Process for correction of a disulfide misfold in Fc molecules

The present invention concerns a process by which a misfold in an Fc fusion molecule can be prevented or corrected. In one embodiment, the process comprises (a) preparing a pharmacologically active compound comprising an Fc domain; (b) treating the pharmacologically active compound with guanidine HCl at a concentration of at least about 4M; (c) increasing the pH to about 8.5; and (d) isolating the treated fusion molecule. The preferred concentration thereof is at least about 10 mM for fusion molecules prepared in E.coli; at least about 30 mM for fusion molecules prepared in CHO cells. Preferred pharmacologically active domains include OPG proteins, leptin proteins, soluble portions of TNF-receptors (e.g., wherein the fusion molecule is etanercept), IL-1ra proteins, and TPO-mimetic peptides. The Fc domain preferably has a human sequence, with an Fc sequence derived from IgG1 most preferred.