Please use this identifier to cite or link to this item:
Title: Cross-species analysis of Fc engineered anti-Lewis-Y human IgG1 variants in human neonatal receptor transgenic mice reveal importance of S254 and Y436 in binding human neonatal Fc receptor
Austin Authors: Burvenich, Ingrid JG;Farrugia, William;Lee, Fook T;Catimel, Bruno;Liu, Zhanqi;Makris, Dahna;Cao, Diana;O'Keefe, Graeme J;Brechbiel, Martin W;King, Dylan ;Spirkoska, Violeta;Allan, Laura C ;Ramsland, Paul A ;Scott, Andrew M 
Affiliation: Tumour Targeting Laboratory, Ludwig Institute for Cancer Research and Olivia Newton-John Cancer Research Institute, Heidelberg, Victoria, Australia
School of Cancer Medicine, La Trobe University, Melbourne, Victoria, Australia
Centre for Biomedical Research, Burnet Institute, Melbourne, Victoria, Australia
Department of Molecular Imaging and Therapy, Austin Health, Heidelberg, Victoria, Australia
Radioimmune Inorganic Chemistry Section, Radiation Oncology Branch, Center for Cancer Research, National Cancer Institute, Bethesda, MD, USA
School of Science, RMIT University, Bundoora, Victoria, Australia
Department of Immunology , Monash University, Melbourne, Victoria, Australia
Department of Surgery Austin Health , University of Melbourne, Heidelberg, Victoria, Australia
Faculty of Medicine, University of Melbourne, Melbourne, Victoria, Australia
Issue Date: Jun-2016
Date: 2016-03-30
Publication information: mAbs 2016; 8(4): 775-786
Abstract: IgG has a long half-life through engagement of its Fc region with the neonatal Fc receptor (FcRn). The FcRn binding site on IgG1 has been shown to contain I253 and H310 in the CH2 domain and H435 in the CH3 domain. Altering the half-life of IgG has been pursued with the aim to prolong or reduce the half-life of therapeutic IgGs. More recent studies have shown that IgGs bind differently to mouse and human FcRn. In this study we characterize a set of hu3S193 IgG1 variants with mutations in the FcRn binding site. A double mutation in the binding site is necessary to abrogate binding to murine FcRn, whereas a single mutation in the FcRn binding site is sufficient to no longer detect binding to human FcRn and create hu3S193 IgG1 variants with a half-life similar to previously studied hu3S193 F(ab')2 (t1/2β, I253A, 12.23 h; H310A, 12.94; H435A, 12.57; F(ab')2, 12.6 h). Alanine substitutions in S254 in the CH2 domain and Y436 in the CH3 domain showed reduced binding in vitro to human FcRn and reduced elimination half-lives in huFcRn transgenic mice (t1/2β, S254A, 37.43 h; Y436A, 39.53 h; wild-type, 83.15 h). These variants had minimal effect on half-life in BALB/c nu/nu mice (t1/2β, S254A, 119.9 h; Y436A, 162.1 h; wild-type, 163.1 h). These results provide insight into the interaction of human Fc by human FcRn, and are important for antibody-based therapeutics with optimal pharmacokinetics for payload strategies used in the clinic.
DOI: 10.1080/19420862.2016.1156285
ORCID: 0000-0002-6656-295X
Journal: mAbs
PubMed URL:
Type: Journal Article
Subjects: Antibody engineering
Fc receptors; molecular biology
neonatal Fc receptor
transgenic mice
Appears in Collections:Journal articles

Show full item record

Page view(s)

checked on Apr 15, 2024

Google ScholarTM


Items in AHRO are protected by copyright, with all rights reserved, unless otherwise indicated.