The regulation of immunoglobulin G (IgG) levels in vivo represents a fundamental aspect of humoral immunity. A central player in this process is the non-classical Fc receptor, FcRn, that transports IgGs within and across cells and salvages them from lysosomal degradation. The current application is directed towards mechanistic studies of engineered antibodies that are designed to inhibit the salvage function of FcRn. Our approach is to engineer Fc fragments so that they competitively inhibit the binding of wild type IgGs to FcRn and thereby enhance their degradation. Such engineered antibodies, or Abdegs (for `antibodies that enhance IgG degradation'), can be used to lower IgG levels in mice. As such, Abdegs hold promise as therapeutics for the clearance of IgGs in antibody-mediated diseases and in inducing the elimination of IgG-drug or IgG-toxin complexes. However, to date, the mechanisms and properties of Abdeg activity are poorly characterized. For example, it is not well understood how the biophysical nature of Abdeg-FcRn interactions correlates with inhibitory activity. The efficacy of Abdegs in the treatment of IgG-mediated autoimmunity has also not been analyzed. Our experiments are designed to address these and other questions, and will involve the use of in vitro and in vivo murine systems.
The Specific aims of the current study are: 1. To understand how Fc-FcRn interaction properties impact FcRn function using in vitro systems;2. To analyze the effects of potential Abdegs with distinct properties on endogenous IgG levels;3. To analyze the effects of Abdegs in murine models of rheumatoid arthritis. This comprehensive mechanistic study in animal models constitutes a crucial component of our longer term research goal, which is to use Abdegs for the treatment of human disease. In addition, this project should provide valuable insight into the molecular mechanisms that regulate the transport and dynamics of IgGs in vivo.

Public Health Relevance

The current application is directed towards the generation and characterization of a class of engineered antibodies that can be used to lower the levels of immunoglobulin G (IgG). Such engineered antibodies would have applications in many clinical situations, such as for the treatment of IgG-mediated autoimmunity (e.g. rheumatoid arthritis and systemic lupus erythematosus) and the clearance of toxins or drugs from the body. We seek funds to carry out mechanistic and efficacy studies in mouse models that are a prerequisite to the use of these reagents to treat human disease.

Agency
National Institute of Health (NIH)
Institute
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Type
Research Project (R01)
Project #
5R01AR056478-05
Application #
8274344
Study Section
Hypersensitivity, Autoimmune, and Immune-mediated Diseases Study Section (HAI)
Program Officer
Mao, Su-Yau
Project Start
2008-07-08
Project End
2014-05-31
Budget Start
2012-06-01
Budget End
2014-05-31
Support Year
5
Fiscal Year
2012
Total Cost
$328,268
Indirect Cost
$119,180
Name
University of Texas Sw Medical Center Dallas
Department
Microbiology/Immun/Virology
Type
Schools of Medicine
DUNS #
800771545
City
Dallas
State
TX
Country
United States
Zip Code
75390
Ward, E Sally; Velmurugan, Ramraj; Ober, Raimund J (2014) Targeting FcRn for therapy: from live cell imaging to in vivo studies in mice. Immunol Lett 160:158-62
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
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
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