The efficacy of antibodies (Abs) to toxins and capsules is a complex function of dose, specificity, isotype, complement activation and FcR engagement. However, 120 years after Ab-mediated immunity was first discovered, the relationships between affinity, isotype, and Fc receptor activation have not been rigorously defined for any microbial toxin or capsule. Our group has generated mAbs to five Bacillus anthracis antigens including anthrax toxin components protective antigen, lethal factor, and edema factor, capsule poly((-Dglutamic acid) (PGA), and Anthrolysin. This application proposes to investigate the structure-function relationship for these immunoglobulins with the goal of identifying the optimal combination of affinity, isotype, and specificity that determines protective efficacy. We propose to apply several state of the art technologies available to us in the form of in vitro somatic hypermutation, human FcR technology, V region expression, and Veloclmmune? system to carry out the first comprehensive analysis of this fundamental immunological question while also generating new Ab reagents that are candidates for passive immune therapies.
Three specific aims are proposed:
Aim 1. To investigate the relationship between affinity and efficacy capacity for Abs to anthrax toxins and PGA;
Aim 2. To investigate the efficacy of constant (C) regions in Abneutralization of anthrax toxins and PGA;
Aim 3. To investigate the relationship between human Fc type and Ab-neutralization of anthrax toxins and PGA, We anticipate that the information generated from these studies will result in the design of more effective passive therapeutic strategies.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Specialized Center--Cooperative Agreements (U54)
Project #
5U54AI057158-07
Application #
8043568
Study Section
Special Emphasis Panel (ZAI1)
Project Start
Project End
Budget Start
2010-03-01
Budget End
2011-02-28
Support Year
7
Fiscal Year
2010
Total Cost
$619,753
Indirect Cost
Name
Columbia University (N.Y.)
Department
Type
DUNS #
621889815
City
New York
State
NY
Country
United States
Zip Code
10032
Li, Xiao-Ping; Kahn, Jennifer N; Tumer, Nilgun E (2018) Peptide Mimics of the Ribosomal P Stalk Inhibit the Activity of Ricin A Chain by Preventing Ribosome Binding. Toxins (Basel) 10:
Goldman, David L; Nieves, Edward; Nakouzi, Antonio et al. (2018) Serum-Mediated Cleavage of Bacillus anthracis Protective Antigen Is a Two-Step Process That Involves a Serum Carboxypeptidase. mSphere 3:
MariƩ, Isabelle J; Chang, Hao-Ming; Levy, David E (2018) HDAC stimulates gene expression through BRD4 availability in response to IFN and in interferonopathies. J Exp Med 215:3194-3212
Uhde, Melanie; Ajamian, Mary; Wormser, Gary P et al. (2017) Reply to Naktin. Clin Infect Dis 64:1145-1146
Chen, Han; Coseno, Molly; Ficarro, Scott B et al. (2017) A Small Covalent Allosteric Inhibitor of Human Cytomegalovirus DNA Polymerase Subunit Interactions. ACS Infect Dis 3:112-118
Aguilar, Jorge L; Varshney, Avanish K; Pechuan, Ximo et al. (2017) Monoclonal antibodies protect from Staphylococcal Enterotoxin K (SEK) induced toxic shock and sepsis by USA300 Staphylococcus aureus. Virulence 8:741-750
Zhou, Yijun; Li, Xiao-Ping; Chen, Brian Y et al. (2017) Ricin uses arginine 235 as an anchor residue to bind to P-proteins of the ribosomal stalk. Sci Rep 7:42912
Basu, Debaleena; Li, Xiao-Ping; Kahn, Jennifer N et al. (2016) The A1 Subunit of Shiga Toxin 2 Has Higher Affinity for Ribosomes and Higher Catalytic Activity than the A1 Subunit of Shiga Toxin 1. Infect Immun 84:149-61
Uhde, Melanie; Ajamian, Mary; Li, Xueting et al. (2016) Expression of C-Reactive Protein and Serum Amyloid A in Early to Late Manifestations of Lyme Disease. Clin Infect Dis 63:1399-1404
Pham, Alissa M; Santa Maria, Felicia Gilfoy; Lahiri, Tanaya et al. (2016) PKR Transduces MDA5-Dependent Signals for Type I IFN Induction. PLoS Pathog 12:e1005489

Showing the most recent 10 out of 655 publications