EXCEED THE SPACE PROVIDED. Bacillus anthracis poses an enormous bioterrorism threat. Although antibiotics can be effective in treating anthrax infection, early diagnosis is essential. In addition, antibiotic resistant strains have been developed. There is also concern about the efficacy and safety of existing vaccines, and safety issues are exacerbated for the vaccination of neonates. Passive immunotherapy with antibodies would provide an attractive, alternative route for protection which would be effective against antibiotic resistant strains. However, suitable (humanized) antibodies are currently not available. The use of passive antibodies in prophylaxis also necessitates frequent doses due to the limited serum half-life of existing antibodies. We will attempt to overcome these shortcomings. First, we plan to use current methods of antibody engineering to generate antibodies that target both spore and toxin components of B. anthracis. Second, we will use technology that has been developed in our laboratory to increase the serum half-life of gammaglobulins (IgGs). We have shown that it is possible to increase the serum persistence by engineering the site of an antibody which interacts with the Fc receptor, FcRn. This Fc receptor also regulates the transfer of IgG across the maternofetal barrier. It is therefore likely that antibodies with increased serum half-lives will be transferred more efficiently to the fetus via increased binding to FcRn.
Our specific aims are: 1) to generate effective anti-protective antigen and anti-spore coat (exosporium) protein antibodies; 2) to increase the serum half-lives of the antibodies; 3) to humanize the most promising candidates for use in further studies; 4) to analyze the transfer of protective antibodies across human and murine maternofetal barriers. The proposed analyses should provide effective reagents for the prophylaxis and treatment of anthrax. They should also give new insight into understanding the role of antibodies in limiting infection, and this has broader relevance to other pathogens. PERFORMANCE SITE ========================================Section End===========================================

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI055556-03
Application #
6833977
Study Section
Special Emphasis Panel (ZRG1-BM-1 (01))
Program Officer
Baker, Phillip J
Project Start
2003-09-15
Project End
2007-12-31
Budget Start
2005-01-01
Budget End
2005-12-31
Support Year
3
Fiscal Year
2005
Total Cost
$351,000
Indirect Cost
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; Devanaboyina, Siva Charan; Ober, Raimund J (2015) Targeting FcRn for the modulation of antibody dynamics. Mol Immunol 67:131-41
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
Vaccaro, Carlos; Bawdon, Roger; Wanjie, Sylvia et al. (2006) Divergent activities of an engineered antibody in murine and human systems have implications for therapeutic antibodies. Proc Natl Acad Sci U S A 103:18709-14
Zhou, Jinchun; Mateos, Fernando; Ober, Raimund J et al. (2005) Conferring the binding properties of the mouse MHC class I-related receptor, FcRn, onto the human ortholog by sequential rounds of site-directed mutagenesis. J Mol Biol 345:1071-81
Vaccaro, Carlos; Zhou, Jinchun; Ober, Raimund J et al. (2005) Engineering the Fc region of immunoglobulin G to modulate in vivo antibody levels. Nat Biotechnol 23:1283-8