The effects of human macrophage inflammatory protein-1α and its genetically modified variant, BB10010, on phagocyte function

BB-10010 is a genetically modified form of human macrophage inflammatory protein-1α (MIP-1α) with a single amino acid substitution of Asp26 by alanine, which inhibits aggregation of the native molecule. BB-10010 has stem cell protective properties, and has entered clinical trials for this purpose. The aim of this study was to determine the effects of BB-10010 on human phagocyte function and compare them with the native molecule. MIP-1α and BB-10010 had identical dose-response curves in assays of calcium mobilization; however, neutrophils were less sensitive than monocytes to either MIP-1α form, suggesting differences in receptor expression. Neither MIP-1α type directly stimulated phagocyte superoxide production, nor did it have any priming effect on agonist-induced superoxide production. Both MIP-1α and BB-10010 enhanced monocyte migration; however, cells were sensitive to the native molecule, with optimal effects seen at 1 ng/ml compared with 100 ng/ml BB-10010. Concomitant alteration of CD11b, CD18, and CD49d (VLA-α4) cell adhesion molecule expression was not seen with either MIP-1α type. With the exception of the difference in monocyte sensitivity in chemotaxis assays, BB-10010 reproduces the effects of the native molecule on phagocytes. BB-10010 does not have pro-inflammatory effects on neutrophil activation, and this bodes well for its clinical use.