Disclosed are methods for producing fusion proteins with the heterodimeric
cytokine, interleukin-12. In order to insure that the proper ratio of
fused and non-fused subunits are obtained in the fusion protein, a
specific stepwise approach to genetic engineering is used. This consists
of first expressing the non-fused p40 IL-12 subunit in a production cell
line, followed by or simultaneously expressing in the same cell, a second
recombinant fusion protein consisting of the fused polypeptide linked by
a peptide bond to the p35 subunit of IL-12. Molecules containing the p35
fusion protein cannot be secreted from the transfected mammalian cell
without first complexing in a one to one ratio with the p40 subunit, thus
ensuring the production of active heterodimeric fusion proteins.