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Toxicologic Pathology
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Development of a Recombinant Growth Factor and Fusion Protein: Lessons from GM-CSF

Joann C.L. Schuh

Department of Molecular Immunology, Immunex Corporation, Seattle, Washington 98101, Immunex Corporation, 51 University Street, Seattle, Washington 98101, jschuh{at}immunex.com.

Philip J. Morrissey

Department of Molecular Immunology, Immunex Corporation, Seattle, Washington 98101

Several colony stimulating factors (CSFs) and cytokines have been successfully used to mobilize hematopoietic cells during myeloablative therapy, bone marrow failure, and transplantation and to provide supportive treatment during sepsis. The use of yeast-derived recombinant human granulocyte-macrophage CSF (rhuGM-CSF) and its interleukin-3 fusion protein, PIXY321, provides an example of issues associated with development programs for recombinant hematopoietic growth factors. Species specificity of rhuGM-CSF, different bioactivity of homologous molecules in mice, and production in laboratory animals of antibodies to human proteins limit preclinical evaluation of such molecules. In clinical trials, rhuGM-CSF was efficacious and well tolerated. The derivation of the recombinant molecule, optimal dosing, scheduling, and confounding effects of concurrent disease and treatments are factors that influence efficacy, adverse responses, and immunogenicity reported in patients treated with CSFs. In comparisons of yeast-derived with Escherichia coli-derived rhuGM-CSF, the reduced severity and frequency of all adverse events, preponderance of low-grade adverse events, and similarity of positive clinical response versus adverse events reported for granulocyte CSF support safety and efficacy of yeast-derived rhuGM-CSF Enhanced pharmacoeconomic evaluations are beginning to limit and redirect clinical applications in this class of biological agents.

Key Words: Recombinant hematopoietic growth factors • IL-3 • fusion protein • PIXY321 • safety assessment • in vitro • preclinical • clinical

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Toxicologic Pathology, Vol. 27, No. 1, 72-77 (1999)
DOI: 10.1177/019262339902700114
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