PRECLINICAL STUDIES AND FUTURE-DIRECTIONS IN THE DEVELOPMENT OF NEW HEMATOLOGIC GROWTH-FACTORS

Normal hematopoiesis is controlled by a cascade of interacting hormones collectively referred to as cytokines. These growth factors have been studied both individually and in specific combinations to determine their optimal clinical use. In some cases, the combination of certain cytokines produces a synergistic effect enhancing their efficacy. Granulocyte-macrophage colony-stimulating factor (GM-CSF) has demonstrated the ability to stimulate early- and late-phase granulocyte and macrophage progenitor cells, activate mature neutrophils and macrophages, and enhance their peripheral infection fighting performance. Interleukin-3 (IL-3), currently undergoing clinical evaluation, acts early in the development of multiple types of white blood cells and, when used in combination with GM-CSF, also produces a synergistic effect in raising white blood cell and platelet levels. A recombinant protein, PIXY321, has recently been developed that contains both IL-3 and GM-CSF domains. The development of this molecule was supported by the discovery of a dual IL-3-GM-CSF receptor on the surface of hematopoietic progenitor cells. PIXY321 provides a significantly enhanced biologic effect (10-fold greater proliferation) via multiple cross-linking of GM-CSF, IL-3, and dual receptor binding sites. PIXY321 has the same molecular weight as the equivalent molar concentrations of GM-CSF and IL-3 combined and offers the advantage of combination therapy in an easy-to-administer regimen. Another recombinant cytokine, mast cell growth factor (MGF), has shown profound hematopoietic activity in vitro and has the ability to enhance proliferation of hematopoietic stem cells. When added to IL-3, MGF demonstrates a 400% enhancement in the generation of pluripotent hematopoietic stem cells, and can also produce a synergistic effect with other late-acting colony-stimulating factors. The optimal clinical use of cytokines will be dependent on understanding and manipulating combinations of growth factors to achieve desired clinical results.