Abstract
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.
Keywords: Antibody, non human primate, immune library, humanization
Mini-Reviews in Medicinal Chemistry
Title: Obtention and Engineering of Non-Human Primate (NHP) Antibodies for Therapeutics
Volume: 9 Issue: 14
Author(s): Thibaut Pelat, Michael Hust and Philippe Thullier
Affiliation:
Keywords: Antibody, non human primate, immune library, humanization
Abstract: 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.
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Cite this article as:
Pelat Thibaut, Hust Michael and Thullier Philippe, Obtention and Engineering of Non-Human Primate (NHP) Antibodies for Therapeutics, Mini-Reviews in Medicinal Chemistry 2009; 9 (14) . https://dx.doi.org/10.2174/138955709791012283
DOI https://dx.doi.org/10.2174/138955709791012283 |
Print ISSN 1389-5575 |
Publisher Name Bentham Science Publisher |
Online ISSN 1875-5607 |
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