MEN 11,300, MEN 11,301, and MEN 11,303 are three recombinant human hybrid proteins that, as has recently been described, induce in vitro erythroid differentiation. This article provides data on their pharmacokinetic and immunogenic behavior after repeated i.v. administration to cynomolgus monkeys at 0.8 or 1.6 micrograms/kg doses. Pharmacokinetic data, obtained after the first administration, showed that the half-life (t1/2) and clearance (CL) values are dose dependent, with no significant differences among the three hybrid proteins. After the tenth administration, MEN 11,300 and MEN 11,301, both a high and low dose, and MEN 11,303 at high dose were undetectable in plasma, whereas MEN 11,303 at the lower dose showed no alteration in its pharmacokinetic profile. Immunologic analyses of plasma provided an explanation for this different pharmacokinetic behavior. In fact, plasma samples from animals treated repeatedly with MEN 11,300 and MEN 11,301 showed specific antibody formation in response to both the high- and the low-dose regimens. These antibodies exerted in vitro a strong neutralizing activity of the hybrid proteins, with a predominant specificity for the erythropoietin (EPO) portion. By contrast, MEN 11,303 at the lower dose did not induce a detectable antibody response whereas the antibodies observed on the high-dose regimen did not exert neutralizing activity against the hybrid proteins nor against granulocyte-macrophage colony-stimulating factor (GM-CSF) or EPO. Hematologic parameters were not affected by the treatments, thus indicating that the anti-EPO neutralizing antibody response does not cross react with the endogenous monkey cytokine. The overall immunogenicity data suggest that among the three fusion proteins, MEN 11,303 could have a lower immunogenic potential.