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 that 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 gamma globulins (IgGs). We have shown that it is possible to increase the serum persistence by engineering the site of an antibody that interacts with the Fc receptor, FcRn. This Fc receptor also regulates the transfer of IgG across the materno-fetal 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 protein antibodies; 2) to increase the serum half-lives of the antibodies; 3) to analyze the transfer of protective antibodies across human and murine maternal-fetal barriers; 4) to humanize the most promising antibodies for use in further studies. 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.
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| 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 |
