECHNICAL SUBJECTS COVERED BY FORMER US CLASSIFICATION
    • Y10T436/00—Chemistry: analytical and immunological testing
    • Y10T436/14—Heterocyclic carbon compound [i.e., O, S, N, Se, Te, as only ring hetero atom]
    • Y10T436/142222—Hetero-O [e.g., ascorbic acid, etc.]
    • Y10T436/143333—Saccharide [e.g., DNA, etc.]
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y10—TECHNICAL SUBJECTS COVERED BY FORMER USPC
    • Y10T—TECHNICAL SUBJECTS COVERED BY FORMER US CLASSIFICATION
    • Y10T436/00—Chemistry: analytical and immunological testing
    • Y10T436/17—Nitrogen containing
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y10—TECHNICAL SUBJECTS COVERED BY FORMER USPC
    • Y10T—TECHNICAL SUBJECTS COVERED BY FORMER US CLASSIFICATION
    • Y10T436/00—Chemistry: analytical and immunological testing
    • Y10T436/24—Nuclear magnetic resonance, electron spin resonance or other spin effects or mass spectrometry

Abstract

The invention relates to methods and products associated with analyzing and monitoring heterogeneous populations of sulfated polysaccharides. In particular therapeutic heparin products including low molecular weight hepar in products and methods of analyzing and monitoring these products are describe d.

Claims (330)

1. A method of analyzing a sample comprising a composition which includes a polysaccharide, the method comprising providing a structural signature for the composition, thereby analyzing the composition.
2. The method of claim 1 wherein the structural signature is provided by determining one or more primary outputs chosen from the following:
a. the presence or the amount of one or more component saccharides or disaccharides;
b. the presence or the amount of one or more block components, wherein a block component is one made up of more than one saccharides or polysaccharide;
c. the presence or amount of one or more saccharide-representative, wherein a saccharide-representative is a saccharide modified to enhance detectability;
d. the presence or amount of an indicator of three dimensional structure or a parameter related to three dimensional structure; and e. the presence or amount of one or more modified saccharides, wherein a modified saccharide is one present in a starting material used to make a preparation but which is altered in the production of the preparation.
3. The method of claim 1 wherein the structural signature is provided by determining one or more secondary outputs chosen from the following:
a. total charge;
b. charge/mass ratio;
c. density of charge;
d. sequence;
e. positioning of an active site; and f. polydispersity.
4. The method of claim 1 wherein the structural signature is determined by one or more methods chosen from the group consisting of MALDI-MS, ESI-MS, CE, HPLC, FPLC, fluorometry, ELISA, NMR UV, chromogenic assay, colorimetric assays, other spectroscopic techniques.
5. The method of claim 1 wherein the composition is chosen from the group consisting of heparin, synthetic heparin, and LMWH.
6. The method of claim 1 wherein the composition further comprises one or more tags.
7. The method of claim 1 wherein the composition further comprises antibodies, lectins, or proteins.
8. The method of claim 1 wherein the composition is completely or incompletely digested.
9. The method of claim 8 wherein the composition is chemically digested.
10. The method of claim 8 wherein the composition is enzymatically digested.
11. The method of claim 10 wherein the enzymatic digestion is carried out with a heparin degrading enzyme.
12. The method of claim 11 wherein the heparin degrading enzyme is chosen from the group consisting of heparinase I, heparinase II, heparinase III, heparinase IV, heparanase and functionally active variants and fragments thereof.
13. The method of claim 9 wherein the chemical digestion is carried out with a chemical chosen from the group consisting of H2O2, Cu+ and H2O2, isoamyl nitrite, nitrous acid, benzyl ester or alkaline treatment.
14. The method of claim 1 further comprising the steps of:
a. analyzing a plurality of compositions to determine the structural signature of each composition;
b. detecting the biological activity of each composition;
c. comparing the structural signature of the compositions to the detected biological activities; and d. correlating the biological activity with a structural signature or component thereof.
15. The method of claim 14 wherein the biological activity is chosen from the group consisting of effects on cellular activities such as undesired cell growth or proliferation; cellular migration, adhesion, or activation;
neovascularization; angiogenesis; coagulation; and inflammatory processes.
16. The method of claim 14 wherein the biological activity includes anti-Xa activity, anti-IIa activity, FGF binding, protamine neutralization, or PF4 binding.
17. The method of claim 14 further comprising using the correlation information to design a heparin, synthetic heparin, or LMWH preparation for a specific indication.
18. The method of claim 17 wherein the specific indication is chosen from the group consisting of renal impairment, cancer, inflammation, Alzheimer's, autoimmunity, fractures including hip fractures, and transplantation.
19. The method of claim 17 wherein the human or veterinary subject is having, at risk for having, or recovering from a condition chosen from the group consisting of disease associated with coagulation, such as thrombosis, cardiovascular disease, vascular conditions or atrial fibrillation; migraine, atherosclerosis; an inflammatory disorder, such as autoimmune disease or atopic disorders; an allergy; a respiratory disorder, such as asthma, emphysema, adult respiratory distress syndrome (ARDS), cystic fibrosis, or lung reperfusion injury; a cancer or metastatic disorder; an angiogenic disorder, such as neovascular disorders of the eye, osteoporosis, psoriasis, and arthritis, Alzheimers', or is undergoing or having undergone surgical procedure, organ transplant, orthopedic surgery, treatment for a fracture such as a hip fracture, hip replacement, knee replacement, percutaneous coronary intervention (PCI), stent placement, angioplasty, coronary artery bypass graft surgery (CABG).
20. The method of claim 17 wherein the specific indication includes cellular activities such as cell growth or proliferation; neovascularization;
angiogenesis; cellular migration, adhesion, or activation; and inflammatory processes.
21. A method for determining bioequivalence comprising the steps of a. providing or determining the structural signature of a first composition;

b. providing or determining the bioavailability of the first composition;
c. providing or determining the structural signature of a second composition;
d. providing or determining the bioavailability of the second composition;
and e. comparing the structural compositions and bioavailability of the first and second compositions;
thus determining the bioequivalence of the compositions.
22. The method of claim 20 wherein bioavailability is determined by a method comprising:
a. determining the absorbance characteristics of the composition in one or more subjects; and b. determining the clearance characteristics of the composition in one or more subjects.
23. The method of claim 23, wherein the subject is a human or veterinary subject or experimental animal.
24. A method of analyzing a polysaccharide drug, the method comprising:
a. determining a first structural signature for a first batch of drug having a first level of preselected patient reaction;
b. determining a second structural signature, for a second batch of drug having a second level of preselected patient reaction; and c. comparing the first and second structural signature determinations to determine the presence or absence of a correlation between a property of the drug with a preselected level of patient reaction.
25. The method of claim 24, wherein the polysaccharide drug is a heparin, synthetic heparin, or LMWH.
26. The method of claim 24, wherein the preselected patient reaction is a preselected level of negative or positive reaction to the drug.
27. The method of claim 24, wherein the method comprises determining the structural signature of a first batch of drug having a relatively high level of undesirable patient reactions, determining the structural signature of a second batch of drug having a relatively low level of undesirable patient reactions, and selecting a primary or secondary output correlated with the high or the low level of patient reactions.
28. A method of analyzing a composition which includes a mixed population of polysaccharides, the method comprising:
a. providing the composition or a sample which includes the composition; and b. determining if one or more of: .DELTA.U2S H NS,6S is present in a preselected range; .DELTA.U2S H NS is present in a preselected range; .DELTA.UH NS,6S is present in a preselected range; .DELTA.U2S H NS,6S is present in a preselected range;
.DELTA.UH NS is present in a preselected range; .DELTA.U2S H NAc is present in a preselected range; .DELTA.UH NAc,6S is present in a preselected range; or .DELTA.UH NAc,6S GH NS,3S,6S, .DELTA.UH NS,6S GH NS,3S,6S, .DELTA.UH NAc,6S GH
NS,3S, or .DELTA.UH NS,6S GH NS,3S or a mixture thereof is present in a preselected range in the composition, thereby analyzing the composition.
29. A method of analyzing a composition which includes a mixed population of polysaccharides, the method comprising the steps of:
a. providing the composition or a sample which includes the composition; and b. determining if one or more of .DELTA.U2s H NS,6S is present in the range of 85 mole %; .DELTA.U2S H NS is present in the range of 0.1-20 mole %;
.DELTA.UH NS,6S is present in the range of 0.1-20 mole %; .DELTA.U2S H NAc,6S
is present in the range of 0.1-10 mole %; .DELTA.UH NS is present in the range of 0.1-10 mole %; .DELTA.U2S H NAc is present in the range of 0.1-5 mole %;
.DELTA.UH NAc,6S is present in the range of 0.1-15 mole %; or .DELTA.UH NAc,6S GH NS,3S,6S, .DELTA.UH NS,6S GH NS,3S,6S, .DELTA.UH NAc,6S GH
NS,3S, or .DELTA.UH NS,6S GH NS,3S or a mixture thereof is present in the range of 0.1-mole % in the composition;
thereby analyzing the composition.
30. The method of claim 29 wherein the determining includes determining if one or more non-natural sugars are present in the range of 0.1-5 mole %, 0.1-2.5 mole %, or 0.1-1 mole %.
31. The method of claim 29 wherein the determining includes determining if peak 9 is present in the range of 0.1-5 mole %, 0.1-2.5 mole %, or 0.1-1 mole %.
32. The method of claim 29 wherein the determining includes determining if peak 10 is present in the range of 0.1-5 mole %, 0.1-2.5 mole %, or 0.1-1 mole %.
33. The method of claim 29 wherein the determining includes determining if peak 11 is present in the range of 0.1-10 mole %, 1-5 mole %, or 2-4 mole %.
34. The method of claim 29 wherein the polysaccharides are glycosaminoglycans.
35. The method of claim 34 wherein the glycosaminoglycans are HLGAGs.
36. The method of claim 35 wherein the HLGAG is unfractionated heparin.
37. The method of claim 35 wherein the HLGAG is fractionated heparin.
38. The method of claim 37 wherein the fractionated heparin is LMWH
39. The method of claim 38 wherein the LMWH is enoxaparin.
40. The method of claim 38 wherein the LMWH is dalteparin.
41. The method of claim 38 wherein the LMWH is ardeparin.
42. The method of claim 38 wherein the LMWH is certoparin.
43. The method of claim 38 wherein the LMWH is parnaparin.
44. The method of claim 38 wherein the LMWH is tinzaparin.
45. The method of claim 38 wherein the LMWH is nadroparin.
46. The method of claim 38 wherein the LMWH is reviparin.
47. The method of claim 38 wherein the LMWH is fondaparinux.
48. The method of claim 29 wherein the determination comprises the steps of:
a. optionally, fractionating the HLGAG;
b. digesting the HLGAG with at least one agent; and c. determining the molecular weight of the digested HLGAG.
49. The method of claim 48 wherein the agent is an enzyme.
50. The method of claim 49 wherein the enzyme is a heparin degrading enzyme.
51. The method of claim 50 wherein the heparin degrading enzyme is chosen from the group consisting of heparinase I, heparinase II, heparinase III, heparinase IV, heparanase and functionally active variants and fragments thereof.
52. The method of claim 48 wherein the agent is a chemical, e.g. a chemical chosen from the group consisting of H2O2, Cu+ and H2O2, isoamyl nitrite, nitrous acid, benzyl ester or alkaline treatment.
53. The method of claim 29 wherein the determining includes determining if .DELTA.U2S H NS,6S is present in the range of 15-85 mole %; .DELTA.U2S H NS is present in the range of 0.1-20 mole %; .DELTA.UH NS,6S is present in the range of 0.1-20 mole %;
.DELTA.U2S H NAc,6S is present in the range of 0.1-10 mole %; .DELTA.UH NS is present in the range of 0.1-10 mole %; .DELTA.U2S H NAc is present in the range of 0.1-5 mole %;
.DELTA.UH NAc,6S is present in the range of 0.1-15 mole %; and .DELTA.UH
NAc,6S GH NS,3S,6S, .DELTA.UH NS,6S GH NS,3S,6S, .DELTA.UH NAc,6S GH NS,3S, .DELTA.NS,6S GH NS,3S
or a mixture thereof is present in the range of 0.1-20 mole % in the composition.
54. The method of claim 29 wherein the determining includes determining if two, three, four, five six or seven of: .DELTA.U2S H NS,6S is present in the range of 15-85 mole %; .DELTA.U2S H NS is present in the range of 0.1-20 mole %; .DELTA.UH
NS,6S is present in the range of 0.1-20 mole %; .DELTA.U2S H NAc,6S is present in the range of 0.1-10 mole %; .DELTA.UH NS is present in the range of 0.1-10 mole %;
.DELTA.U2S H NAc is present in the range of 0.1-5 mole %; .DELTA.UH NAc,6s is present in the range of 0.1-15 mole %; or .DELTA.UH NAc,6S GH NS,3S,6S, .DELTA.UH NS,6S GH NS,3S,6S, .DELTA.UH NAc,6S GH NS,3S, .DELTA.UH NS,6s GH NS,3s or a mixture thereof is present in the range of 0.1-20 mole in the composition.
55. The method of claim 29 wherein the determining includes determining if .DELTA.U2S H NS,6S is present in the range of 45-80 mole %, 50-75 mole %, 55-mole %, or 60-65 mole %.
56. The method of claim 29 wherein the determining includes determining if .DELTA.U2S H NS is present in the range of 2-15 mole %, 5-10 mole %, or 6-9 mole %.
57. The method of claim 29 wherein the determining includes determining if .DELTA.UH NS,6S is present in the range of 5-18 mole %, 7-15 mole %, or 10-12 mole %.
58. The method of claim 29 wherein the determining includes determining if .DELTA.U2S H NAc,6S is present in the range of 0.5-7.5 mole %, 1-5 mole % or 1.5-3 mole %.
59. The method of claim 29 wherein the determining includes determining if .DELTA.UH NS is present in the range of 1-7 mole %, 2-5 mole % or 3-4 mole %.
60. The method of claim 29 wherein the determining includes determining if .DELTA.U2S H NAc is present in the range of 0.1-5 mole %, 0.5-3 mole % or 1-2.5 mole %.
61. The method of claim 29 wherein the determining includes determining if .DELTA.UH Nac,6S is present in the range of 0.1-12 mole %, 0.5-10 mole % or 1-6 mole %.
62. The method of claim 29 wherein the determining includes determining if .DELTA.UH NAc,6S GH NS,3S,6S;.DELTA.UH NS,6S GH NS,3S,6S;.DELTA.UH NAc,6S GH
NS,3S;
.DELTA.UH NS,6S GH NS,3S or a mixture thereof is present in the range of 1-15 mole %;
2-10 mole %; 3-8 mole %; or 5-7 mole %.
63. The method of claim 28 wherein the sample is derived from a human or veterinary subject, an experimental animal, a cell, or any commercially available preparation of polysaccharides, e.g., UFH or LMWH, e.g., enoxaparn.
64. The method of claim 63 wherein the commercially available preparation of polysaccharides is UFH or LMWH.
65. The method of claim 64 wherein the LMWH is enoxaparin, dalteparin, ardeparin, certoparin, parnaparin, tinzaparin, nadroparin, reviparin, or fondaparinux.
66. The method of claim 28 wherein the method includes monitoring the presence, tissue distribution, spatial distribution, temporal distribution or retention time, in a cell or a subject.
67. The method of claim 1 wherein the method includes determining the structural signature of one or more batches of a product.
68. The method of claim 67 further comprising selecting a batch as a result of the determination.
69. The method of claim 68 wherein the method further comprises comparing the results of the determination to preselected values, e.g., a reference standard.
70. The method of claim 1 further comprising detecting one or more biological activities of the sample.
71. The method of claim 70 wherein a biological activity to be measured includes effects on cellular activities such as undesired cell growth or proliferation;
cellular migration, adhesion, or activation; neovascularization; angiogenesis;
coagulation; HIT propensity; and inflammatory processes.
72. The method of claim 70 wherein the biological activity to be measured includes anti-Xa activity, anti-IIa activity, FGF binding, protamine neutralization, or PF4 binding.
73. The method of claim 70 further comprising correlating one or more biological activity to the structural signature of the sample.
74. The method of claim 70 further comprising creating a reference standard having information correlating the biological activity to the structural signature.
75. A method for predicting the level of activity of a LMWH preparation comprising the steps of:
a. Determining the structural signature of the LMWH preparation;
b. Comparing the determined structural signature to the reference standard of claim 74;
thereby predicting the level of activity of the LMWH preparation.
76. The method of claim 75 wherein the activity is chosen from the group consisting of effects on cellular activities such as cell growth or proliferation;
cellular migration, adhesion, or activation; neovascularization; angiogenesis;
coagulation; and inflammatory processes.
77. The method of claim 75 wherein the activity is chosen from the group consisting of anti-Xa activity, anti-IIa activity, FGF binding, protamine neutralization, or PF4 binding.
78. A method of analyzing a sample of a heparin having a selected biological activity, comprising the steps of a. providing the sample; and b. determining if a component known to be correlated with the selected activity is present in the sample;
thereby analyzing the sample.
79. The method of claim 78 further comprising determining the level of the component.
80. The method of claim 78 wherein the biological activity to be measured includes effects on cellular activities such as undesired cell growth or proliferation; cellular migration, adhesion, or activation;
neovascularization;
angiogenesis; coagulation; and inflammatory processes.
81. The method of claim 78 wherein the biological activity to be measured includes anti-Xa activity, anti-IIa activity, FGF binding, protamine neutralization, or PF4 binding.
82. The method of claim 78 wherein the presence of U2S H NS,6S is indicative of PF4 binding activity.
83. The method of claim 82 wherein U2S H NS,6S, is present in a range of 0.1-mole %,
84. The method of claim 78 wherein the presence of .DELTA.UH NAc,6S GH
NS,3S,6S
.DELTA.UH NS,6S GH NS,3S,6S;.DELTA.UH NAc,6S GH NS,3S; .DELTA.UH NS,6S GH
NS,3S or a mixture thereof is indicative of anti-Xa activity
85. The method of claim 84, wherein .DELTA.UH NAc,6S GH NS,3S,6S;.DELTA.UH
NS,6S GH NS,3S,6S;
.DELTA.UH NAc,6S GH NS,3S; .DELTA.NS,6S GH NS,3S or a mixture thereof is present in the range of 0.1-100 mole %.
86. The method of claim 78 wherein the sample is derived from a human or veterinary subject, an experimental animal, a cell, or any commercially available preparation of polysaccharides, e.g., UFH or LMWH, e.g., enoxapann.
87. The method of claim 86 wherein the human or veterinary subject is having, at risk for having, or recovering from a surgical intervention, for example, angioplasty, stmt placement, cardiopulmonary bypass procedure, tissue or organ transplant, coronary revascularization surgery, orthopedic surgery, treatment for a fracture such as a hip fracture, hip replacement, knee replacement, PCI, and prosthesis replacement surgery.
88. The method of claim 86 wherein the human or veterinary subject is a patient with abnormal renal function as measured by RFI, urea, creatinine, phosphorus, GFR or BUN levels in blood or GFR or urine.
89. The method of claim 86 wherein the human or veterinary subject has or is at risk for having complications associated with receiving heparin or LMWH.
90. The method of claim 89, wherein the complication associated with receiving heparin or LMWH is HIT.
91. The method of claim 86 wherein the human or veterinary subject is overweight or obese, for example a subject who is 20, 30, 40, 50 or more pounds overweight.
92. The method of claim 86 wherein the human or veterinary subject is extremely thin or frail, for example a subject who is 20, 30, 40, 50 or more pounds underweight, or who is suffering from an immune deficiency.
93. The method of claim 92, wherein the immune deficiency is HIV/AIDS.
94. The method of claim 86 wherein the human subject is a pediatric patient.
95. The method of claim 86 wherein the human or veterinary subject is pregnant.
96. The method of claim 86 wherein the human or veterinary subject is a patient having a spinal or epidural hematoma.
97. The method of claim 86 wherein the human subject is a patient with a prosthetic heart valve.
98. The method of claim 86 wherein the human or veterinary subject has an ATIII
deficiency or abnormality.
99. The method of claim 86 wherein the human or veterinary subject has a factor Xa deficiency or abnormality.
100. The method of claim 78 wherein the method further comprises monitoring for presence, tissue distribution, spatial distribution, temporal distribution or retention time, in a cell or a subject, e.g., an experimental animal.
101. The method of claim 78 wherein the method includes determining the structural signature of one or more batches of a product.
102. The method of claim 101 further comprising selecting a batch as a result of the determination.
103. The method of claim 78 wherein the method further comprises comparing the results of the determination to preselected values, e.g., a reference standard.
104. A method of analyzing a sample of LMWH comprising the steps of:
a. providing the sample; and b. determining if a non-natural sugar, e.g., a modified sugar, is present in the sample;
thereby analyzing the sample.
105. The method of claim 104 wherein the non-natural sugar is selected from the group consisting of p9, p10, and p11.
106. The method of claim 105 wherein the non-natural sugar comprises peak 9.
107. The method of claim 105 wherein the non-natural sugar comprises peak 10.
108. The method of claim 105 wherein the non-natural sugar comprises peak 11.
109. The method of claim 105 wherein the sample is derived from a human or veterinary subject, an experimental animal, a cell, or any commercially available preparation of polysaccharides, e.g., UFH or LMWH, e.g., enoxaparin.
110. The method of claim 109 wherein the human or veterinary subject is having, at risk for having, or recovering from a condition chosen from the group consisting of disease associated with coagulation, such as thrombosis, cardiovascular disease, vascular conditions or atrial fibrillation; migraine, atherosclerosis; an inflammatory disorder, such as autoimmune disease or atopic disorders; an allergy; a respiratory disorder, such as asthma, emphysema, adult respiratory distress syndrome (ARDS), cystic fibrosis, or lung reperfusion injury; a cancer or metastatic disorder; an angiogenic disorder, such as neovascular disorders of the eye, osteoporosis, psoriasis, and arthritis, Alzheimers', or is undergoing or having undergone surgical procedure, organ transplant, orthopedic surgery, treatment for a fracture such as a hip fracture, hip replacement, knee replacement, percutaneous coronary intervention (PCI), stent placement, angioplasty, coronary artery bypass graft surgery (CABG).
111. The method of claim 109 wherein the human or veterinary subject is a patient with abnormal renal function as measured by RFI, urea, creatinine, phosphorus, GFR or BUN levels in blood or urine.
112. The method of claim 109 wherein the human or veterinary subject has or is at risk for having complications associated with receiving heparin or LMWH, e.g., HIT.
113. The method of claim 109 wherein the human or veterinary subject is overweight or obese, for example a subject who is 20, 30, 40, 50 or more pounds overweight.
114. The method of claim 109 wherein the human or veterinary subject is extremely thin or frail, for example a, subject who is 20, 30, 40, 50 or more pounds underweight, or who is suffering from an immune deficiency, e.g., HIV/AIDS.
115. The method of claim 109 wherein the human subject is a pediatric patient.
116. The method of claim 109 wherein the human or veterinary subject is pregnant.
117. The method of claim 109 wherein the human or veterinary subject is a patient having a spinal or epidural hematoma.
118. The method of claim 109 wherein the human subject is a patient with a prosthetic heart valve.
119. The method of claim 104 wherein the method further comprises monitoring for presence, tissue distribution, spatial distribution, temporal distribution or retention time, in a cell or a subject.
120. The method of claim 104 wherein the method includes determining the structural signature of one or more batches of a product.
121. The method of claim 120 further comprising selecting a batch as a result of the determination.
122. The method of claim 121 wherein the method further comprises comparing the results of the determination to preselected values.
123. The method of claim 122, wherein the preselected value is a reference standard.
124. The method of claim 104 wherein the sample includes a population of polysaccharides wherein less than or equal to 20% are <2000 Da species, greater than or equal to 68% are 2000-8000 Da species, and less than or equal to 18% are >8000 Da species, or the same as is found in commercially available enoxaparin preparations, preferably with an average molecular weight of about 4500 Da.
125. The method of claim 104 wherein the sample has approximately 100 IU/mg anti-Xa activity.
126. The method of claim 104 wherein the sample has a pH of 5.5-7.5.
127. The method of claim 104 wherein one or more components of the sample is tagged or labeled.
128. A method of analyzing a sample or a subject the method comprising the steps of:
a. providing a sample;
b. determining if one or more components chosen from the group consisting of .DELTA.UH NAc,6S GH NS,3S,6S; .DELTA.UH NS,6S GH NS,3S,6S;
.DELTA.UH NAc,6S GH NS,3S; UH NS,6S GH NS,3S or a fragment or fragments thereof is present in the sample; and c. optionally, measuring the level of the component or components;
thereby monitoring the subject.
129. The method of claim 128, wherein the sample is from a subject.
130. The method of claim 129, wherein the subject is from a human or veterinary subject or an experimental animal.
131. The method of claim 128 wherein the method further comprises establishing a baseline prior to the subject receiving the heparin.
132. The method of claim 128 wherein the method further comprises determining if .DELTA.U2S H NS,6S;.DELTA.U2S H NS;.DELTA.UH NS,6S;.DELTA.U2S H
NAc,6S;.DELTA.UH NS;
.DELTA.U2S H NAc; or .DELTA.UH NAc,6S is present in the sample.
133. The method of claim 128 wherein the method further comprises determining if the components of one or more of peak 9, peak 10, or peak 11 is present in the sample.
134. The method of claim 128 wherein the heparin comprises UFH.
135. The method of claim 128 wherein the heparin comprises a LMWH.
136. The method of claim 128 wherein the heparin comprises a LMWH
having anti-Xa activity.
137. The method of claim 135 wherein the LMWH is chosen from the group consisting of M118, M115, M411, M108, M405, M312, enoxaparin;
dalteparin; certoparin; ardeparin; nadroparin; parnaparin; reviparin;
tinzaparin, or fondaparinux.
138. The method of claim 128 wherein the sample comprises a bodily fluid.
139. The method of claim 138 wherein the bodily fluid comprises blood or is blood-derived.
140. The method of claim 138 wherein the bodily fluid comprises urine.
141. The method of claim 128 wherein the method further comprises one or more repetitions of steps a through c at pre-selected intervals of time.
142. The method of claim 141, wherein the pre-selected interval of time is every two to twenty-four hours, every four to twelve hours, every six to ten hours, or continuous monitoring.
143. The method of claim 128 wherein the method further comprises monitoring for presence, tissue distribution, spatial distribution, temporal distribution or retention time, in a cell or a subject, e.g., an experimental animal.
144. The method of claim 128 wherein the method includes determining the structural signature of one or more batches of a product.
145. The method of claim 144 further comprising selecting a batch as a result of the determination.
146. The method of claim 128 wherein the method further comprises comparing the results of the determination to a preselected value.
147. The method of claim 146 wherein the preselected value is a reference standard.
148. The method of claim 128 wherein the determination comprises the steps of:
a. purifying the sample;
b. optionally fractionating the sample;
c. contacting the sample with at least one agent; and d. determining the structural signature of the digested sample.
149. The method of claim 148 wherein the agent is an enzyme.
150. The method of claim 149 wherein the enzyme is a heparin degrading enzyme.
151. The method of claim 150 wherein the heparin degrading enzyme is chosen from the group consisting of heparinase I, heparinase II, heparinase III, heparinase IV, heparanase and functionally active variants and fragments thereof.
152. The method of claim 151 wherein the agent is a chemical
153. The method of claim 152 wherein the agent is a chemical chosen from group consisting of H2O2, Cu+ and H2O2, isoamyl nitrite, nitrous acid, benzyl ester or alkaline treatment.
154. The method of claim 128 wherein the determining comprises the steps of:
a. optionally, purifying the sample b. contacting the sample with a reagent specific for one or more of the components; and c. detecting the binding of the antibody to the component, thereby determining the presence of the component.
155. The method of claim 154 wherein the reagent specific for one or more of the components is a peptide, protein, lectin, or antibody.
156. The method of claim 154 wherein the determination comprises determining if one or more components chosen from the group consisting of .DELTA.UH NAc,6S GH NS,3S,6S;.DELTA.UH NS,6S GH NS,3S,6S;.DELTA.UH NAc,6S GH
NS,3S;
.DELTA.UH NS,6S GH NS,3S or a fragment or fragments thereof is present in the range of 0.1-20 mole %.
157. The method of claim 130 wherein the human or veterinary subject is having, at risk for having, or recovering from a condition chosen from the group consisting of disease associated with coagulation, such as thrombosis, cardiovascular disease, vascular conditions or atrial fibrillation; migraine, atherosclerosis; an inflammatory disorder, such as autoimmune disease or atopic disorders; an allergy; a respiratory disorder, such as asthma, emphysema, adult respiratory distress syndrome (ARDS), cystic fibrosis, or lung reperfusion injury; a cancer or metastatic disorder; an angiogenic disorder, such as neovascular disorders of the eye, osteoporosis, psoriasis, and arthritis, Alzheimers', or is undergoing or having undergone surgical procedure, organ transplant, orthopedic surgery, treatment of a fracture including a hip fracture, hip replacement, knee replacement, percutaneous coronary intervention (PCI), stent placement, angioplasty, coronary artery bypass graft surgery (CABG).
158. The method of claim 130 wherein the human or veterinary subject is a patient with abnormal renal function as measured by RFI, urea, creatinine, phosphorus, GFR or BUN levels in blood or urine.
159. The method of claim 130 wherein the human or veterinary subject has or is at risk for having complications associated with receiving heparin or LMWH, e.g., HIT.
160. The method of claim 130 wherein the human or veterinary subject is overweight or obese, for example a subject who is 20, 30, 40, 50 or more pounds overweight.
161. The method of claim 130 wherein the human or veterinary subject is extremely thin or frail, for example a subject who is 20, 30, 40, 50 or more pounds underweight, or who is suffering from an immune deficiency, e.g., HIV/AIDS.
162. The method of claim 130 wherein the human subject is a pediatric patient.
163. The method of claim 130 wherein the human or veterinary subject is pregnant.
164. The method of claim 130 wherein the human or veterinary subject is a patient having a spinal or epidural hematoma.
165. The method of claim 130 wherein the human subject is a patient with a prosthetic heart valve.
166. The method of claim 116 wherein the sample includes a population of polysaccharides wherein less than or equal to 20% are <2000 Da species, greater than or equal to 68% are 2000-8000 Da species, and less than or equal to 18% are >8000 Da species, or the same as is found in commercially available enoxaparin preparations, preferably with an average molecular weight of about 4500 Da.
167. The method of claim 166 wherein the polysaccharides, e.g., LMWH, have approximately 100 IU/mg anti-Xa activity.
168. The method of claim 166 wherein the sample has a pH of 5.5-7.5.
169. The method of claim 128 wherein one or more components of the sample is tagged or labeled.
170. A method of analyzing a sample, the method comprising the steps of:
a. providing a sample; and b. determining if one or more structural signature outputs known to be associated with anti-IIa activity is present in the sample; and c. optionally, determining the level of the component or components;
thereby analyzing the sample or subject.
171. The method of claim 170, wherein the sample is from a subject.
172. ~The method of claim 171, wherein the subject is a human or veterinary subject, or an experimental animal.
173. The method of claim 170, wherein the subject is receiving a heparin having anti-IIa activity.
174. The method of claim 170 wherein the structural signature output associated with anti-IIa activity is a polysaccharide comprising at least one of .DELTA.UH NAc,6S GH NS,3S,6S, .DELTA.UH NS,6S GH NS,3S,6S, .DELTA.UH NAc,6S GH
NS,3S, or .DELTA.UH NS,6S GH NS,3S with one or more other disaccharide units.
175. The method of claim 170 wherein the method further comprises establishing a baseline for the component or components prior to the subject receiving the heparin.
176. The method of claim 170 wherein the method further comprises monitoring presence, tissue distribution, spatial distribution, temporal distribution or retention time, in a cell or a subject.
177. The method of claim 176, wherein the subject is an experimental animal.
178. The method of claim 170 wherein the method includes determining the structural signature of one or more batches of a product.
179. The method of claim 178 further comprising selecting a batch as a result of the determination.
180. The method of claim 170 wherein the method further comprises comparing the results of the determination to a preselected value.
181. The method of claim 179, wherein the preselected value is a reference standard.
182. The method of claim 170 wherein the heparin comprises UFH.
183. The method of claim 170 wherein the heparin comprises a LMWH.
184. The method of claim 170 wherein the heparin comprises a LMWH
having anti-IIa activity.
185. The method of claim 184 wherein the LMWH is chosen from the group consisting of M118, M115, M411, M108, M405, M312, enoxaparin;

dalteparin; certoparin; ardeparin; nadroparin; parnaparin; reviparin;
tinzaparin, and , fondaparinux.
186. The method of claim 170 wherein the sample comprises a bodily fluid.
187. The method of claim 186 wherein the bodily fluid comprises blood or is blood-derived.
188. The method of claim 186 wherein the bodily fluid comprises urine.
189. The method of claim 170 wherein the method further comprises one or more repetitions of steps a through c at pre-selected intervals of time.
190. The method of claim 189, wherein the pre-selected interval of time is every two to twenty-four hours, every four to twelve hours, every six to ten hours, or continuously.
191. The method of claim 170 wherein the determination comprises the steps of:
a. purifying the sample;
b. optionally, fractionating the sample;
c. contacting the sample with at least one agent;
d. determining the structural signature of the digested sample.
192. The method of claim 191 wherein the agent is an enzyme.
193. The method of claim 192 wherein the enzyme is a heparin degrading enzyme.
194. The method of claim 193 wherein the heparin degrading enzyme is chosen from the group consisting of heparinase I, heparinase II, heparinase III, heparinase IV, heparanase and functionally active variants and fragments thereof.
195. The method of claim 191 wherein the agent is a chemical, e.g., a chemical chosen from group consisting of oxidative depolymerization with H2O2 or Cu+ and H2O2, deaminative cleavage with isoamyl nitrite, or nitrous acid, .beta.-eliminative cleavage with benzyl ester of heparin by alkaline treatment or by heparinase.
196. The method of claim 191 wherein the determining comprises the steps of:

a. optionally purifying the sample b. contacting the sample with an antibody specific for one or more of the components; and c. detecting the binding of the antibody to the component, d. thereby determining the presence of the component.
197. The method of claim 191 wherein the human or veterinary subject is having, at risk for having, or recovering from a condition chosen from the group consisting of disease associated with coagulation, such as thrombosis, cardiovascular disease, vascular conditions or atrial fibrillation; migraine, atherosclerosis; an inflammatory disorder, such as autoimmune disease or atopic disorders; an allergy; a respiratory disorder, such as asthma, emphysema, adult respiratory distress syndrome (ARDS), cystic fibrosis, or lung reperfusion injury; a cancer or metastatic disorder; an angiogenic disorder, such as neovascular disorders of the eye, osteoporosis, psoriasis, and arthritis, Alzheimers', or is undergoing or having undergone surgical procedure, organ transplant, orthopedic surgery, treatment for a fracture such as a hip fracture, hip replacement, knee replacement, percutaneous coronary intervention (PCI), stent placement, angioplasty, coronary artery bypass graft surgery (CABG).
198. The method of claim 191 wherein the human or veterinary subject is a patient with abnormal renal function as measured by RFI, urea, creatinine, phosphorus, GFR or BUN levels in blood or urine.
199. The method of claim 191 wherein the human or veterinary subject has or is at risk for having complications associated with receiving heparin or LMWH, e.g., HIT.
200. The method of claim 191 wherein the human or veterinary subject is overweight or obese, for example a subject who is 20, 30, 40, 50 or more pounds overweight.
201. The method of claim 191 wherein the human or veterinary subject is extremely thin or frail, for example a subject who is 20, 30, 40, 50 or more pounds underweight, or who is suffering from an immune deficiency, e.g., HIV/AIDS.
202. The method of claim 191 wherein the human subject is a pediatric patient.
203. The method of claim 191 wherein the human or veterinary subject is pregnant.
204. The method of claim 191 wherein the human or veterinary subject is a patient having a spinal or epidural hematoma.
205. The method of claim 191 wherein the human subject is a patient with a prosthetic heart valve.
206. The method of claim 191 wherein the method further comprises monitoring for presence, tissue distribution, spatial distribution, temporal distribution or retention time, in a cell or a subject, e.g., an experimental animal.
207. The method of claim 191 wherein the method includes determining the structural signature of one or more batches of a product.
208. The method of claim 207 further comprising selecting a batch as a result of the determination.
209. The method of claim 191 wherein the method further comprises comparing the results of the determination to preselected values.
210. The method of claim 209, wherein the preselected value is a reference standard.
211. The method of claim 191 wherein the sample includes a population of polysaccharides wherein less than or equal to 20% are <2000 Da species, greater than or equal to 68% are 2000-8000 Da species, and less than or equal to 18% are >8000 Da species, or the same as is found in commercially available enoxaparin preparations, preferably with an average molecular weight of about 4500 Da.
212. The method of claim 211 wherein the polysaccharides, e.g., LMWH, have approximately 100 IU/mg anti-Xa activity.
213. The method of claim 211 wherein the sample has a pH of 5.5-7.5.
214.~ The method of claim 191 wherein one or more components of the sample is tagged or labeled.
215. ~ A method of analyzing a sample or a subject, the method comprising the steps of:
a. providing a sample; and b. determining if one or more non-natural sugars, e.g., modified sugars, is present in the sample; and c. optionally, determining the level of the non-natural sugar;
thereby monitoring the subject.
216. ~ The method of claim 215, wherein the analyzing is monitoring a LMWH in sample or a subject.
217. The method of claim 215, wherein the sample is from a subject.
218. The method of claim 217, wherein the subject is a human or veterinary subject or an experimental animal
219. The method of claim 216 wherein the LMWH is enoxaparin.
220. The method of claim 215 wherein the non-natural sugars are benzylated.
221. The method of claim 215 wherein the non-natural sugars comprise one or more of peaks 9 and 10.
222. The method of claim 215 wherein the sample comprises a bodily fluid.
223. The method of claim 222wherein the bodily fluid comprises blood or is blood-derived.
224. The method of claim 222 wherein the bodily fluid comprises urine.
225. The method of claim 215 wherein the method further comprises one or more repetitions of steps a through c at pre-selected intervals of time.
226. The method of claim 215 wherein the determination comprises the steps of:
a. purifying the sample;
b. optionally fractionating the sample;
c. contacting the sample with at least one agent; and d. determining a physicochemical property of the digested sample, e.g., molecular weight.
227. The method of claim 226 wherein the agent is an enzyme.
228. The method of claim 227 wherein the enzyme is a heparin degrading enzyme.
229. The method of claim 228 wherein the heparin degrading enzyme is chosen from the group consisting of heparinase I, heparinase II, heparinase III, heparinase IV, heparanase and functionally active variants and fragments thereof.
230. The method of claim 226 wherein the agent is a chemical, e.g., a chemical chosen from group consisting of oxidative depolymerization with H2O2 or Cu+ and H2O2, deaminative cleavage with isoamyl nitrite, or nitrous acid, .beta.-eliminative cleavage with benzyl ester of heparin by alkaline treatment or by heparinase.
231. The method of claim 215 wherein the determining comprises the steps of:
a. optionally purifying the sample b. contacting the sample with an antibody specific fox one or more of the components; and c. detecting the binding of the antibody to the component, d. thereby determining the presence of the component.
232. The method of claim 215 wherein the human or veterinary subject is having, at risk for having, or recovering from a condition chosen from the group consisting of disease associated with coagulation, such as thrombosis, cardiovascular disease, vascular conditions or atrial fibrillation; migraine, atherosclerosis; an inflammatory disorder, such as autoimmune disease or atopic disorders; an allergy; a respiratory disorder, such as asthma, emphysema, adult respiratory distress syndrome (ARDS), cystic fibrosis, or lung reperfusion injury; a cancer or metastatic disorder; an angiogenic disorder, such as neovascular disorders of the eye, osteoporosis, psoriasis, and arthritis, Alzheimers', or is undergoing or having undergone surgical procedure, organ transplant, orthopedic surgery, treatment for a fracture such as a hip fracture, hip replacement, knee replacement, percutaneous coronary intervention (PCI), stent placement, angioplasty, coronary artery bypass graft surgery (CABG).
233.~ The method of claim 215 wherein the human or veterinary subject is a patient with abnormal renal function as measured by RFI, urea, creatinine, phosphorus, GFR or BUN in blood or urine.
234.~ The method of claim 215 wherein the human or veterinary subject has or is at risk for having complications associated with receiving heparin or LMWH, e.g., HIT.
235.~ The method of claim 215 wherein the human or veterinary subject is overweight or obese, for example a subject who is 20, 30, 40, 50 or more pounds overweight.
236.~ The method of claim 215 wherein the human or veterinary subject is extremely thin or frail, for example a subject who is 20, 30, 40, 50 or more pounds underweight, or who is suffering from an immune deficiency.
237.~ The method of claim 236, wherein the immune deficiency is HIV/AIDS.
238.~ The method of claim 215 wherein the human subject is a pediatric patient.
239.~ The method of claim 215 wherein the human or veterinary subject is pregnant.
240. The method of claim 215 wherein the human or veterinary subject is a patient having a spinal or epidural hematoma.
241. The method of claim 215 wherein the human subject is a patient with a prosthetic heart valve.
242. The method of claim 215 wherein the method further comprises monitoring for presence, tissue distribution, spatial distribution, temporal distribution or retention time, in a cell or a subject, e.g., an experimental animal.
243.~ The method of claim 215 wherein the method includes determining the structural signature of one or more batches of a product.
244.~ The method of claim 243 further comprising selecting a batch as a result of the comparison.
245.~ The method of claim 215 wherein the method further comprises comparing the results of the determination to preselected value.
246. The method of claim 245, wherein the preselected value is a reference standard.
247. The method of claim 215 wherein the sample includes a population of polysaccharides wherein less than or equal to 20% are <2000 Da species, greater than or equal to 68% are 2000-8000 Da species, and less than or equal to 18% are >8000 Da species, or the same as is found in commercially available enoxaparin preparations, preferably with an average molecular weight of about 4500 Da.
248.~ The method of claim 247 wherein the polysaccharides, e.g., LMWH, have approximately 100 IU/mg anti-Xa activity.
249. The method of claim 247 wherein the sample has a pH of 5.5-7.5.
250. The method of claim 215 wherein one or more component of the sample is tagged or labeled.
251. A LMWH composition comprising a tag.
252. The composition of claim 251 wherein the tag emits detectable electromagnetic radiation.
253. The composition of claim 251 wherein the tag is chosen from the group consisting of a fluorescent label, a mass-label compatible with mass-spectrometric methods, O18, yttrium, 3H, affinity label, pH sensitive label, and radioactive label.
254. A method of evaluating a sample for the presence of a LMWH
comprising a tag comprising the steps of a. providing a sample;
b. optionally purifying the sample; and c. determining the presence of the tag in the sample, thereby evaluating the presence of the LMWH in the sample.
255. The method of claim 254 further comprising the step of determining the level of the tag.
256. The method of claim 254 wherein the sample is from a subject, e.g., a human or veterinary subject or an experimental animal, receiving the LMWH
comprising a tag.
257. The method of claim 254 wherein the LMWH is chosen from the group consisting of M118, M115, M411, M108, M405, M312, enoxaparin;
dalteparin; certoparin; ardeparin; nadroparin; parnaparin; reviparin;
tinzaparin, and , fondaparinux.
258. The method of claim 254 wherein the sample is a bodily fluid
259. The method of claim 258 wherein the bodily fluid is chosen from group consisting of blood, blood plasma, and urine.
260. A kit for performing the method of claim 254 which includes one or more of the following: a tag; a compound for attaching the tag to a polysaccharide, and a standard, e.g., a polysaccharide or a tagged polysaccharide.
261. A LMWH preparation having an increased or decreased ratio of anti-IIa activity and anti-Xa activity.
262. A method of producing a LMWH preparation having or not having a pre-selected biological activity, the method comprising the steps of:
a. providing one or more aliquots of heparin;
b. optionally fractionating the heparin;
c. modifying the aliquots of heparin under conditions designed to produce the activity; and d. optionally purifying the digested aliquots.
263. The method of claim 262 wherein the desired biological activity is chosen from the group consisting of effects on cellular activities such as cell growth or proliferation; cellular migration, adhesion, or activation;
neovascularization; angiogenesis; coagulation; and inflammatory processes.
264. The method of claim 262 wherein the desired biological activity is anti-IIa activity; anti-Xa activity; platelet factor 4 binding; FGF binding;
or sensitivity to neutralization with protamine.
265. The method of claim 262 wherein the desired biological activity is anti-IIa activity and anti-Xa activity.
266. The method of claim 262 wherein the modifying is performed by chemically or enzymatically digesting the FH or UFH.
267. The method of claim 266 wherein the enzymatic digestion is carried out using one or more heparin degrading enzymes.
268. The method of claim 267 wherein the heparin degrading enzyme is chosen from the group consisting of heparinase I, heparinase II, heparinase III, heparinase IV, heparanase and functionally active variants and fragments thereof.
269. The method of claim 266 wherein the chemical digestion is carried out by a chemical chosen from the group consisting of oxidative depolymerization with H2O2 or Cu+ and H2O2, deaminative cleavage with isoamyl nitrite, or nitrous acid, .beta.-eliminative cleavage with benzyl ester of heparin by alkaline treatment or by heparinase
270. A LMWH preparation prepared by the method of claim 262.
271. A LMWH preparation having anti-IIa activity and anti-Xa activity prepared by the method of claim 262.
272. The method of claim 262 further comprising testing the LMWH
preparation for the desired biological activity.
273. A panel of two or more LMWH preparations having different ratios of anti-IIa activity and anti-Xa activity.
274. A method of treating a subject, comprising a. providing a panel of two or more LMWH preparations having different ratios of anti-IIa activity and anti-Xa activity;
b. selecting a LMWH preparation having a desired ratio; and c. administering one or more doses of a therapeutically effective amount of the LMWH preparation to the subject.
275. The method of claim 274, wherein the subject is a human or veterinary subject.
276. The method of claim 274 further comprising monitoring the levels of LMWH in the subject.
277. The method of claim 274 further comprising repeatedly monitoring the levels of LMWH in the subject over time.
278. The method of claim 274 further comprising adjusting the doses of the LMWH preparation.
279. The method of claim 274 wherein the method further comprises monitoring the status of the subject in response to the administration of the LMWH preparation.
280. The method of claim 274 further comprising monitoring the status of the subject over a period of time.
281. The method of claim 274 further comprising administering a different LMWH preparation based on changes in the status of the subject over time.
282. A method of inhibiting coagulation in a patient, comprising administering one or more doses of a therapeutic amount of a LMWH
preparation of claim 244 having high anti-Xa and anti-IIa activity, monitoring the status of the subject, then administering one or more doses of a therapeutic amount of a LMWH preparation of claim 244 having high anti-Xa activity alone.
283. The method of claim 274 further comprising providing or determining the structural signature of the LMWH preparation.
284. The method of claim 283 further comprising correlating the status of the subject to the structural signature of the LMWH.
285. A method of treating a subject who has previously been diagnosed with HIT, comprising administering to the subject a therapeutically effective dose of a composition of claim 274 having decreased PF4 binding activity.
286. A LMWH composition having both anti-Xa and anti-IIa activity comprising less than or equal to 20% <2000 Da species, greater than or equal to 68% 2000-8000 Da species, and less than or equal to 18% >8000 Da species, preferably with an average molecular weight of about 4500 Da, wherein the anti-Xa activity is >50% neutralizable by protamine and the anti-IIa activity is >70% neutralizable by protamine.
287. The LMWH composition of claim 286 having approximately 100 Iu/mg anti-Xa activity.
288. The LMWH composition of claim 286 having a pH of 5.5-7.5.
289. The LMWH composition of claim 286 comprising .DELTA.U2S H NS,6S in the range of 15-85 mole %; .DELTA.U2S H NS in the range of 0.1-20 mole %;
.DELTA.UH NS,6S in the range of 0.1-20 mole %; .DELTA.U2S H NAc,6S in the range of 0.1-10 mole %;
.DELTA.UH NS in the range of 0.1-10 mole %; .DELTA.U2S H NAc in the range of 0.1-5 mole %; .DELTA.UH NAc,6S in the range of 0.1-15 mole %; and .DELTA.UH NAc,6S GH
NS,3S,6S in the range of 0.1-20 mole %.
290. The LMWH composition of claim 286 that is free of or substantially free of non-natural sugars.
291. The LMWH composition of claim 286 further comprising greater than 30 IU/mg anti-IIa activity.
292. A LMWH that is substantially free of non-natural sugars and comprising less than or equal to 20% <2000 Da species, greater than or equal to 68% 2000-8000 Da species, and less than or equal to 18% >8000 Da species, preferably with an average molecular weight of about 4500 Da.
293. The LMWH composition of claim 292 having approximately 100 IU/mg anti-Xa activity.
294. The LMWH composition of claim 292 having a pH of 5.5-7.5.
295. The LMWH composition of claim 292 comprising .DELTA.U2S H NS,6S in the range of 15-85 mole %; .DELTA.U2S H NS in the range of 0.1-20 mole %;
.DELTA.UH NS,6S in the range of 0.1-20 mole %; .DELTA.U2S H NAc,6S in the range of 0.1-10 mole %;
.DELTA.UH NS in the range of 0.1-10 mole %; .DELTA.U2S H NAc in the range of 0.1-5 mole %; .DELTA.UH NAc,6S in the range of 0.1-15 mole %; and .DELTA.UH NAc,6S GH
NS,3S,6S in the range of 0.1-20 mole %.
296. The LMWH composition of claim 292 further comprising greater than 30 IU/mg anti-IIa activity.
297. A LMWH which, as compared with enoxaparin, is enriched in non-natural sugars and comprising less than or equal to 20% <2000 Da species, greater than or equal to 68% 2000-8000 Da species, and less than or equal to 18% >8000 Da species, preferably with an average molecular weight of about 4500 Da.
298. The LMWH of claim 297 which, as compared with enoxaparin has 5%, 10%, or 20% more non-natural sugars.
299. The LMWH of claim 298, wherein the non-natural sugars are the sugars associated with peaks 9 or 10.
300. The LMWH composition of claim 297 having approximately 100 IU/mg anti-Xa activity.
301. The LMWH composition of claim 297 having a pH of 5.5-7.5.
302. The LMWH composition of claim 297 comprising .DELTA.U2S H NS,6S in the range of 15-85 mole %; .DELTA.U2s H NS in the range of 0.1-20 mole %;
.DELTA.UH NS,6S in the range of 0.1-20 mole %; .DELTA.U2S H NAc,6s in the range of 0.1-10 mole %;
.DELTA.UH NS in the range of 0.1-10 mole %; .DELTA.U2S H NAc in the range of 0.1-5 mole %; .DELTA.U H NAc,6S in the range of 0.1-15 mole %; and .DELTA.UH NAc,6S GH
NS,3S,6S in the range of 0.1-20 mole %.
303. The LMWH composition of claim 297 further comprising greater than 30 IU/mg anti-IIa activity.
304. A method of making one or more batches of a LMWH preparation which has a batch-to-batch variation of a preselected range from a preselected value for one or more component saccharide chosen from the group consisting of .DELTA.U2SH NS,6S; .DELTA.U2S H NS; .DELTA.UH NS,6S; .DELTA.U2S H NAC,6S;
.DELTA.UH NS; .DELTA.U2S H NAC;
.DELTA.UH NAc,6S; and .DELTA.UH NAc,6S GH NS,3S,6S the method comprising the steps of a. selecting a desired value;
b. providing an aliquot of UFH;
c. optionally fractionating the aliquot;
d. determining the level of the component in the aliquot; and e. selecting a batch or batches with less than the preselected range of variation from the desired value.
305. The method of claim 304 wherein the preselected variation is less than 2.5%, more preferably less than 2% or less than 1%.
306. The method of claim 304 wherein the preselected variation for p1 is less than 3%, less than 2%, or less than 1%.
307. The method of claim 304 wherein the preselected variation for p2 is less than 16%, less than 15%, less than 11%, less than 10%, less than 5%, less than 1 %.
308. The method of claim 304 wherein the preselected variation for p3 is less than 8%, less than 4%, less than 2%, less than 1%.
309. The method of claim 304 wherein the preselected variation for p4 is less than 22%, less than 15%, less than 10%, less than 5%, less than 1%.
310. The method of claim 304 wherein the preselected variation for p5 is less than 3%, less than 2%, or less than 1%.
311. The method of claim 304 wherein the preselected variation for p6 is less than 10%, less than 5%, less than 2%, less than 1%.
312. The method of claim 304 wherein the preselected variation for p7 is less than 90%, less than 75%, less than 50%, less than 25%, less than 10%, less than 5%.
313. The method of claim 304 wherein the preselected variation for p8 is less than 12%, less than 10%, less than 8%, less than 5%, less than 4%, less than 2%.
314. A method of making one or more batches of a LMWH preparation which has a batch-to-batch variation of less than a preselected range from a preselected value, e.g., less than 2.5%, more preferably less than 2% or less than 1 %, for one or more component saccharide chosen from the group consisting of p1-p8, the method comprising the steps of:
a. selecting a value;
b. providing an aliquot of UFH or LMWH;
c. precipitating the aliquot d. optionally subjecting the aliquot to an ion exchange process e. contacting the aliquot with an agent under conditions such that the desired value will result.
315. The method of claim 314 wherein the agent is a heparin degrading enzyme chosen from the group consisting of heparinase I, heparinase II, heparinase III, and functionally active variants and fragments thereof.
316. The method of claim 314 wherein the agent is a chemical.
317. The method of claim 316 wherein the chemical is chosen from the group consisting of H2O2, Cu+ and H2O2, isoamyl nitrite, nitrous acid, benzyl ester or alkaline treatment.
318. A composition comprising multiple batches of a LMWH preparation, wherein, for each of the batches, the mole % of one or more component chosen from the group consisting of p1-p8 varies less than a preselected variation,
319. The composition of claim 318 wherein the preselected variation is less than 2.5%, less than 2% or less than 1%.
320. A composition comprising multiple batches of a LMWH preparation, wherein the glycoprofile of each of the batches for one or more component chosen from the group consisting of p9-p10 varies less than a preselected variation.
321. The composition of claim 320 wherein the preselected variation is less than 2.5%, less than 2% or less than 1%.
322. A composition comprising multiple batches of a LMWH preparation prepared by the method of claim 281.
323. A composition comprising a LMWH preparation prepared by the method of claim 314.
324. A record having an element which identifies a polysaccharide an element which identifies one or more components of the polysaccharide, and an element which identifies a range of mole % of the components.
325. The method of claim 324, wherein the record is a computer readable record.
326. The method of claim 324, wherein the polysaccharide is UFH or LMWH.
327. A method for determining the safety or suitability of a heparin for use in a particular indication, comprising the steps of:
a. providing the structural signature of the heparin;
b. providing a reference structural signature;
c. determining if the heparin is acceptable.
328. The method of claim 327, wherein the determining if the heparin is acceptable is by comparing the structural signature of the heparin with the reference structural signature; where a preselected index of similarity is met, the heparin is safe or suitable.
329. The method of claim 327, wherein the reference structural signature is associated with one or more undesired effects.
330. The method of claim 327, wherein the reference structural signature is associated with one or more desired effects.
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