全合成免疫原。第三部分。铰链肽/胃泌素缀合物的合成及其免疫学性质。

E Wünsch, L Moroder, G Hübener, H J Musiol, R Von Grünigen, W Göhring, R Scharf, C H Schneider
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摘要

我们选择了人类IgG1铰链片段225-232/225'-232'作为抗原肽多重附着的核心分子。该双链双胱氨酸基铰链肽的两种缀合物分别是:i)通过将其c端与[NIe15]-人-小胃素-[2,17]连接,ii)通过在两个n端与人大胃素序列1-14延长所得到的铰链肽/[NIe15]-小胃素-[2-17]缀合物,得到大胃素-[1-14]/铰链肽/小胃素-[2-17]缀合物。对于这些肽结构的合成,采用了预形成的双链双半胱氨酸肽和经过适当保护的单体双半胱氨酸肽的合成途径。对于后一种方法,采用了先前关于双半胱氨酸铰链肽225-232优先氧化为平行排列二聚体的观察。两种合成途径都能得到相同的产品。在豚鼠中使用合成杂交体进行免疫实验,产生了令人惊讶的强免疫反应,其抗little-gastrin抗体滴度与iso1 -细胞色素c/little-gastrin-[2-17]偶联物作为载体-半抗原系统诱导的抗体滴度相当。这些发现表明,这两种胃泌素结构是完全胜任的免疫原。此外,抗体的胃泌素受体样特异性表明,合成杂交体和细胞色素c偶联物都允许表达与这种激素的生物活性结构相似的胃泌素特异性构象表位。这种合成杂交体的有用性进一步得到证实,观察到含有小胃泌素2-17和大胃泌素1-14序列的二价免疫原能够诱导针对这两种抗原序列的免疫应答,尽管效率不同。这些结果充分证实了我们的预期。
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Fully synthetic immunogens. Part III. Synthesis of hinge-peptide/gastrin conjugates and their immunological properties.

As core molecule for the multiple attachment of antigenic peptides we have selected the human IgG1 hinge fragment 225-232/225'-232'. Two types of conjugates of this double-chain bis-cystinyl hinge-peptide were prepared i) by linking its C-termini to [NIe15]-human-little-gastrin-[2,17] and ii) by elongating the resulting hinge-peptide/[NIe15]-little-gastrin-[2-17] conjugate at the two N-termini with the human big-gastrin sequence 1-14 to produce the big-gastrin-[1-14]/hinge-peptide/little-gastrin-[2-17] conjugate. For the synthesis of these peptide structures both the route via the preformed double-chain bis-cystinyl peptide and the route via suitably protected monomeric bis-cysteinyl peptides were used. For the latter approach advantage was taken of the previous observation about the preferred oxidation of the bis-cysteinyl hinge-peptide 225-232 to the dimer in parallel alignment. Both synthetic routes led to identical products. Immunization experiments in guinea pigs with the synthetic hybrids led to surprisingly strong immune responses with anti-little-gastrin antibody titers comparable to those induced by the iso-1-cytochrome c/little-gastrin-[2-17] conjugate as carrier-hapten system. These findings show that the two gastrin constructs are fully competent immunogens. Additionally, the gastrin receptor-like specificity of the antibodies indicates that both the synthetic hybrids and the cytochrome c conjugate allow for expression of a little-gastrin-specific conformational epitope similar to the bioactive structure of this hormone. The usefulness of such synthetic hybrids is further confirmed by the observation that the bivalent immunogen, containing both the little-gastrin 2-17 and the big-gastrin 1-14 sequence, is capable of inducing an immune response against both antigenic sequences, although with different efficiency. These results fully confirm our expectations.

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