Journal
MABS
Volume 7, Issue 5, Pages 922-930Publisher
TAYLOR & FRANCIS INC
DOI: 10.1080/19420862.2015.1067353
Keywords
CH2; FcRn; half-life; CH3; macaques; transcytosis; antibody domains
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Funding
- NIH, National Cancer Institute, Center for Cancer Research
- NIH, National Cancer Institute [N01-CO-12400]
- Shanghai Pujiang Talent Program
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Engineered antibody domains (eAds) are promising candidate therapeutics but their half-life is relatively short partly due to weak or absent binding to the neonatal Fc receptor (FcRn). We developed a novel approach to increase the eAd binding to FcRn based on a combination of structure-based design, computational modeling and phage display methodologies. By using this approach, we identified 2 IgG1 CH2-derived eAds fused to a short FcRn-binding motif derived from IgG1 CH3 that exhibited greatly enhanced FcRn binding with strict pH dependency. Importantly, the increased affinity resulted in significantly enhanced FcRn-mediated epithelial transcytosis and prolonged elimination half-life (mean 44.1hours) in cynomolgus macaques. These results demonstrate for the first time that the half-life of isolated eAds can be prolonged (optimized) by increasing their binding to FcRn while maintaining their small size, which has important implications for development of therapeutics, including eAd-drug conjugates with enhanced penetration in solid tissues.
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