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

被引:15
作者
Coscarella, A
Liddi, R
Di Loreto, M
Bach, S
Faiella, A
van der Meide, PH
Mele, A
De Santis, R
机构
[1] Menarini Ric SPA, Dept Biotechnol Res, I-00040 Pomezia, Italy
[2] Biomed Primate Res Ctr, Lab Cytokine Biol, NL-2280 GH Rijswijk, Netherlands
关键词
GM-CSF fusion protein; immunogenicity; primate model;
D O I
10.1006/cyto.1998.0384
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
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. (C) 1998 Academic Press.
引用
收藏
页码:964 / 969
页数:6
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