Pre-clinical toxicity of IL-4: a model for studying protein therapeutics.

The purpose of this presentation was to review issues and findings in the pre-clinical development and evaluation of recombinant human protein therapeutics. Since human cytokines and lymphokines are endogenous proteins, their pre-clinical development and evaluation would seem straightforward and their toxicities minimal. Unfortunately, the pre-clinical development of this class of agents has been problematic and confounding. Some of the clinical toxicities and pharmacodynamics have been predicted by the pre-clinical evaluation and others have not. Some molecules are species specific which limits species selection for pre-clinical evaluation. Other confounding issues include: route of exposure, synergy of toxicity with other lymphokines, length of study design, immunogenicity, predictiveness of pre-clinical evaluation and iatrogenic toxicities. An approach used by SWPRD in the evaluation of this class of molecules was discussed. Insight gained during the pre-clinical and clinical development of these molecules should simplify the further development of protein therapeutics that follow. Specific studies with recombinant human interleukin-4 (rhuIL-4) were reviewed in detail as part of a pre-clinical safety evaluation. Native IL-4 has properties that exemplify many of the immune recognition-induced lymphokines and is produced principally by activated T-lymphocytes CD4+. It is a co-factor in B-cell proliferation and enhances ex vivo B-cell expansion and is believed to be a candidate for the treatment of refractory cancer based on this immune enhancement ability. rhuIL-4 is a 15,400 molecular weight cytokine produced in a yeast expression system.(ABSTRACT TRUNCATED AT 250 WORDS)