CA2326720A1 - Hemoglobin-haptoglobin complexes - Google Patents

Hemoglobin-haptoglobin complexes Download PDF

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Publication number
CA2326720A1
CA2326720A1 CA002326720A CA2326720A CA2326720A1 CA 2326720 A1 CA2326720 A1 CA 2326720A1 CA 002326720 A CA002326720 A CA 002326720A CA 2326720 A CA2326720 A CA 2326720A CA 2326720 A1 CA2326720 A1 CA 2326720A1
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CA
Canada
Prior art keywords
complex
construct
hemoglobin
modifying substance
cross
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Granted
Application number
CA002326720A
Other languages
French (fr)
Other versions
CA2326720C (en
Inventor
Jolanta Maria Wodzinska
Marie Sylvie Celine Moore
Gordon J. Adamson
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Therapure Biopharma Inc
Original Assignee
Individual
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Priority claimed from CA002236344A external-priority patent/CA2236344A1/en
Application filed by Individual filed Critical Individual
Priority to CA2326720A priority Critical patent/CA2326720C/en
Publication of CA2326720A1 publication Critical patent/CA2326720A1/en
Application granted granted Critical
Publication of CA2326720C publication Critical patent/CA2326720C/en
Anticipated expiration legal-status Critical
Expired - Fee Related legal-status Critical Current

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/62—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being a protein, peptide or polyamino acid
    • A61K47/64—Drug-peptide, drug-protein or drug-polyamino acid conjugates, i.e. the modifying agent being a peptide, protein or polyamino acid which is covalently bonded or complexed to a therapeutically active agent
    • A61K47/6445—Haemoglobin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/62—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being a protein, peptide or polyamino acid
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents

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  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Public Health (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Epidemiology (AREA)
  • Molecular Biology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Organic Chemistry (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Medicinal Preparation (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

Construct-complexes of a hemoglobin, a hepatocyte modifying substance bound to the hemoglobin, and a haptoglobin bound to the hemoglobin, are provided, for administration to mammalian patients. The construct-complex may be formed before administration, or a hemoglobin-hepatocyte modifying substance combination may be administered to the patient so that haptoglobin in the mammalian body bonds thereto to form the construct-complex in vivo. Disorders of the liver may be diagnosed and treated using construct-complexes described herein.

Claims (22)

1. A hemoglobin construct-complex comprising a non-cross-linked hemoglobin capable of binding to haptoglobin and a hepatocyte modifying substance bound to the hemoglobin.
2. The construct-complex of claim 1 further including haptoglobin bound to the hemoglobin portion thereof.
3. The constrict-complex of claim 2 formed in vivo by administering to a mammalian patient the construct-complex of non-cross-linked hemoglobin and hepatocyte modifying substance bound thereto according to claim 1.
4. The construct-complex of claim 2 formed ex vivo by reaction of the hepatocyte modifying substance with non-cross-linked hemoglobin and by reaction of haptoglobin with the non-cross-linked hemoglobin.
5. A synthetic, ex vivo prepared construct-complex comprising hemoglobin, haptoglobin bound to the hemoglobin, and a hepatocyte modifying substance also bound to the hemoglobin.
6. The construct-complex of claim 5 represented by the general formula:
(Hp)a - (Hb)b - (L c - A d) c where a - 1 to about 10:
b = 0.5 to about 10:
c = 0 to about 10;
d = 1 to about 20;
e = 1 to about 20:
Hp is haptoglobin;
Hb is a hemoglobin:
L is a linker as described herein;
and A is a hepatocyte modifying agent as described herein, in which the stoichiometry of Hp to Hb in the complex is from about 1:0,5 to 1:2.
7. The construct-complex of any preceding claim wherein the hepatocyte modifying substance is bound to the hemoglobin through the intermediary of a chemical linker.
8. The construct-complex of any preceding claim wherein the hepatocyte modifying substance is an agent capable of interacting with hepatocytes and consequently capable of acting in vivo at the liver of a mammalian patient, and selected from therapeutic agents, diagnostic agents and markers.
9. The construct-complex of claim 8 wherein the hepatocyte modifying substance is a therapeutic agent selected from antineoplastic substances, antiviral substances, anti-inflammatory substances, anti-parasitic substances, anti-microbial substances, antioxidant substances, hepatoprotective agents, cytoprotective agents, fibrosis-affecting agents, nucleic acids, lipid matabolism agents, anti-toxicants, proteins and enzymes.
10. The construct-complex of claim 9 wherein the hepatocyte modifying substance is a nucleic acid.
11. The construct-complex of claim 10 wherein the hepatocyte modifying substance is a gene coding for a protein of interest.
12. The construct-complex of claim 9 wherein the hepatocyte modifying substance is putrescine.
13. The construct-complex of claim 9 wherein the hepatocyte modifying substance is primaquine.
14. The construct-complex of claim 8 wherein the hegatocyte modifying substance is a diagnostic agent.
15. The construct-complex of claim 14 wherein the diagnostic compound is a radiolabelled compound or a fluorescent compound.
16. The construct-complex of any of claim 3, claim 6 or claims 7-15 as appendant to claim 5 or claim 6 wherein the hemoglobin is an intramolecularly cross-linked human hemoglobin.
17. The construct-complex of claim 16 wherein the hemoglobin is intramolecularly cross-linked with a cross-linking reagent which leaves residual chemical groups available for subsequent reaction with the hepatocyte modifying agent either directly or through the intermediary of a chemical linker group.
18. The construct-complex of claim 17 wherein the cross-linking reagent is a trifunctional reagent which utilizes two of its functional groups for intramolecular cross-linking of hemoglobin and leaves its third functional group available for reaction with a nucleophile.
19. The construct complex of claim 18 wherein the cross-linking reagent is trimesoyl tris(3,5-dibromosalicylate).
20. Use, in the preparation of a medicament for treating hepatic disorders in a mammalian patient, of a construct-complex as defined in any of the preceding claims.
21. Use in the preparation of a medicament for diagnosis of hepatic disorders in a mammalian patient, of a construct-complex as defined in any of claims 1-19.
22. Use, in the preparation of a medicament for treating metastatic cells carrying a haptoglobin receptor, in a mammalian patient, of a construct-complex as defined in any of claims 1-19.
CA2326720A 1998-04-30 1999-04-30 Hemoglobin-haptoglobin complexes Expired - Fee Related CA2326720C (en)

Priority Applications (1)

Application Number Priority Date Filing Date Title
CA2326720A CA2326720C (en) 1998-04-30 1999-04-30 Hemoglobin-haptoglobin complexes

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
CA002236344A CA2236344A1 (en) 1998-04-30 1998-04-30 Hemoglobin-haptoglobin complexes
CA2,236,344 1998-04-30
CA2326720A CA2326720C (en) 1998-04-30 1999-04-30 Hemoglobin-haptoglobin complexes
PCT/CA1999/000396 WO1999056723A2 (en) 1998-04-30 1999-04-30 Hemoglobine-haptoglobin complexes for targeted drug delivery

Publications (2)

Publication Number Publication Date
CA2326720A1 true CA2326720A1 (en) 1999-11-11
CA2326720C CA2326720C (en) 2010-12-07

Family

ID=25680178

Family Applications (1)

Application Number Title Priority Date Filing Date
CA2326720A Expired - Fee Related CA2326720C (en) 1998-04-30 1999-04-30 Hemoglobin-haptoglobin complexes

Country Status (1)

Country Link
CA (1) CA2326720C (en)

Also Published As

Publication number Publication date
CA2326720C (en) 2010-12-07

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Effective date: 20190430