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International Immunology Advance Access published online on October 31, 2006
International Immunology, doi:10.1093/intimm/dxl110
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Published by Oxford University Press 2006.
Received April 25, 2006
Accepted September 20, 2006

Article

Enhanced half-life of genetically engineered human IgG1 antibodies in a humanized FcRn mouse model: potential application in humorally mediated autoimmune disease

Stefka B. Petkova 1, Shreeram Akilesh 2, Thomas J. Sproule 1, Gregory J. Christianson 1, Hana Al Khabbaz 1, Aaron C. Brown 1, Leonard G. Presta 3, Y. Gloria Meng 4, and Derry C. Roopenian 1 *

1 Jackson Laboratory, Bar Harbor, ME 04609, USA
2 Jackson Laboratory, Bar Harbor, ME 04609, USA; Present address: Department of Pathology, Washington University, St Louis, MO, USA
3 Department of Antibody Engineering, Genentech Inc., South San Francisco, CA, USA; Present address: Schering-Plough Biopharma, Palo Alto, CA, USA
4 Department of Assay and Automation Technology, Genentech Inc., South San Francisco, CA, USA

* To whom correspondence should be addressed.
Derry C. Roopenian, E-mail: dcr{at}jax.org


  Abstract

The MHC class I-like Fc receptor FcRn plays an essential role in extending the half-life (t1/2) of IgG antibodies and IgG-Fc-based therapeutics in the circulation. The goal of this study was to analyze the effect of human IgG1 (hIgG1) antibodies with enhanced in vitro binding to FcRn on their in vivo t1/2 in mice expressing human FcRn (hFcRn). Mutants of the humanized monoclonal Herceptin antibody (Hu4D5-IgG1), directed against human epidermal growth factor receptor 2 (p185 HER2), show altered pH-dependent binding to hFcRn in vitro. Two engineered IgG1 mutants (N434A and T307A/E380A/N434A) showed a considerably extended t1/2 in vivo compared with wild-type antibody in mice expressing an hFcRn transgene (Tg) but not in mice expressing the endogenous mouse FcRn. The efficiency of hFcRn-mediated protection was dependent on hFcRn Tg copy number. Moreover, when injected into FcRn-humanized mice at a concentration sufficient to partially saturate hFcRn, the engineered IgG1 mutants with an extended serum t1/2 were most effective in reducing the t1/2 of a tracer hIgG1 antibody. Finally, administration of mutant with high binding to hFcRn ameliorated arthritis induced by passive transfer with human pathogenic plasma. These results indicate that Fc regions modified for high binding affinity to hFcRn increases serum persistence of therapeutic antibodies, that the same approach can be exploited as an anti-autoimmune therapy to promote the clearance of endogenous pathogenic IgG and that FcRn-humanized mice are a promising surrogate for hIgG therapeutic development.

Keywords: antibody; FcRn transgenic mice; neonatal receptor FcRn; rheumatoid arthritis.
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