PIXY321 (GM-CSF/IL-3 fusion protein): biology and early clinical development.
Granulocyte-macrophage colony-stimulating factor (GM-CSF) and interleukin-3 (IL-3) are functionally related hematopoietins with overlapping but distinct hematopoietic effects. GM-CSF supports more myeloid progenitor cells, whereas IL-3 promotes more erythroid, megakaryocytic and multipotential progenitor cells. Their complementary in vivo biological effects and cross competition for receptor binding prompted the development of PIXY321, a synthetic hybrid protein of GM-CSF and IL-3. PIXY321 binds to cell lines expressing specific receptors for either ligand, and it exhibits enhanced biological activity in human hematopoietic progenitor cell assays. In preclinical studies, PIXY321 has been shown to accelerate both neutrophil and platelet recovery in rhesus monkeys subjected to sublethal irradiation. Based on these preclinical observations, clinical trials have been initiated examining the therapeutic potential of this agent in ameliorating treatment- or disease-related hematopoietic suppression. The early results indicate that PIXY321 can stimulate multilineage hematopoiesis in vivo and enhance neutrophil and platelet recovery following chemotherapy and bone marrow transplantation (BMT). These results suggest that PIXY321 elicits the biological effects of both its component cytokines and represents a novel means of delivering two independent but interactive cytokines in combination.
Vadhan-Raj
S
S
Department of Clinical Immunology and Biological Therapy, University of Texas M. D. Anderson Cancer Center, Houston 77030.
D000818:Animals; D000970:Antineoplastic Agents / Q000009:adverse effects; D001792:Blood Platelets / Q000166:cytology / Q000187:drug effects; D016026:Bone Marrow Transplantation / Q000009:adverse effects / Q000502:physiology; D002986:Clinical Trials as Topic; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000378:metabolism / Q000494:pharmacology* / Q000627:therapeutic use*; D006410:Hematopoiesis / Q000187:drug effects; D006412:Hematopoietic Stem Cells / Q000166:cytology / Q000187:drug effects*; D006801:Humans; D007377:Interleukin-3 / Q000378:metabolism / Q000494:pharmacology* / Q000627:therapeutic use*; D008253:Macaca mulatta; D008958:Models, Molecular; D009369:Neoplasms / Q000188:drug therapy / Q000628:therapy*; D009504:Neutrophils / Q000166:cytology / Q000187:drug effects; D017433:Protein Structure, Secondary; D016187:Receptors, Granulocyte-Macrophage Colony-Stimulating Factor / Q000378:metabolism; D016185:Receptors, Interleukin-3 / Q000378:metabolism; D011993:Recombinant Fusion Proteins / Q000378:metabolism / Q000494:pharmacology* / Q000627:therapeutic use
D000970:Antineoplastic Agents; D007377:Interleukin-3; C078524:PIXY321 fusion protein, recombinant; D016187:Receptors, Granulocyte-Macrophage Colony-Stimulating Factor; D016185:Receptors, Interleukin-3; D011993:Recombinant Fusion Proteins; D016178:Granulocyte-Macrophage Colony-Stimulating Factor