Département de biologie des agents transmissibles, Centre de Recherche du Service de Santé des Armées, La Tronche, France.
Mini Rev Med Chem. 2009 Dec;9(14):1633-8. doi: 10.2174/138955709791012283.
Recombinant antibodies are therapeutic molecules of choice regarding their efficacy, pharmacokinetics and tolerance - all the more if they are human. The efficacy of antibodies generally depends on their affinity for their antigens. The most straightforward approach to isolate human antibodies with high affinities is the construction and screening of human immune libraries, but Humans cannot be immunized with all antigens of interest, for ethical and practical reasons. We circumvented that difficulty by utilizing non-human primates (NHP) instead of Humans and, in the course of our different studies, we have obtained several antibody fragments with high or very high affinities (from 3 nM to 50 pM) and neutralizing properties. The framework regions (FR) - the regions most implicated in tolerance - of these NHP antibody fragments were shown to be very similar to FR encoded by human germline genes. In one case, in a process called "germline humanization" (or "super-humanization"), we have increased that level of similarity and managed to go even beyond the level observed for human antibodies, without any loss of affinity. Here, the methodological peculiarities of our approach, in comparison with immune libraries built from immunised Humans, and the rationales behind these peculiarities, will be reviewed. The isolation of NHP antibody fragments from immune libraries, followed by the "super-humanization" process, opens a new and highly efficient approach for the production of high-quality recombinant antibodies for therapeutic uses.
重组抗体因其疗效、药代动力学和耐受性而成为治疗选择，尤其是如果它们是人类来源的话。抗体的疗效通常取决于它们与抗原的亲和力。分离具有高亲和力的人类抗体的最直接方法是构建和筛选人类免疫文库，但出于伦理和实际原因，人类不能用所有感兴趣的抗原进行免疫。我们通过利用非人类灵长类动物（NHP）代替人类来规避这一困难，在我们的不同研究中，我们已经获得了几种具有高或非常高亲和力（3 nM 至 50 pM）和中和特性的抗体片段。这些 NHP 抗体片段的框架区（FR）——与耐受性最相关的区域——被证明与人类种系基因编码的 FR 非常相似。在一种情况下，我们采用了一种称为“种系人源化”（或“超人源化”）的过程，提高了这种相似性水平，甚至超过了人类抗体的水平，而没有任何亲和力的损失。在这里，我们将比较从免疫的 NHP 中构建免疫文库的方法的特点，以及这些特点背后的原理。从免疫文库中分离 NHP 抗体片段，然后进行“超人源化”过程，为治疗用途生产高质量的重组抗体开辟了一条新的、高效的途径。
