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BB-10010: an active variant of human macrophage inflammatory protein-1
alpha with improved pharmaceutical properties
MG Hunter, L Bawden, D Brotherton, S Craig, S Cribbes, LG Czaplewski, TM Dexter, AH Drummond, AH Gearing and CM Heyworth
British Biotech Pharmaceuticals Ltd, Oxford, UK.
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.
Volume 86,
Issue 12,
pp. 4400-4408,
12/15/1995
Copyright © 1995 by The American Society of Hematology
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