The neonatal Fc receptor (FcRn) has four major functions: catabolic protection of IgG and albumin, transcytosis of IgG and antigen presentation. FcRn functions across many tissues and is critical for neonatal acquisition of maternal IgG via colostrum and milk, the pulmonary secretion of IgG and bidirectional transport of both IgG and immune complexes across the adult intestinal epithelium. It is also involved in T cell antigen presentation. A major clinical success of IgGs is as a "magic bullet" precisely targeting and treating a wide array of human disorders, especially cancer and inflammatory diseases. This success is due, in part, to their long half-life in vivo compared to other serum proteins. With our understanding of the critical role of FcRn in this process, a new therapeutic field addressing serum proteins and small molecules half-life has emerged. The major players of this new field are the IgG Fc domain and albumin: clinically relevant molecules are attached to these via fusion extending their functional in vivo half- life. Functional half-life extension of compounds has a number of clinical benefits including: (i) reduction of effective dosage (reducing adverse reactions);(ii) reduced frequency of administration (extended pharmacokinetics);(iii) improved bioavailability;and (iv) a reduction of production costs. Critical for therapeutic development of IgGs and fusion compounds are preclinical models, which accurately reflect human physiology. However, FcRn exhibits species-discrimination binding differences between human and rodents. To overcome this, mice lacking the mouse FcRn and expressing human FcRn (hPcRn) were developed. Although useful, these models express mouse IgGs, which are not effectively protected by hFcRn and mouse albumin. This does not reflect the normal physiological situation. For albumin there is currently no model easily available. To establish models that better reflect the human physiological processes, we propose to exchange the Fc domain of mouse lgG2b with human Fc and to replace the mouse albumin gene with human albumin. To do this, we will use TAL effector nucleases to introduce heterospecific recombinase target sites flanking the region of interest, followed by recombination mediated cassette exchange to directly genetically engineer the zygote of existing humanized FcRn mouse models. By creating these new strains via sequential modification of current models we will build upon their previous use and reputation (data), speeding their implementation. After verification, these novel strains will be distributed via the JAX Mouse Repository. We fully expect these models to more accurately reflect human IgG and human albumin biology and, therefore, rapidly advance drug development and FcRn biology.

Public Health Relevance

Accurate pharmacokinetic data of therapeutic monoclonal antibodies (mAb) and albumin fusion proteins is crucial to their development. mAbs show promise for the treatment of cancer, autoimmune and inflammatory diseases. Albumin based delivery systems have great potential in the treatment of diabetes and the delivery of anticancer compounds. Our proposed work will develop models, which accurately reflect human physiology. The general approach will speed the construction of humanized models relevant to public health encompassing a broad base of preclinical research of relevance to NCI, NIDDK and NIAID.

Agency
National Institute of Health (NIH)
Institute
Office of The Director, National Institutes of Health (OD)
Type
Resource-Related Research Projects (R24)
Project #
1R24OD016473-01
Application #
8476421
Study Section
Special Emphasis Panel (ZTR1-CM-6 (01))
Program Officer
Moro, Manuel H
Project Start
2013-06-13
Project End
2017-03-31
Budget Start
2013-06-13
Budget End
2014-03-31
Support Year
1
Fiscal Year
2013
Total Cost
$168,747
Indirect Cost
$72,320
Name
Jackson Laboratory
Department
Type
DUNS #
042140483
City
Bar Harbor
State
ME
Country
United States
Zip Code
04609
Brehm, Michael A; Wiles, Michael V; Greiner, Dale L et al. (2014) Generation of improved humanized mouse models for human infectious diseases. J Immunol Methods 410:3-17
Low, Benjamin E; Krebs, Mark P; Joung, J Keith et al. (2014) Correction of the Crb1rd8 allele and retinal phenotype in C57BL/6N mice via TALEN-mediated homology-directed repair. Invest Ophthalmol Vis Sci 55:387-95