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 mu rine models from the cytotoxic effects of chemotherapy. Clinical use o f 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 hematop oietic cells, suggesting an additional clinical use in peripheral bloo d 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 alph a, BE-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 it s production and clinical formulation. We confirmed the potency of BE- 10010 as a human MIP-1 alpha-like agonist in receptor binding, calcium mobilization, inhibition of colony formation, and thymidine suicide a ssays. The myeloprotective activity of BE-10010 was shown in a murine model of repeated chemotherapy using hydroxyurea. BE-10010 is therefor e an ideal variant with which to evaluate the therapeutic potential of recombinant human MIP-1 alpha. (C) 1995 by The American Society of He matology.