Artificial proteins with reduced immunogenicity

本发明涉及人工改变的蛋白质，优选地涉及融合蛋白，当暴露于物种体内时其与亲本未改变分子相比具有降低的免疫原性。本发明尤其涉及新的免疫球蛋白融合蛋白，其基本上由免疫球蛋白分子或其片段通过其C-末端共价融合至生物活性的非免疫球蛋白分子(优选多肽或蛋白质或其生物活性片段)的N-末端组成。在一个具体的实施方案中，本发明涉及这样的融合蛋白，其由抗体的Fc部分按如上所述融合至引起生物或药学功效的非免疫靶分子上组成。本发明的分子与未改变的分子相比具有在一个或多个氨基酸残基位置处被改变的氨基酸序列但原则上相同的生物活性。这些改变是在分子中鉴定为T细胞表位的区域内进行的，其中所述T细胞表位对活的宿主体内的免疫反应起作用。因此，本发明也涉及通过鉴定所述表位制备此类融合蛋白的新方法，其包括使用计算机辅助方法计算肽中针对MHC II类分子结合位点的T细胞表位值。 The invention relates to artificial modified proteins, preferably fusion proteins, having a reduced immunogenicity compared to the parent non-modified molecule when exposed to a species in vivo. The invention relates, above all, to novel immunoglobulin fusion proteins which essentially consist of an immunoglobulin molecule or a fragment thereof covalently fused via its C-terminus to the N-terminus of a biologically active non-immunoglobulin molecule, preferably a polypeptide or protein or a biologically active fragment thereof. In a specific embodiment, the invention relates to fusion proteins consisting of an Fc portion of an antibody which is fused as mentioned to the non-immunological target molecule which elicits biological or pharmacological efficacy. The molecules of the invention have amino acid sequences which are altered in one or more amino acid residue positions but have in principal the same biological activity as compared with the non-altered molecules. The changes are made in regions of the molecules which are identified as T-cell epitopes, which contribute to an immune reaction in a living host. Thus, the invention also relates to a novel method of making such fusion proteins by identifying said epitopes comprising calculation of T-cell epitope values for MHC Class II molecule binding sites in a peptide by computer-aided methods.