The rhGM-CSF-EPO hybrid protein MEN 111300 induces anti-EPO antibodies andsevere anaemia in rhesus monkeys

A recombinant human GM-CSF-EPO hybrid protein named MEN 11300 was administe red biweekly for a total of 6 weeks to rhesus monkeys in order to evaluate its pharmacokinetic behaviour, tolerability and immunogenicity, In this pri mate species a strong antibody response was induced which neutralized the i n vitro biological activity of human EPO while no antibody response could b e detected against human GM-CSF, A severe drop in reticulocyte counts at ap proximately 2 weeks after initiation of treatment was followed by a dramati c decrease in the number of erythrocytes, No effects were observed on GM-CS F-dependent hematopoietic lineages and the clinical chemistry analyses did not reveal signs of general toxicity. Reticulocyte and erythrocyte counts s tarted to recover 3-4 weeks after discontinuation of treatment in concert w ith a decline in anti EPO antibody titres, Nevertheless, cell numbers remai ned below basal levels up to 50 days after the last MEN 11300 administratio n. Haematological impairment indicates that the administration to non-human primate of human EPO fused to human GM-CSF, induces neutralizing autoantib odies to the self EPO, Present data do not allow prediction of the immunoge nic potential of the fusion protein in humans and a dose-escalating phase I study should be addressed to investigate the safety of the product. (C) 19 98 Academic Press.