title: Pre- and postexposure protection against virulent anthrax infection in mice by humanized monoclonal antibodies to Bacillus anthracis capsule.
abstract: One of the two essential virulence factors of Bacillus anthracis is the poly-γ-D-glutamic acid (γDPGA) capsule. Five γDPGA-specific antibody antigen-binding fragments (Fabs) were generated from immunized chimpanzees. The two selected for further study, Fabs 11D and 4C, were both converted into full-length IgG1 and IgG3 mAbs having human IgG1 or IgG3 constant regions. These two mAbs had similar binding affinities, in vitro opsonophagocytic activities, and in vivo efficacies, with the IgG1 and IgG3 subclasses reacting similarly. The mAbs bound to γDPGA specifically with estimated binding affinities (K(d)) of 35-70 nM and effective affinities (effective K(d)) of 0.1-0.3 nM. The LD(50) in an opsonophagocytic bactericidal assay was ≈10 ng/mL of 11D or 4C. A single 30-μg dose of either mAb given to BALB/c mice 18 h before challenge conferred about 50% protection against a lethal intratracheal spore challenge by the virulent B. anthracis Ames strain. More importantly, either mAb given 8 h or 20 h after challenge provided significant protection against lethal infection. Thus, these anti-γDPGA mAbs should be useful, alone or in combination with antitoxin mAbs, for achieving a safe and efficacious postexposure therapy for anthrax.
authors.affiliation: Laboratory of Infectious Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA. zc20a@nih.gov
authors.forename: Zhaochun
authors.initials: Z
authors.lastname: Chen
authors.forename: Rachel
authors.initials: R
authors.lastname: Schneerson
authors.forename: Julie
authors.initials: J
authors.lastname: Lovchik
authors.forename: C Rick
authors.initials: CR
authors.lastname: Lyons
authors.forename: Huaying
authors.initials: H
authors.lastname: Zhao
authors.forename: Zhongdong
authors.initials: Z
authors.lastname: Dai
authors.forename: Joanna
authors.initials: J
authors.lastname: Kubler-Kielb
authors.forename: Stephen H
authors.initials: SH
authors.lastname: Leppla
authors.forename: Robert H
authors.initials: RH
authors.lastname: Purcell
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D000881:Anthrax / Q000276:immunology / Q000517:prevention & control* / Q000628:therapy*; D000890:Anti-Infective Agents / Q000494:pharmacology; D000911:Antibodies, Monoclonal / Q000737:chemistry*; D001408:Bacillus anthracis / Q000378:metabolism*; D006801:Humans; D007074:Immunoglobulin G / Q000737:chemistry; D007700:Kinetics; D051379:Mice; D008807:Mice, Inbred BALB C; D008969:Molecular Sequence Data; D002679:Pan troglodytes; D010587:Phagocytosis; D011485:Protein Binding; D017386:Sequence Homology, Amino Acid; D020349:Surface Plasmon Resonance
chemical_list: D000890:Anti-Infective Agents; D000911:Antibodies, Monoclonal; D007074:Immunoglobulin G