The present invention relates to Erythropoietin (Epo) that exhibit in vivo stability greater than the corresponding wild type Epo. The present invention particularly relates to the Epo variants having increased protease resistance The present invention also relates to the identification of site(s) on the inter-helical regions of the Erythropoietin (rHuEpo) molecule that are susceptible to cathepsin-L protease cleavage, possibly in the lysosome of target organs and mutations therein. Importantly, we show significant effect of some of these mutations influencing in vivo half-life of mutant Epo proteins.
