BB-10010: an active variant of human macrophage inflammatory protein-1 alpha with improved pharmaceutical properties.
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Hunter MG, Bawden L, Brotherton D, Craig S, Cribbes S, Czaplewski LG, Dexter TM, Drummond AH, Gearing AH, Heyworth CM, Lord BI, McCourt M, Varley PG, Wood LM, Edwards RM, Lewis PJ
BB-10010: an active variant of human macrophage inflammatory protein-1 alpha with improved pharmaceutical properties.
Blood. 1995 Dec 15;86(12):4400-8.
- PubMed ID
- 8541527 [ View in PubMed]
- Abstract
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.