The first goal of this proposal is to extend our existing studies concerning the molecular mechanisms by which murine IgGs persist in the circulation and are transcytosed across the neonatal intestine to maternal-fetal transfer across the yolk sac. To date, we have used site- directed mutagenesis to locate the region of the murine IgG1 molecule that is involved in the first two of these processes. Our available data suggest that the serum persistence of IgGs and IgG transcytosis (across neonatal intestine and yolk sac) are regulated by similar mechanisms, involving closely related receptors. Thus, our second goal is to use current protein engineering techniques to isolate Fc mutants that have higher affinity for binding to the receptor involved in IgG transcytosis, FcRn. This receptor is expressed at high levels in both neonatal intestine and murine yolk sac, consistent with its role in maternal-fetal and neonatal transfer. The increased affinity mutants would be expected to compete more effectively with the high levels of endogenous IgGs for binding to FcRn on murine yolk sac, resulting in higher efficiency of maternal-fetal transfer. Furthermore, the overlap between the catabolic site of murine IgG and the FcRn binding site suggest that the mutants may also persist for longer in the circulation. This study has direct relevance to the improvement of antibodies for maternal-fetal transfer in humans, as first, a receptor that is a homolog of rodent FcRn has recently been isolated from human placenta, and is therefore most likely the receptor involved in IgG transcytosis. Second, the amino acid residues of the murine IgG1 molecule that regulate serum persistence and IgG transytosis are highly conserved in human IgGs, suggesting that the molecular mechanisms involved in these processes are shared between mouse and man.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI039167-03
Application #
2517324
Study Section
Special Emphasis Panel (SRC (41))
Project Start
1995-09-30
Project End
1999-08-31
Budget Start
1997-09-01
Budget End
1999-08-31
Support Year
3
Fiscal Year
1997
Total Cost
Indirect Cost
Name
University of Texas Sw Medical Center Dallas
Department
Microbiology/Immun/Virology
Type
Schools of Medicine
DUNS #
City
Dallas
State
TX
Country
United States
Zip Code
75390
Ward, E Sally; Ober, Raimund J (2018) Targeting FcRn to Generate Antibody-Based Therapeutics. Trends Pharmacol Sci 39:892-904
Ward, E Sally; Devanaboyina, Siva Charan; Ober, Raimund J (2015) Targeting FcRn for the modulation of antibody dynamics. Mol Immunol 67:131-41
Gan, Zhuo; Ram, Sripad; Ober, Raimund J et al. (2013) Using multifocal plane microscopy to reveal novel trafficking processes in the recycling pathway. J Cell Sci 126:1176-88
Ram, Sripad; Kim, Dongyoung; Ober, Raimund J et al. (2012) 3D single molecule tracking with multifocal plane microscopy reveals rapid intercellular transferrin transport at epithelial cell barriers. Biophys J 103:1594-603
Patel, Dipesh A; Puig-Canto, Alberto; Challa, Dilip Kumar et al. (2011) Neonatal Fc receptor blockade by Fc engineering ameliorates arthritis in a murine model. J Immunol 187:1015-22
Ram, Sripad; Prabhat, Prashant; Chao, Jerry et al. (2010) 3D single molecule tracking of quantum-dot labeled antibody molecules using multifocal plane microscopy. Proc SPIE Int Soc Opt Eng 7575:
Chao, Jerry; Ward, E Sally; Ober, Raimund J (2010) A software framework for the analysis of complex microscopy image data. IEEE Trans Inf Technol Biomed 14:1075-87
Abraham, Anish V; Ram, Sripad; Chao, Jerry et al. (2010) Comparison of estimation algorithms in single-molecule localization. Proc SPIE Int Soc Opt Eng 7570:757004
Ram, Sripad; Prabhat, Prashant; Ward, E Sally et al. (2009) Dual objective fluorescence microscopy for single molecule imaging applications. Proc SPIE Int Soc Opt Eng 7184:71840C
Ward, E Sally; Ober, Raimund J (2009) Chapter 4: Multitasking by exploitation of intracellular transport functions the many faces of FcRn. Adv Immunol 103:77-115

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