Myeloid progenitor cell proliferation and mobilization effects of BB10010, a genetically engineered variant of human macrophage inflammatory protein-1α, in a phase I clinical trial in patients with relapsed/refractory breast cancer

Hal Broxmeyer, Attilio Orazi, Nancy L. Hague, George W. Sledge, Henrik Rasmussen, Michael S. Gordon

Research output: Contribution to journalArticle

35 Citations (Scopus)

Abstract

Macrophage Inflammatory Protein (MIP)-1α is myelosuppressive in vitro and in vivo for hematopoietic stem and immature subsets of myeloid progenitor cells, demonstrates some myeloprotective effects in mice treated with Ara-C and hydroxyurea, and has stern/progenitor cell mobilizing activity in mice. Based on these observations, BB10010, a genetic variant of MIP-1α, was assessed for effects on marrow and blood myeloid progenitor cells in patients with relapsed/refractory breast cancer. MIP-1α readily polymerizes, whereas BB10010 has a reduced tendency to form large polymers at physiological pH and ionic strength and retains biological activity. Patients were injected with 5, 10, 30 or 100 μg/kg BB10010 s.c. daily for 3 days. BB10010 significantly reduced the cycling status of marrow myeloid progenitors from pretreatment levels of 39-58% to 0 - 11% one day after the third and last injection of BB10010. This was associated with significant decreases in frequency of marrow progenitors (number of colonies formed per number of cells plated) and percent biopsied marrow CD34+ cells. The suppressive effects were reversible in patients and the rapidity of this reversal demonstrated in mouse studies. BB10010 had no effect on nucleated cellularity or on the proliferation of nucleated cells as assessed in marrow biopsies from the patients. These latter effects may in part reflect the noted decreased apoptosis of nucleated cells by BB10010. BB10010 also demonstrated significant but modest myeloid progenitor cell mobilizing capacity. Blood progenitors were in a slow or non- cycling state prior to treatment and this did not change after administration of BB10010. The above effects of B 10010 were similar at the four different dosage levels assessed. These results demonstrate in humans the suppressive and mobilizing effects of MIP-1α and BB10010 previously noted in vivo in mice.

Original languageEnglish
Pages (from-to)14-30
Number of pages17
JournalBlood Cells, Molecules and Diseases
Volume24
Issue number1
DOIs
StatePublished - Mar 1998

Fingerprint

Myeloid Progenitor Cells
Macrophage Inflammatory Proteins
Clinical Trials, Phase I
Bone Marrow
Cell Proliferation
Breast Neoplasms
Hydroxyurea
Cytarabine
Osmolar Concentration
Blood Cells
Polymers
Stem Cells
Cell Count
Apoptosis
Biopsy
Injections

Keywords

  • BB10010
  • Cell cycle
  • Chemokine
  • Clinical trial
  • Hematopoietic progenitor cells
  • MIP-1α
  • Myelopoiesis

ASJC Scopus subject areas

  • Molecular Biology
  • Molecular Medicine
  • Hematology

Cite this

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title = "Myeloid progenitor cell proliferation and mobilization effects of BB10010, a genetically engineered variant of human macrophage inflammatory protein-1α, in a phase I clinical trial in patients with relapsed/refractory breast cancer",
abstract = "Macrophage Inflammatory Protein (MIP)-1α is myelosuppressive in vitro and in vivo for hematopoietic stem and immature subsets of myeloid progenitor cells, demonstrates some myeloprotective effects in mice treated with Ara-C and hydroxyurea, and has stern/progenitor cell mobilizing activity in mice. Based on these observations, BB10010, a genetic variant of MIP-1α, was assessed for effects on marrow and blood myeloid progenitor cells in patients with relapsed/refractory breast cancer. MIP-1α readily polymerizes, whereas BB10010 has a reduced tendency to form large polymers at physiological pH and ionic strength and retains biological activity. Patients were injected with 5, 10, 30 or 100 μg/kg BB10010 s.c. daily for 3 days. BB10010 significantly reduced the cycling status of marrow myeloid progenitors from pretreatment levels of 39-58{\%} to 0 - 11{\%} one day after the third and last injection of BB10010. This was associated with significant decreases in frequency of marrow progenitors (number of colonies formed per number of cells plated) and percent biopsied marrow CD34+ cells. The suppressive effects were reversible in patients and the rapidity of this reversal demonstrated in mouse studies. BB10010 had no effect on nucleated cellularity or on the proliferation of nucleated cells as assessed in marrow biopsies from the patients. These latter effects may in part reflect the noted decreased apoptosis of nucleated cells by BB10010. BB10010 also demonstrated significant but modest myeloid progenitor cell mobilizing capacity. Blood progenitors were in a slow or non- cycling state prior to treatment and this did not change after administration of BB10010. The above effects of B 10010 were similar at the four different dosage levels assessed. These results demonstrate in humans the suppressive and mobilizing effects of MIP-1α and BB10010 previously noted in vivo in mice.",
keywords = "BB10010, Cell cycle, Chemokine, Clinical trial, Hematopoietic progenitor cells, MIP-1α, Myelopoiesis",
author = "Hal Broxmeyer and Attilio Orazi and Hague, {Nancy L.} and Sledge, {George W.} and Henrik Rasmussen and Gordon, {Michael S.}",
year = "1998",
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T1 - Myeloid progenitor cell proliferation and mobilization effects of BB10010, a genetically engineered variant of human macrophage inflammatory protein-1α, in a phase I clinical trial in patients with relapsed/refractory breast cancer

AU - Broxmeyer, Hal

AU - Orazi, Attilio

AU - Hague, Nancy L.

AU - Sledge, George W.

AU - Rasmussen, Henrik

AU - Gordon, Michael S.

PY - 1998/3

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N2 - Macrophage Inflammatory Protein (MIP)-1α is myelosuppressive in vitro and in vivo for hematopoietic stem and immature subsets of myeloid progenitor cells, demonstrates some myeloprotective effects in mice treated with Ara-C and hydroxyurea, and has stern/progenitor cell mobilizing activity in mice. Based on these observations, BB10010, a genetic variant of MIP-1α, was assessed for effects on marrow and blood myeloid progenitor cells in patients with relapsed/refractory breast cancer. MIP-1α readily polymerizes, whereas BB10010 has a reduced tendency to form large polymers at physiological pH and ionic strength and retains biological activity. Patients were injected with 5, 10, 30 or 100 μg/kg BB10010 s.c. daily for 3 days. BB10010 significantly reduced the cycling status of marrow myeloid progenitors from pretreatment levels of 39-58% to 0 - 11% one day after the third and last injection of BB10010. This was associated with significant decreases in frequency of marrow progenitors (number of colonies formed per number of cells plated) and percent biopsied marrow CD34+ cells. The suppressive effects were reversible in patients and the rapidity of this reversal demonstrated in mouse studies. BB10010 had no effect on nucleated cellularity or on the proliferation of nucleated cells as assessed in marrow biopsies from the patients. These latter effects may in part reflect the noted decreased apoptosis of nucleated cells by BB10010. BB10010 also demonstrated significant but modest myeloid progenitor cell mobilizing capacity. Blood progenitors were in a slow or non- cycling state prior to treatment and this did not change after administration of BB10010. The above effects of B 10010 were similar at the four different dosage levels assessed. These results demonstrate in humans the suppressive and mobilizing effects of MIP-1α and BB10010 previously noted in vivo in mice.

AB - Macrophage Inflammatory Protein (MIP)-1α is myelosuppressive in vitro and in vivo for hematopoietic stem and immature subsets of myeloid progenitor cells, demonstrates some myeloprotective effects in mice treated with Ara-C and hydroxyurea, and has stern/progenitor cell mobilizing activity in mice. Based on these observations, BB10010, a genetic variant of MIP-1α, was assessed for effects on marrow and blood myeloid progenitor cells in patients with relapsed/refractory breast cancer. MIP-1α readily polymerizes, whereas BB10010 has a reduced tendency to form large polymers at physiological pH and ionic strength and retains biological activity. Patients were injected with 5, 10, 30 or 100 μg/kg BB10010 s.c. daily for 3 days. BB10010 significantly reduced the cycling status of marrow myeloid progenitors from pretreatment levels of 39-58% to 0 - 11% one day after the third and last injection of BB10010. This was associated with significant decreases in frequency of marrow progenitors (number of colonies formed per number of cells plated) and percent biopsied marrow CD34+ cells. The suppressive effects were reversible in patients and the rapidity of this reversal demonstrated in mouse studies. BB10010 had no effect on nucleated cellularity or on the proliferation of nucleated cells as assessed in marrow biopsies from the patients. These latter effects may in part reflect the noted decreased apoptosis of nucleated cells by BB10010. BB10010 also demonstrated significant but modest myeloid progenitor cell mobilizing capacity. Blood progenitors were in a slow or non- cycling state prior to treatment and this did not change after administration of BB10010. The above effects of B 10010 were similar at the four different dosage levels assessed. These results demonstrate in humans the suppressive and mobilizing effects of MIP-1α and BB10010 previously noted in vivo in mice.

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