BB-10010: an active variant of human macrophage inflammatory protein-1 alpha with improved pharmaceutical properties
| Autor: | Brotherton D, T M Dexter, Michael George Hunter, Ajh Gearing, Lewis Pj, B I Lord, P G Varley, Stewart Craig, Richard Mark Edwards, S. Cribbes, A.H. Drummond, Lloyd George Czaplewski, Matthew John Mccourt, L. M. Wood, C M Heyworth, Lindsay Bawden |
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| Rok vydání: | 1995 |
| Předmět: | |
| Zdroj: | Blood. 86:4400-4408 |
| ISSN: | 1528-0020 0006-4971 |
| DOI: | 10.1182/blood.v86.12.4400.bloodjournal86124400 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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