Myeloid progenitor cell proliferation and mobilization effects of BB10010, a genetically engineered variant of human macrophage inflammatory protein-1alpha, in a phase I clinical trial in patients with relapsed/refractory breast cancer.
Macrophage Inflammatory Protein (MIP)-1alpha 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 stem/progenitor cell mobilizing activity in mice. Based on these observations, BB10010, a genetic variant of MIP-1alpha, was assessed for effects on marrow and blood myeloid progenitor cells in patients with relapsed/refractory breast cancer. MIP-1alpha 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 microg/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 BB10010 were similar at the four different dosage levels assessed. These results demonstrate in humans the suppressive and mobilizing effects of MIP-1alpha and BB10010 previously noted in vivo in mice.
Broxmeyer
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HE
Department of Microbiology/Immunology and Walther Oncology Center, Indiana University School of Medicine, Indianapolis, IN 46202, USA. hal_broxmeyer@iucc.iupui.edu
Orazi
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Hague
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Sledge
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Rasmussen
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H
Gordon
M S
MS
D000328:Adult; D000818:Animals; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000473:pathology; D002453:Cell Cycle / Q000187:drug effects; D002455:Cell Division / Q000187:drug effects; D054405:Chemokine CCL3; D054407:Chemokine CCL4; D004305:Dose-Response Relationship, Drug; D005260:Female; D005818:Genetic Engineering; D019650:Hematopoietic Stem Cell Mobilization; D006412:Hematopoietic Stem Cells / Q000187:drug effects* / Q000473:pathology; D006801:Humans; D019402:Macrophage Inflammatory Proteins / Q000235:genetics / Q000627:therapeutic use*; D051379:Mice; D008815:Mice, Inbred Strains; D009364:Neoplasm Recurrence, Local / Q000188:drug therapy* / Q000473:pathology
D054405:Chemokine CCL3; D054407:Chemokine CCL4; D019402:Macrophage Inflammatory Proteins