Clinical validation of the "in silico" prediction of immunogenicity of a human recombinant therapeutic protein
Clinical validation of the "in silico" prediction of immunogenicity of a human recombinant therapeutic protein
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DOI：
10.1016/j.clim.2007.03.544
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发表时间：
2007-07-01
影响因子：
8.6
通讯作者：
Martin, W.
中科院分区：
文献类型：
--
作者：
Koren, E.;De Groot, A. S.;Martin, W.
由蛋白质疗法引起的抗体会对人体产生严重的副作用。我们研究了一种重组融合蛋白（FPX）的免疫原性，该蛋白由两个相同的、具有生物活性的肽组成，附着在人Fc片段上。EpiMatrix是一个二氧化硅表位定位工具，预测了FPX肽部分14个氨基酸羧基末端区域内混杂的t细胞表位。76名健康人注射FPX后，37%的人在单次注射后产生抗体。在抗体阳性而非抗体阴性的受试者中观察到针对上述肽的羧基末端的记忆t细胞反应。预测的t细胞表位的混杂性被抗体阳性受试者中所有常见HLA等位基因的代表所证实。根据EpiMatrix的预测，HLA单倍型DRB1*0701/1501与最高的t细胞和抗体应答相关。综上所述，二氧化硅预测可以成功地用于鉴定治疗蛋白中的II类限制性t细胞表位并预测其在人体内的免疫原性。(c) 2007年Elsevier Inc.出版
Antibodies elicited by protein therapeutics can cause serious side effects in humans. We studied immunogenicity of a recombinant fusion protein (FPX) consisting of two identical, biologically active, peptides attached to human Fc fragment. EpiMatrix, an in silica epitope-mapping toot, predicted promiscuous T-cell epitope(s) within the 14-amino-acid carboxyterminal region of the peptide portion of FPX. On administration of FPX in 76 healthy human subjects, 37% developed antibodies after a single injection. A memory T-cell response against the above carboxy-terminus of the peptide was observed in antibody-positive but not in antibody-negative subjects. Promiscuity of the predicted T-cell epitope(s) was confirmed by representation of all common HLA alleles in antibody-positive subjects. As predicted by EpiMatrix, HLA haplotype DRB1*0701/1501 was associated with the highest T-cell and antibody response. In conclusion, in silica prediction can be successfully used to identify Class II restricted T-cell epitopes within therapeutic proteins and predict immunogenicity thereof in humans. (c) 2007 Published by Elsevier Inc.