The rhGM-CSF-EPO hybrid protein MEN 11300 induces anti-EPO antibodies and severe anaemia in rhesus monkeys.
A recombinant human GM-CSF-EPO hybrid protein named MEN 11300 was administered biweekly for a total of 6 weeks to rhesus monkeys in order to evaluate its pharmacokinetic behaviour, tolerability and immunogenicity. In this primate species a strong antibody response was induced which neutralized the in vitro biological activity of human EPO while no antibody response could be detected against human GM-CSF. A severe drop in reticulocyte counts at approximately 2 weeks after initiation of treatment was followed by a dramatic decrease in the number of erythrocytes. No effects were observed on GM-CSF-dependent hematopoietic lineages and the clinical chemistry analyses did not reveal signs of general toxicity. Reticulocyte and erythrocyte counts started to recover 3-4 weeks after discontinuation of treatment in concert with a decline in anti-EPO antibody titres. Nevertheless, cell numbers remained below basal levels up to 50 days after the last MEN 11300 administration. Haematological impairment indicates that the administration to non-human primate of human EPO fused to human GM-CSF, induces neutralizing autoantibodies to the self EPO. Present data do not allow prediction of the immunogenic potential of the fusion protein in humans and a dose-escalating phase I study should be addressed to investigate the safety of the product.
Coscarella
A
A
Menarini Ricerche S.p.A., Department of Biotechnology Research, Via Tito Speri 10-00040 Pomezia, Rome, Italy.
Liddi
R
R
Di Loreto
M
M
Bach
S
S
Faiella
A
A
van der Meide
P H
PH
Mele
A
A
De Santis
R
R
D000740:Anemia / Q000097:blood / Q000209:etiology* / Q000276:immunology; D000818:Animals; D000917:Antibody Formation; D000918:Antibody Specificity; D016207:Cytokines / Q000276:immunology; D004920:Erythropoiesis / Q000187:drug effects; D004921:Erythropoietin / Q000276:immunology* / Q000493:pharmacokinetics / Q000494:pharmacology*; D005260:Female; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000276:immunology / Q000493:pharmacokinetics / Q000494:pharmacology*; D006801:Humans; D008253:Macaca mulatta; D008297:Male; D009500:Neutralization Tests; D011993:Recombinant Fusion Proteins / Q000276:immunology / Q000493:pharmacokinetics / Q000494:pharmacology; D011994:Recombinant Proteins
D016207:Cytokines; D011993:Recombinant Fusion Proteins; D011994:Recombinant Proteins; D004921:Erythropoietin; D016178:Granulocyte-Macrophage Colony-Stimulating Factor