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首页> 外文期刊>Molecular biotechnology >Pharmacokinetic and immunogenic behavior of three recombinant human GM-CSF-EPO hybrid proteins in cynomolgus monkeys.
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Pharmacokinetic and immunogenic behavior of three recombinant human GM-CSF-EPO hybrid proteins in cynomolgus monkeys.

机译：三种重组人GM-CSF-EPO杂合蛋白在食蟹猴中的药代动力学和免疫原性行为。

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摘要

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.
机译：MEN 11,300，MEN 11,301和MEN 11,303是三种重组人杂种蛋白，如最近所述，它们可以诱导体外类红细胞分化。本文提供了重复静脉输注后其药代动力学和免疫原性行为的数据。以0.8或1.6微克/千克的剂量向食蟹猴给药。首次给药后获得的药代动力学数据表明，半衰期（t1 / 2）和清除率（CL）值是剂量依赖性的，三种杂合蛋白之间无显着差异。第十次给药后，血浆中无法检测到高剂量和低剂量的MEN 11,300和MEN 11,301，以及高剂量的MEN 11,303，而较低剂量的MEN 11,303则没有显示其药代动力学特征的改变。血浆的免疫学分析为这种不同的药代动力学行为提供了解释。实际上，经过MEN 11,300和MEN 11,301反复治疗的动物的血浆样品显示了对高剂量和低剂量方案的特异性抗体形成。这些抗体在体外发挥了杂合蛋白的强大中和活性，对促红细胞生成素（EPO）部分具有主要特异性。相比之下，较低剂量的MEN 11,303不会诱导可检测的抗体反应，而在高剂量方案中观察到的抗体没有对杂交蛋白或粒细胞-巨噬细胞集落刺激因子（GM-CSF）或EPO。血液学参数不受治疗的影响，因此表明抗EPO中和抗体反应不会与内源性猴细胞因子发生交叉反应。总体免疫原性数据表明，在三种融合蛋白中，MEN 11,303可能具有较低的免疫原性。

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