WO2001036459A2 - Novel use of hcc-2 - Google Patents
Novel use of hcc-2 Download PDFInfo
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- WO2001036459A2 WO2001036459A2 PCT/EP2000/011274 EP0011274W WO0136459A2 WO 2001036459 A2 WO2001036459 A2 WO 2001036459A2 EP 0011274 W EP0011274 W EP 0011274W WO 0136459 A2 WO0136459 A2 WO 0136459A2
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- Prior art keywords
- hcc
- cells
- medicament
- use according
- manufacturing
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
- C07K14/52—Cytokines; Lymphokines; Interferons
- C07K14/521—Chemokines
- C07K14/523—Beta-chemokines, e.g. RANTES, I-309/TCA-3, MIP-1alpha, MIP-1beta/ACT-2/LD78/SCIF, MCP-1/MCAF, MCP-2, MCP-3, LDCF-1, LDCF-2
Definitions
- HCC-2 human chemokine HCC-2 (MlP-ld, small inducible cytokine subfamily A (Cys-Cys) member 15, hmrp-2b, MIP-5, NCC-3) was recently identified by Pardigol et al. (1) and was demonstrated to be a ligand for the chemokine receptors CCR-1 and CCR-3.
- HCC-2 is a potent chemoattractant and inducer of enzyme release in monocytes and a moderately active attractant for eosinophils.
- HCC-2 is preferentially produced in the liver and gut.
- hematopoietic progenitors at different stages of differentiation and multiple, positively and negatively acting cytokines.
- increased plasma levels of positively acting cytokines are found to improve the immune response by increasing the output of mature leukocytes from the bone marrow.
- cytokines like G-CSF, GM-CSF, bFGF, IL-2, IL-5, IL-7, or IL-10 (2-5) were identified.
- Chemokines are known to be involved in inflammation (6, 7), infection (8), sepsis (9), and cancer (10, 11) and may regulate the migratory properties of infiltrating leukocytes, enhancing their ability to invade the extracellular matrix of the tissue (12-14) e.g. into an area of injury. Furthermore, chemokines like MlP-la, MPIF, MIP-2a, IL-8 and PF-4 were shown to act on early hematopoietic progenitor cells as negative regulators (15-18).
- a first aspect of the invention is the use of HCC-2 as an inhibitor of stem cells, hematopoietic stem cells and/or progenitor cells.
- a second aspect of the invention is the use of HCC-2 for the manufacturing of a medicament for the protection of bone marrow cells during chemotherapy and radiation therapy, in therapies where bone marrow cells are treated with cytokines, for the treatment of neoplasia and/or for the treatment of autoimmune diseases and rheumatic diseases.
- a third aspect of the invention are natural hyoccuring fragments of HCC-2, identified from human hemofiltrate:
- HCC-2 33-113) or HCC-2 (46-113) are used as HCC-2 in the present invention.
- a further aspect of the invention is a medicament comprising HCC-2 (33-113) and/or HCC-2 (46-113).
- HCC-2 Western blot analysis shows phase-fractions from pH pool fractions V. and VI. Western blot analysis shows at least two major immunoreactive components with molecular weights of 6 to 7 kDa and 8 to 9 kDa. No other immuno-reactive lanes were identified. Comparison of the relative mobility of the detected lanes with that of synthesized HCC-2 (22-113) reveals that these lanes represent truncated forms of the mature HCC-2 (22-113).
- the immuno-reactive material in the hemofiltrate fractions represents approximately 140 ng/L hemofiltrate. Since peptides with a MW ⁇ 10 kDa filter through the hemofilters almost unrestricted, the HCC-2 concentration of the HF roughly represents that of HCC-2 blood concentration. Estimating a molecular weight of 8 to 10 kDa for HCC-2, the plasma levels of HCC-2 range within 10 to 20 pM.
- HCC-2 The isolated HCC-2 fragments were identified as HCC-2 (33-113) and HCC-2 (46-113).
- FIG. 3 shows the result of the single cell assay
- HCC-2 regulates the colony formation of hematopoietic progenitor cells
- HCC-2 was tested in colony- and single cell colony-assays using human CD34+ cells and in a murine CFU-A assay.
- CFU-A assay detects primitive hematopoietic progenitor cells with self- renewal properties.
- the CFU-A cells produce colonies > 2 mm. Pragnell et al. (20) found that these colonies are derived from minimally cycling cells. Replated colonies formed secondary colonies, which were macroscopically identical in morphology to the primary colonies.
- CD34 + cells from human bone marrow were isolated using the Mini- MACS immunomagnetic separation system (Miltenyi Biotec, Bergisch Gladbach, Germany) according to the manufacturer ' s instruction. 3 x 10 3 CD34+ cells were incubated in 0,9 % methylcellulose suspended in IMDM supplemented with 20 % FCS (Hyclone Laboratory), 1 U/ml erythropoietin, 50 ng/ml GM- CSF, 20 ng/ml IL-3. rhHCC-2 and rhMIP-la was used in concentrations of 50, 200 and 500 ng/ml. Dishes were incubated in a humidified atmosphere with 5 % CO 2 , 95 % air for 20 days. CFU-C (white cell colonies) were scored.
- mice 5 x 10 4 bone marrow cells from phenylhydracine-treated mice were incubated in 0,3 % agar suspended in Iscove modified Dulbecco ' s Medium (IMDM) (GIBCO BRL) supplemented with 10 % fetal calf serum (Hyclone Laboratory), 250 pg/ml murine GM-CSF and 100 U/ml human M-CSF. Dishes were incubated in a humidified atmosphere containing 5 % C0 2 , 95 % air for 11 days. Colonies were stained with p-iodonitrotetrazolium violet (Sigma) and those colonies with an overall diameter equal to or greater than 2 mm were scored as CFU-A.
- IMDM Iscove modified Dulbecco ' s Medium
- HCC-2 inhibits the proliferation of primitive human hematopoietic progenitor cells. There is a significant reduction of colonies by 55 to 62 % for MlP-la and from 62 to 79% for HCC-2.
- CD34 +++ cells were separated from umbilical cord CD34+ cells on a Coulter dual Laser Flow Cytometer, and a single cell was directly sorted into one well of 384-well Kawasaki Plate containing 50 ⁇ l Iscove ' s modified Dulbecco ' s medium, 30 % fetal bovine scrum (Hyclone Laboratory), 1 U/mi rhEpo, 50 ng/ml rhSCF, 200 U/ml rhIL-3, 200 U/ml rhGM-CSF. RhHCC-2 and rhMIP-la was used in a concentration of 200 ng/ml. Cells were incubated at 5% CO 2 and 37°C in a humidified chamber for 12 days and were assessed for colony formation.
- Circulating HCC-2 may have endocrine functions, e.g. regulation of the immune response and the hematopoiesis.
- the results in the stem cell assays demonstrated the HCC-2 exhibits stem cell inhibitory activity. This is in accordance with the findings of other groups who identified other chemokines as stem cell inhibitors. These inhibitors are useful for protection of stem cells in vivo against the effects of cyctotoxic drugs used for cancer therapy.
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- Gastroenterology & Hepatology (AREA)
- Biochemistry (AREA)
- Biophysics (AREA)
- Zoology (AREA)
- Genetics & Genomics (AREA)
- Medicinal Chemistry (AREA)
- Molecular Biology (AREA)
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Abstract
Use of HCC-2 as an inhibitor of stem cells, hematopoietic stem cells and/or progenitor cells.
Description
Novel Use of HCC-2
The human chemokine HCC-2 (MlP-ld, small inducible cytokine subfamily A (Cys-Cys) member 15, hmrp-2b, MIP-5, NCC-3) was recently identified by Pardigol et al. (1) and was demonstrated to be a ligand for the chemokine receptors CCR-1 and CCR-3. HCC-2 is a potent chemoattractant and inducer of enzyme release in monocytes and a moderately active attractant for eosinophils. HCC-2 is preferentially produced in the liver and gut.
Maintenance of an appropriate output of mature leukocytes in vivo relies on an effective interplay between hematopoietic progenitors at different stages of differentiation and multiple, positively and negatively acting cytokines. In different patho-physiological situations increased plasma levels of positively acting cytokines are found to improve the immune response by increasing the output of mature leukocytes from the bone marrow. In inflammation, infection, sepsis and tumor diseases increased levels of cytokines like G-CSF, GM-CSF, bFGF, IL-2, IL-5, IL-7, or IL-10 (2-5) were identified. Since positively acting cytokines are inducing differentiation and proliferation in all developmental stages of hematopoietic progenitors an increase of negatively acting cytokines in the above mentioned diseases may be necessary to maintain the self- renewal-capacity of hematopoiesis.
Chemokines are known to be involved in inflammation (6, 7), infection (8), sepsis (9), and cancer (10, 11) and may regulate the migratory properties of infiltrating leukocytes, enhancing their ability to invade the extracellular matrix of the tissue (12-14) e.g. into an area of injury. Furthermore, chemokines like MlP-la, MPIF, MIP-2a, IL-8 and PF-4 were shown to act on early hematopoietic progenitor cells as negative regulators (15-18).
A first aspect of the invention is the use of HCC-2 as an inhibitor of stem cells, hematopoietic stem cells and/or progenitor cells.
A second aspect of the invention is the use of HCC-2 for the manufacturing of a medicament for the protection of bone marrow cells during chemotherapy and radiation therapy, in therapies where bone marrow cells are treated with cytokines, for the treatment of neoplasia and/or for the treatment of autoimmune diseases and rheumatic diseases.
A third aspect of the invention are natural hyoccuring fragments of HCC-2, identified from human hemofiltrate:
HCC-2 (33-113)
MSKLPLENPVVLNSFHFAADCCTSYISQSIPCSLMKSYFEΞTSSECSKPGVIFLTKKGRQV CAKPSGPGVQDCMKKLKPYSI
HCC-2 (46-113)
SFHFAADCCTSYISQSIPCSLMKSYFETSSECSKPGVIFLTKKGRQVCAKPSGPGVQDC MKKLKPYSI
Therefore it is preferred that HCC-2 (33-113) or HCC-2 (46-113) are used as HCC-2 in the present invention.
A further aspect of the invention is a medicament comprising HCC-2 (33-113) and/or HCC-2 (46-113).
Several blood-derived molecular forms of the chemokine HCC-2 were identified by the use of HCC-2 Western blot analysis. In a peptide bank made from human hemofiltrate, immuno-reactive HCC-2 was detected in several reverse phase-fractions from pH pool fractions V. and VI. Western blot analysis shows
phase-fractions from pH pool fractions V. and VI. Western blot analysis shows at least two major immunoreactive components with molecular weights of 6 to 7 kDa and 8 to 9 kDa. No other immuno-reactive lanes were identified. Comparison of the relative mobility of the detected lanes with that of synthesized HCC-2 (22-113) reveals that these lanes represent truncated forms of the mature HCC-2 (22-113). Due to the specificity of the used antibody K228 The antibody does not cross react with different other chemokines. Using a HCC-2 RIA the immuno-reactive material in the hemofiltrate fractions represents approximately 140 ng/L hemofiltrate. Since peptides with a MW < 10 kDa filter through the hemofilters almost unrestricted, the HCC-2 concentration of the HF roughly represents that of HCC-2 blood concentration. Estimating a molecular weight of 8 to 10 kDa for HCC-2, the plasma levels of HCC-2 range within 10 to 20 pM.
The Western blot analysis suggests that HCC-2 circulates in the blood in different molecular forms. The immuno-reactive material was subsequently isolated and characterized.
The isolated HCC-2 fragments were identified as HCC-2 (33-113) and HCC-2 (46-113).
Figure 1 shows the results of the colony assay
Figure 2 shows the result of the CFU-A assay
Figure 3 shows the result of the single cell assay
To investigate whether HCC-2 regulates the colony formation of hematopoietic progenitor cells HCC-2 was tested in colony- and single cell colony-assays using human CD34+ cells and in a murine CFU-A assay.
In the CFU-A assay a dose dependent reduction of CFU-A colonies was found. The CFU-A assay detects primitive hematopoietic progenitor cells with self- renewal properties. The CFU-A cells produce colonies > 2 mm. Pragnell et al. (20) found that these colonies are derived from minimally cycling cells. Replated colonies formed secondary colonies, which were macroscopically identical in morphology to the primary colonies.
In detail, CD34+ cells from human bone marrow were isolated using the Mini- MACS immunomagnetic separation system (Miltenyi Biotec, Bergisch Gladbach, Germany) according to the manufacturer ' s instruction. 3 x 103 CD34+ cells were incubated in 0,9 % methylcellulose suspended in IMDM supplemented with 20 % FCS (Hyclone Laboratory), 1 U/ml erythropoietin, 50 ng/ml GM- CSF, 20 ng/ml IL-3. rhHCC-2 and rhMIP-la was used in concentrations of 50, 200 and 500 ng/ml. Dishes were incubated in a humidified atmosphere with 5 % CO2 , 95 % air for 20 days. CFU-C (white cell colonies) were scored.
In the single cell assay, single human cord blood CD34+ CD38l0W cells were sorted into individual wells in the presence of EPO, SLF, IL-3, GM-CSF and serum. There is a clear reduction of colonies by 50 % in the presence of HCC-2 but this effect did not reach significance, using the student T-test. Interestingly, cord blood cells were much less sensitive to MlP-la than to HCC- 2. The weak inhibitory activity of MlP-la on cord blood cells is in accordance with earlier findings (21) demonstrating that MlP-la inhibits colony growth of CD34+ CD38l0W cells from bone marrow much more than that of cord blood.
In detail, 5 x 104 bone marrow cells from phenylhydracine-treated mice were incubated in 0,3 % agar suspended in Iscove modified Dulbecco 's Medium (IMDM) (GIBCO BRL) supplemented with 10 % fetal calf serum (Hyclone Laboratory), 250 pg/ml murine GM-CSF and 100 U/ml human M-CSF. Dishes were incubated in a humidified atmosphere containing 5 % C02 , 95 % air for 11 days. Colonies were stained with p-iodonitrotetrazolium violet (Sigma) and
those colonies with an overall diameter equal to or greater than 2 mm were scored as CFU-A.
Also, the colony assays using human bone marrow CD34+ showed that HCC-2 inhibits the proliferation of primitive human hematopoietic progenitor cells. There is a significant reduction of colonies by 55 to 62 % for MlP-la and from 62 to 79% for HCC-2.
In detail, CD34+++ cells were separated from umbilical cord CD34+ cells on a Coulter dual Laser Flow Cytometer, and a single cell was directly sorted into one well of 384-well Kawasaki Plate containing 50 μl Iscove 's modified Dulbecco 's medium, 30 % fetal bovine scrum (Hyclone Laboratory), 1 U/mi rhEpo, 50 ng/ml rhSCF, 200 U/ml rhIL-3, 200 U/ml rhGM-CSF. RhHCC-2 and rhMIP-la was used in a concentration of 200 ng/ml. Cells were incubated at 5% CO2 and 37°C in a humidified chamber for 12 days and were assessed for colony formation.
Circulating HCC-2 may have endocrine functions, e.g. regulation of the immune response and the hematopoiesis. The results in the stem cell assays demonstrated the HCC-2 exhibits stem cell inhibitory activity. This is in accordance with the findings of other groups who identified other chemokines as stem cell inhibitors. These inhibitors are useful for protection of stem cells in vivo against the effects of cyctotoxic drugs used for cancer therapy.
Literature
1. Pardigol, A., Forssmann, U., Zucht, H.D., Loetscher, P., Schulz-Knappe P., Baggiolini, M., Forssmann, W.G.; Magert, H.J. (1998) Proc. Natl. Acad. Sci. USA 95:6308-13.
2. Duru, F., Ertem, U., Tacyildiz, N., Kirazli, S. (1995) J.Med. 26:241-52.
3. Kawakami, M., Tsutsumi, H., Kumakawa, T., Abe, H., Hirai, M., Kurosawa, S., Mori, M., Fukushima, M. (1999), Blood 76:1962-4
4. Chopra, V., Dinh, T.V., Hannigan, E.V. (1997) J. Cancer. Res. Clin. Oncol. 123:167-72
5. Kann, H., Ogata, T., Taniyama, A., Migita, M., Matsuda, I., Nawa, Y. (1995) Pediatrics 96:351-4
6. Gallo, R.C., Garzino-Demo, A., De Vico, A.L. (1999) J. Clin. Immunol. 19:293-9
7. O 'Grady, N.P., Tropea, M., Preas, H.L. 2nd , Reda, D., Vandivier, R.W., Banks, S.M., Suffredini, A.F. (1999) J. Infect. Dis. 179:136-41
8. Valkovic, T., Lucin, K., Krstulja, M., Dobi-Babic, R., Jonjic, N. (1998) Pathol. Res. Pract. 194:335-40
9. Amann, B., Perabo, F.G., Wirger, A., Hugenschmidt, H., Schultze- Seemann, W. (1998) Br. J. Urol. 82:118-21.
10. Ferrero, E., Fabbri, M., Poggi, A., Galati, G., Bemasconi, S., Zochhi, M.R. (1998) Eur. J. Immunol. 28:2530-6
11. Tannenbaum, C.S., Tubbs, R., Armstrong, D., Finke, J.H., Bukowski, R.M., Hamilton, T.A. (1998) J. Immunol. 161:927-32
12. Tannenbaum, C.S., Wicker, N., Armstrong, D., Tubbs, R., Finke, J., Bukowski, R.M., Hamilton T.A. (1996) J Immunol. 156:693-9
13. Graham, G.J., Wright, E.G., Hewick, R., Wolpe, S.D., Wilkie, N.M., Donaldson, D., Lorimore, S., Pragnell, LB. (1990) Nature 344:442-4
14. H. Broxmeyer, B. Sherry, S. Cooper, L. Lu, R. Maze, M. Beckmann, A. Cerami, P. Ralph. (1993) J Immunol. 150:3448-3458
15. B. Lord, T. Dexter, j. Clements, M. Hunter, A. Gearing. (1992) Blood 79:2605-2609
16. D.J. Dunlop, E.G. Wright, S. Lormore, G.J. Graham, T. Holyoake, D.J. Kerr, S.D. Wolpe, LB. Pragnell (1992) Blood 79:2221-2225
17. Schulz-Knappe, P., Schrader, M., Standker, L., Richter, R., Hess, R., Jurgens, M., Forssmann, W.G. (1997) J. Chromatogr. A 776:125-32
18. Pragnell, LB., Wright, E.G., Lormore, S.A., Adam, J., Rosendaal, M., De Lamarter, J.F., Freshney, M., Eckmann, L., Sproul, A., Wilkie, N. (1988) Blood 72:196-201
19. Lu, L., Xiao, M., Grigsby, S., Wang, W.X., Wu, B., Shen, R.N., Broxmeyer, H.E. (1993) Exp. Hematol. 21:1442-6
Claims
1. Use of HCC-2 as an inhibitor of stem cells, hematopoietic stem cells and/or progenitor cells.
2. Use according to claim 1 wherein HCC-2 is used for the manufacturing of a medicament for the protection of bone marrow cells during chemotherapy and radiation therapy.
3. Use according to claim 1, wherein HCC-2 is used for the manufacturing of a medicament in therapies where bone marrow cells are treated with cytokines.
4. Use according to claim 1, wherein HCC-2 is used for the manufacturing of a medicament for the treatment of neoplasia.
5. Use according to claim 1, wherein HCC-2 is used for the manufacturing of a medicament for the treatment of autoimmune diseases.
6. Use according to claim 1, wherein HCC-2 is used for the manufacturing of a medicament for the treatment of rheumatic diseases.
7. Use according to claim 1, wherein HCC-2 is HCC-2 (33 - 113) or HCC-2 (46 - 113) are used.
8. A medicament comprising HCC-2 (33 - 113) or HCC-2 (46 - 113).
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| AU25056/01A AU2505601A (en) | 1999-11-15 | 2000-11-15 | Novel use of hcc-2 |
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US16571799P | 1999-11-15 | 1999-11-15 | |
| EP99122655 | 1999-11-15 | ||
| US60/165,717 | 1999-11-15 | ||
| EP99122655.6 | 1999-11-15 |
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| Publication Number | Publication Date |
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| WO2001036459A2 true WO2001036459A2 (en) | 2001-05-25 |
| WO2001036459A3 WO2001036459A3 (en) | 2001-11-15 |
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| PCT/EP2000/011274 WO2001036459A2 (en) | 1999-11-15 | 2000-11-15 | Novel use of hcc-2 |
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| AU (1) | AU2505601A (en) |
| WO (1) | WO2001036459A2 (en) |
Citations (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1997012041A1 (en) * | 1995-09-29 | 1997-04-03 | Smithkline Beecham Corporation | SHORT FORMS OF CHEMOKINE β-8 |
| WO1997015594A1 (en) * | 1995-10-24 | 1997-05-01 | Smithkline Beecham Corporation | Novel chemokine for mobilizing stem cells |
| WO1997021812A2 (en) * | 1995-12-08 | 1997-06-19 | Schering Corporation | Mammalian chemokine ccf8 and chemokine receptor cckr3 |
| WO1997041230A2 (en) * | 1996-04-30 | 1997-11-06 | Forssmann Wolf Georg | Cc-type chemokines |
| EP0905240A1 (en) * | 1997-09-29 | 1999-03-31 | Applied Research Systems Ars Holding N.V. | Amino-terminally truncated c-c chemokines as chemokine antagonists |
| WO1999028473A1 (en) * | 1997-11-27 | 1999-06-10 | Korea Green Cross Corporation | A cDNA ENCODING C6 β-CHEMOKINE LEUKOTACTIN-1(Lkn-1) ISOLATED FROM HUMAN |
| WO2000073456A1 (en) * | 1999-05-27 | 2000-12-07 | Korea Green Cross Corporation | A VARIANT OF C6 β-CHEMOKINE LEUKOTACTIN-1(shLkn-1) WITH ENHANCED BIOLOGICAL ACTIVITY |
-
2000
- 2000-11-15 AU AU25056/01A patent/AU2505601A/en not_active Abandoned
- 2000-11-15 WO PCT/EP2000/011274 patent/WO2001036459A2/en active Application Filing
Patent Citations (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1997012041A1 (en) * | 1995-09-29 | 1997-04-03 | Smithkline Beecham Corporation | SHORT FORMS OF CHEMOKINE β-8 |
| WO1997015594A1 (en) * | 1995-10-24 | 1997-05-01 | Smithkline Beecham Corporation | Novel chemokine for mobilizing stem cells |
| WO1997021812A2 (en) * | 1995-12-08 | 1997-06-19 | Schering Corporation | Mammalian chemokine ccf8 and chemokine receptor cckr3 |
| WO1997041230A2 (en) * | 1996-04-30 | 1997-11-06 | Forssmann Wolf Georg | Cc-type chemokines |
| EP0905240A1 (en) * | 1997-09-29 | 1999-03-31 | Applied Research Systems Ars Holding N.V. | Amino-terminally truncated c-c chemokines as chemokine antagonists |
| WO1999028473A1 (en) * | 1997-11-27 | 1999-06-10 | Korea Green Cross Corporation | A cDNA ENCODING C6 β-CHEMOKINE LEUKOTACTIN-1(Lkn-1) ISOLATED FROM HUMAN |
| WO1999028472A1 (en) * | 1997-11-27 | 1999-06-10 | Korea Green Cross Corporation | A cDNA ENCODING C6 β-CHEMOKINE LEUKOTACTIN-1(Lkn-1) ISOLATED FROM HUMAN |
| WO2000073456A1 (en) * | 1999-05-27 | 2000-12-07 | Korea Green Cross Corporation | A VARIANT OF C6 β-CHEMOKINE LEUKOTACTIN-1(shLkn-1) WITH ENHANCED BIOLOGICAL ACTIVITY |
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| Publication number | Publication date |
|---|---|
| AU2505601A (en) | 2001-05-30 |
| WO2001036459A3 (en) | 2001-11-15 |
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