Nature Biotechnology
- 24, 1279 - 1284 (2006)
Published online: 17 September 2006; | doi:10.1038/nbt1248
Human C5aR knock-in mice facilitate the production and assessment of anti-inflammatory monoclonal antibodiesHyun Lee1, David Zahra1, 2, Alexis Vogelzang1, 2, Rebecca Newton1, Jenny Thatcher1, Annie Quan1, Trina So1, Jörg Zwirner3, Frank Koentgen4, Søren B Padkjær5, Fabienne Mackay1, Peter L Whitfeld2 & Charles R Mackay1, 21
Immunology and Inflammation Department, Garvan Institute of Medical Research, 384 Victoria Street, Darlinghurst, NSW 2010, Australia. 2
G2 Inflammation Pty. Ltd., 384 Victoria Street, Darlinghurst, NSW 2010, Australia. 3
Department of Immunology, Georg-August-University Göttingen, Kreuzbergring 57, D-37075 Göttingen, Germany. 4
Ozgene Pty. Ltd., P.O. Box 1128 Bentley DC, WA 6983 Australia. 5
Novo Nordisk A/S, Novo Nordisk Park, DK-2760 Måløv, Denmark.
Correspondence should be addressed to Charles R Mackay c.mackay@garvan.org.au Complement component C5a binds C5a receptor (C5aR) and facilitates leukocyte chemotaxis and release of inflammatory mediators. We used neutrophils from human C5aR knock-in mice, in which the mouse C5aR coding region was replaced with that of human C5aR, to immunize wild-type mice and to generate high-affinity antagonist monoclonal antibodies (mAbs) to human C5aR. These mAbs blocked neutrophil migration to C5a in vitro and, at low doses, both prevented and reversed inflammatory arthritis in the murine K/BxN model. Of  40 mAbs generated to C5aR, all potent inhibitors recognized a small region of the second extracellular loop that seems to be critical for regulation of receptor activity. Human C5aR knock-in mice not only facilitated production of high-affinity mAbs against an important human therapeutic target but were also useful in preclinical validation of the potency of these antagonists. This strategy should be applicable to other important mAb therapeutics.
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