BB-10010: an active variant of human macrophage inflammatory protein-1 alpha with improved pharmaceutical properties.
The stem cell inhibitor, macrophage inflammatory protein-1 alpha (MIP-1 alpha) or LD78, protects multipotent hematopoietic progenitors in murine models from the cytotoxic effects of chemotherapy. Clinical use of human MIP-1 alpha during chemotherapy could therefore lead to faster hematologic recovery and may allow dose intensification. We have also shown that human MIP-1 alpha causes the rapid mobilization of hematopoietic cells, suggesting an additional clinical use in peripheral blood stem cell transplantation. However, the clinical evaluation of human MIP-1 alpha is complicated by its tendency to associate and form high molecular weight polymers. We have produced a variant of rhMIP-1 alpha, BB-10010, carrying a single amino acid substitution of Asp26 > Ala, with a reduced tendency to form large polymers at physiologic pH and ionic strength. This greatly increases its solubility, facilitating its production and clinical formulation. We confirmed the potency of BB-10010 as a human MIP-1 alpha-like agonist in receptor binding, calcium mobilization, inhibition of colony formation, and thymidine suicide assays. The myeloprotective activity of BB-10010 was shown in a murine model of repeated chemotherapy using hydroxyurea. BB-10010 is therefore an ideal variant with which to evaluate the therapeutic potential of recombinant human MIP-1 alpha.
British Biotech Pharmaceuticals Ltd, Oxford, UK.
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MG
Hunter
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Bawden
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Brotherton
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Craig
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Cribbes
L G
LG
Czaplewski
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Dexter
A H
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Drummond
A H
AH
Gearing
C M
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Heyworth
B I
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Lord
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McCourt
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Varley
L M
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Wood
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Edwards
P J
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Lewis
D000595:Amino Acid Sequence; D000818:Animals; D001704:Biopolymers; D001853:Bone Marrow / Q000187:drug effects; D001855:Bone Marrow Diseases / Q000139:chemically induced / Q000188:drug therapy; D002118:Calcium / Q000378:metabolism; D002453:Cell Cycle / Q000187:drug effects; D054405:Chemokine CCL3; D054407:Chemokine CCL4; D003114:Colony-Forming Units Assay; D006131:Growth Inhibitors / Q000494:pharmacology; D006412:Hematopoietic Stem Cells / Q000187:drug effects; D006801:Humans; D006918:Hydroxyurea / Q000633:toxicity; D019402:Macrophage Inflammatory Proteins; D051379:Mice; D008969:Molecular Sequence Data; D015846:Monokines / Q000737:chemistry / Q000235:genetics / Q000493:pharmacokinetics* / Q000494:pharmacology; D016297:Mutagenesis, Site-Directed; D017354:Point Mutation; D011833:Radiation Injuries, Experimental / Q000188:drug therapy; D019707:Receptors, Chemokine; D018121:Receptors, Cytokine / Q000378:metabolism; D011993:Recombinant Fusion Proteins / Q000737:chemistry / Q000235:genetics / Q000493:pharmacokinetics*; D016415:Sequence Alignment; D017386:Sequence Homology, Amino Acid; D012995:Solubility; D013329:Structure-Activity Relationship
D001704:Biopolymers; D054405:Chemokine CCL3; D054407:Chemokine CCL4; D006131:Growth Inhibitors; D019402:Macrophage Inflammatory Proteins; D015846:Monokines; D019707:Receptors, Chemokine; D018121:Receptors, Cytokine; D011993:Recombinant Fusion Proteins; C080633:macrophage inflammatory protein 1alpha receptor; D002118:Calcium; D006918:Hydroxyurea