Methods to mobilize progenitor/stem cells

• US 6,987,102 B2
• Filed: 07/30/2002
• Issued: 01/17/2006
• Est. Priority Date: 07/31/2001
• Status: Expired due to Term

• Current Assignee: Genzyme Corporation (Sanofi )
• Original Assignee: AnorMED, Inc. (Sanofi )
• Inventors: Dale, David C., Abrams, Michael J., Bridger, Gary J., Calandra, Gary B., Broxmeyer, Hal E., MacFarland, Ronald Trevor, Henson, Geoffrey W.
• Primary Examiner(s): Campell, Bruce R.
• Assistant Examiner(s): Kosar, Andrew D.
• Application Number:
  US10/209,001
• Publication Number:
  US 20030130250A1
• Time in Patent Office: 1,267 Days
• Field of Search: 514/183, 540/473, 540/474
• US Class Current: 514/183
• CPC Class Codes: A61K 2035/124 the cells being hematopoietic, bone marrow derived or blood cells
• 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 31/33 Heterocyclic compounds
• CPC Class Codes: A61K 31/395 having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
• CPC Class Codes: A61K 31/4427 containing further heterocyclic ring systems
• CPC Class Codes: A61K 31/496 Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
• CPC Class Codes: A61K 31/55 having seven-membered rings, e.g. azelastine, pentylenetetrazole
• CPC Class Codes: A61K 31/551 having two nitrogen atoms, e.g. dilazep
• CPC Class Codes: A61K 31/555 containing heavy metals, e.g. hemin, hematin, melarsoprol
• CPC Class Codes: A61K 35/28 Bone marrow; Haematopoietic stem cells; Mesenchymal stem cells of any origin, e.g. adipose-derived stem cells
• CPC Class Codes: A61K 38/193 Colony stimulating factors [CSF]
• CPC Class Codes: A61K 38/195 Chemokines, e.g. RANTES
• CPC Class Codes: A61P 17/02 for treating wounds, ulcers, burns, scars, keloids, or the like
• CPC Class Codes: A61P 31/04 Antibacterial agents
• CPC Class Codes: A61P 31/12 Antivirals
• CPC Class Codes: A61P 35/02 specific for leukemia
• CPC Class Codes: A61P 37/00 Drugs for immunological or allergic disorders
• CPC Class Codes: A61P 37/04 Immunostimulants
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: A61P 7/00 Drugs for disorders of the blood or the extracellular fluid
• CPC Class Codes: A61P 7/06 : Antianaemics
• CPC Class Codes: A61P 9/00 : Drugs for disorders of the cardiovascular system
• CPC Class Codes: C12N 5/0647 : Haematopoietic stem cells; Uncommitted or multipotent progenitors

Abstract

Certain nitrogen-containing compounds that bind the chemokine receptor CXCR4 are able to mobilize progenitor and/or stem cells into the peripheral blood to permit harvesting them for stem cell transplantation.

Claims

1. A method to obtain progenitor and/or stem cells from a subject

which method comprises

(a) administering to said subject a compound of the formula

Z-linker-Z′

 

 

(1)

or pharmaceutically acceptable salt or prodrug form thereof

wherein Z is a cyclic polyamine containing 9–

32 ring members of which 2–

8 are nitrogen atoms, said nitrogen atoms separated from each other by at least 2 carbon atoms, and wherein said heterocycle may optionally contain additional heteroatoms besides nitrogen and/or may be fused to an additional ring system;

or Z is of the formula

wherein A comprises a monocyclic or bicyclic fused ring system containing at least one N and B is H or an organic moiety of 1–

20 atoms,

Z′

is either embodied in a form as defined by Z above, or is of the formula

—

N(R)—

(CR₂)_n—

X

wherein each R is independently H or straight, branched or cyclic alkyl (1–

6C), n is 1 or 2, and X is an aromatic ring, including heteroaromatic rings, or is a mercaptan;

“

linker”

represents a bond, alkylene (1–

6C) or may comprise aryl, fused aryl, and/or oxygen atoms contained in an alkylene chain, and/or may contain keto groups and/or nitrogen or sulfur atoms;

in an amount effective to mobilize said progenitor and/or stem cells into the peripheral blood of said subject;

followed by

(b) harvesting said progenitor and/or stem cells by apheresis.

2. The method of claim 1 wherein Z and Z′

are both cyclic polyamines.

3. The method of claim 1 wherein Z and Z′

are identical.

4. The method of claim 1 wherein Z is a cyclic polyamine that contains 10–

24 members and contains 4 nitrogen atoms.

5. The method of claim 3 wherein Z and Z′

are both 1,4,8,11-tetraazocyclotetradecane.

6. The method of claim 1 wherein the linker comprises an aromatic ring bracketed by two methylene moieties.

7. The method of claim 6 wherein the linker is 1,4-phenylene-bis-methylene.

8. The method of claim 7 wherein the compound of formula (1) is 1,1′

-[1,4-phenylene-bis-(methylene)]-bis-1,4,8,11-tetraazacyclotetradecane.

9. The method of claim 1 wherein

Z is of the formula

wherein A comprises a monocyclic or bicyclic fused ring system containing at least one N and B is H or an organic moiety of 1–

20 atoms.

10. The method of claim 1 wherein formula (1) is in the form of its acid addition salt.

11. The method of claim 10 wherein the acid addition salt is hydrochloride.

12. The method of claim 1 wherein the compound is administered to said subject by an intravenous or subcutaneous route.

13. The method of claim 1 wherein the compound of formula (1) is administered to said subject in the dosage range of about 0.1 μ

g/kg–

5 mg/kg of body weight.

14. The method of claim 1 which further comprises administering macrophage inflammatory protein to said subject.

15. The method of claim 1 which further comprises administering G-CSF to said subject prior to performing said method.

17. The method of claim 4 wherein Z′

is

—

N(R)—

(CR₂)_n—

X

wherein each R, N and X are as defined in claim 1.

18. The method of claim 17 wherein the linker is 1,4-phenylene-bis-(methylene).

19. The method of claim 18 wherein Z′

is 2-aminomethyl-pyridine.

20. The method of claim 19 wherein the compound of formula (1) is N[1,4,8,11-tetraazacyclotetradecanyl-1,4-phenylene-bis-(methylene)]-2-aminomethyl-pyridine.

21. The method of claim 1 wherein the subject is human.

16. A method to obtain progenitor and/or stem cells from a subject which method comprises

(a) administering to said subject an amount of a compound that binds to the chemokine receptor CXCR4 sufficient to mobilize said progenitor and/or stem cells into the peripheral blood of said subject;

followed by

(b) harvesting said progenitor and/or stem cells by apheresis.

22. The method of claim 16 wherein the subject is human.