scholarly journals Human Monoclonal Antibody AVP-21D9 to Protective Antigen Reduces Dissemination of the Bacillus anthracis Ames Strain from the Lungs in a Rabbit Model

2007 ◽  
Vol 75 (7) ◽  
pp. 3414-3424 ◽  
Author(s):  
Johnny W. Peterson ◽  
Jason E. Comer ◽  
Wallace B. Baze ◽  
David M. Noffsinger ◽  
Autumn Wenglikowski ◽  
...  
Keyword(s):  
Monoclonal Antibody ◽  
Bacillus Anthracis ◽  
Protective Antigen ◽  
Human Monoclonal Antibody ◽  
Rabbit Model ◽  
Concomitant Treatment ◽  
Dependent Manner ◽  
Lethal Challenge ◽  
Tissue Sections ◽  
Inhalation Anthrax

ABSTRACT Dutch-belted and New Zealand White rabbits were passively immunized with AVP-21D9, a human monoclonal antibody to protective antigen (PA), at the time of Bacillus anthracis spore challenge using either nasal instillation or aerosol challenge techniques. AVP-21D9 (10 mg/kg) completely protected both rabbit strains against lethal infection with Bacillus anthracis Ames spores, regardless of the inoculation method. Further, all but one of the passively immunized animals (23/24) were completely resistant to rechallenge with spores by either respiratory challenge method at 5 weeks after primary challenge. Analysis of the sera at 5 weeks after primary challenge showed that residual human anti-PA levels decreased by 85 to 95%, but low titers of rabbit-specific anti-PA titers were also measured. Both sources of anti-PA could have contributed to protection from rechallenge. In a subsequent study, bacteriological and histopathology analyses revealed that B. anthracis disseminated to the bloodstream in some naïve animals as early as 24 h postchallenge and increased in frequency with time. AVP-21D9 significantly reduced the dissemination of the bacteria to the bloodstream and to various organs following infection. Examination of tissue sections from infected control animals, stained with hematoxylin-eosin and the Gram stain, showed edema and/or hemorrhage in the lungs and the presence of bacteria in mediastinal lymph nodes, with necrosis and inflammation. Tissue sections from infected rabbits dosed with AVP-21D9 appeared comparable to corresponding tissues from uninfected animals despite lethal challenge with B. anthracis Ames spores. Concomitant treatment with AVP-21D9 at the time of challenge conferred complete protection in the rabbit inhalation anthrax model. Early treatment increased the efficacy progressively and in a dose-dependent manner. Thus, AVP-21D9 could offer an adjunct or alternative clinical treatment regimen against inhalation anthrax.

scholarly journals Phase I Study Evaluating the Safety and Pharmacokinetics of MDX-1303, a Fully Human Monoclonal Antibody against Bacillus anthracis Protective Antigen, in Healthy Volunteers

2011 ◽  
Vol 18 (12) ◽  
pp. 2136-2142 ◽  
Author(s):  
Valerie Riddle ◽  
Phillip Leese ◽  
Diann Blanset ◽  
Melany Adamcio ◽  
Matthew Meldorf ◽  
...  
Keyword(s):  
Monoclonal Antibody ◽  
Adverse Events ◽  
Phase I ◽  
Bacillus Anthracis ◽  
Phase I Study ◽  
Protective Antigen ◽  
Human Monoclonal Antibody ◽  
Systemic Exposure ◽  
Healthy Human ◽  
Serious Adverse Events

ABSTRACTMDX-1303 (Valortim) is a fully human monoclonal antibody (hMAb) with a high affinity forBacillus anthracisprotective antigen (PA). MDX-1303 binds to PA and interferes with the activity of the anthrax toxin; it was selected based on its superior functional activity in the toxin neutralization activity (TNA) assay. MDX-1303 has demonstrated efficacy in the postexposure and therapeutic settings in New Zealand White rabbits, cynomolgus monkeys, and African green monkeys. This phase I study sought to characterize the safety, tolerability, immunogenicity, and pharmacokinetics (PK)/pharmacodynamics (PD) of MDX-1303 in healthy human subjects. Cohorts of 3 to 10 subjects were administered MDX-1303 as either a single intravenous (i.v.) dose at dose levels of 0.3, 1, 3, 10, and 20 mg/kg of body weight or as a single intramuscular (i.m.) dose at 100 mg. Forty-six subjects were enrolled, and 16 (35%) of these subjects experienced one or more grade 1 adverse events considered to be related to treatment with MDX-1303. There were no grade 2 to 4 adverse events or serious adverse events (SAEs) considered to be related to treatment. The mean half-life of MDX-1303 ranged from 22 to 33 days across the i.v. administration cohorts and was approximately 32 days following i.m. administration. Systemic exposure following 100-mg i.m. administration was within the range of exposure following 1-mg/kg i.v. administration with a relative bioavailability of approximately 65%. MDX-1303 was generally well tolerated, and no anti-MDX-1303 antibodies were detected following a single dose.

scholarly journals Mechanism of Lethal Toxin Neutralization by a Human Monoclonal Antibody Specific for the PA20 Region of Bacillus anthracis Protective Antigen

Toxins ◽  
2011 ◽  
Vol 3 (8) ◽  
pp. 979-990 ◽  
Author(s):  
Donald Reason ◽  
Justine Liberato ◽  
Jinying Sun ◽  
Jessica Camacho ◽  
Jianhui Zhou
Keyword(s):  
Monoclonal Antibody ◽  
Bacillus Anthracis ◽  
Protective Antigen ◽  
Human Monoclonal Antibody ◽  
Lethal Toxin

scholarly journals A Phase 1 Study of PAmAb, a Fully Human Monoclonal Antibody against Bacillus anthracis Protective Antigen, in Healthy Volunteers

2005 ◽  
Vol 41 (1) ◽  
pp. 12-20 ◽  
Author(s):  
G. M. Subramanian ◽  
P. W. Cronin ◽  
G. Poley ◽  
A. Weinstein ◽  
S. M. Stoughton ◽  
...  
Keyword(s):  
Monoclonal Antibody ◽  
Healthy Volunteers ◽  
Bacillus Anthracis ◽  
Protective Antigen ◽  
Phase 1 ◽  
Human Monoclonal Antibody ◽  
Phase 1 Study

scholarly journals Functional Analysis of Bacillus anthracis Protective Antigen by Using Neutralizing Monoclonal Antibodies

2004 ◽  
Vol 72 (11) ◽  
pp. 6313-6317 ◽  
Author(s):  
Fabien Brossier ◽  
Martine Lévy ◽  
Annie Landier ◽  
Pierre Lafaye ◽  
Michèle Mock
Keyword(s):  
Functional Analysis ◽  
Monoclonal Antibodies ◽  
Bacillus Anthracis ◽  
Protective Antigen ◽  
Lethal Factor ◽  
Cell Receptor ◽  
Lethal Challenge ◽  
Edema Factor

ABSTRACT Protective antigen (PA) is central to the action of the lethal and edema toxins produced by Bacillus anthracis. It is the common cell-binding component, mediating the translocation of the enzymatic moieties (lethal factor [LF] and edema factor) into the cytoplasm of the host cell. Monoclonal antibodies (MAbs) against PA, able to neutralize the activities of the toxins in vitro and in vivo, were screened. Two such MAbs, named 7.5 and 48.3, were purified and further characterized. MAb 7.5 binds to domain 4 of PA and prevents the binding of PA to its cell receptor. MAb 48.3 binds to domain 2 and blocks the cleavage of PA into PA63, a step necessary for the subsequent interaction with the enzymatic moieties. The epitope recognized by this antibody is in a region involved in the oligomerization of PA63; thus, MAb 48.3 does not recognize the oligomer form. MAbs 7.5 and 48.3 neutralize the activities of anthrax toxins produced by B. anthracis in mice. Also, there is an additive effect between the two MAbs against PA and a MAb against LF, in protecting mice against a lethal challenge by the Sterne strain. This work contributes to the functional analysis of PA and offers immunotherapeutic perspectives for the treatment of anthrax disease.

scholarly journals Bacillus anthracis Edema Toxin Impairs Neutrophil Actin-Based Motility

2009 ◽  
Vol 77 (6) ◽  
pp. 2455-2464 ◽  
Author(s):  
Sarah E. Szarowicz ◽  
Russell L. During ◽  
Wei Li ◽  
Conrad P. Quinn ◽  
Wei-Jen Tang ◽  
...  
Keyword(s):  
Bacillus Anthracis ◽  
Protective Antigen ◽  
Fold Increase ◽  
Polymorphonuclear Neutrophil ◽  
Actin Assembly ◽  
Anthrax Lethal Toxin ◽  
Edema Factor ◽  
Low Concentrations ◽  
Inhalation Anthrax ◽  
Edema Toxin

ABSTRACT Inhalation anthrax results in high-grade bacteremia and is accompanied by a delay in the rise of the peripheral polymorphonuclear neutrophil (PMN) count and a paucity of PMNs in the infected pleural fluid and mediastinum. Edema toxin (ET) is one of the major Bacillus anthracis virulence factors and consists of the adenylate cyclase edema factor (EF) and protective antigen (PA). Relatively low concentrations of ET (100 to 500 ng/ml of PA and EF) significantly impair human PMN chemokinesis, chemotaxis, and ability to polarize. These changes are accompanied by a reduction in chemoattractant-stimulated PMN actin assembly. ET also causes a significant decrease in Listeria monocytogenes intracellular actin-based motility within HeLa cells. These defects in actin assembly are accompanied by a >50-fold increase in intracellular cyclic AMP and a >4-fold increase in the phosphorylation of protein kinase A. We have previously shown that anthrax lethal toxin (LT) also impairs neutrophil actin-based motility (R. L. During, W. Li, B. Hao, J. M. Koenig, D. S. Stephens, C. P. Quinn, and F. S. Southwick, J. Infect. Dis. 192:837-845, 2005), and we now find that LT combined with ET causes an additive inhibition of PMN chemokinesis, polarization, chemotaxis, and FMLP (N-formyl-met-leu-phe)-induced actin assembly. We conclude that ET alone or combined with LT impairs PMN actin assembly, resulting in paralysis of PMN chemotaxis.

scholarly journals Attenuated Nontoxinogenic and Nonencapsulated Recombinant Bacillus anthracis Spore Vaccines Protect against Anthrax

2000 ◽  
Vol 68 (8) ◽  
pp. 4549-4558 ◽  
Author(s):  
S. Cohen ◽  
I. Mendelson ◽  
Z. Altboum ◽  
D. Kobiler ◽  
E. Elhanany ◽  
...  
Keyword(s):  
Bacillus Anthracis ◽  
Protective Immunity ◽  
Protective Antigen ◽  
Cell Vaccine ◽  
Lethal Challenge ◽  
Electrospray Mass Spectroscopy ◽  
Immunological Tests ◽  
Anthrax Spores ◽  
Biochemical Analyses ◽  
Recombinant Protective Antigen

ABSTRACT Several highly attenuated spore-forming nontoxinogenic and nonencapsulated Bacillus anthracis vaccines differing in levels of expression of recombinant protective antigen (rPA) were constructed. Biochemical analyses (including electrospray mass spectroscopy and N terminus amino acid sequencing) as well as biological and immunological tests demonstrated that the rPA retains the characteristics of native PA. A single immunization of guinea pigs with 5 × 107 spores of one of these recombinant strains, MASC-10, expressing high levels of rPA (≥100 μg/ml) from a constitutive heterologous promoter induced high titers of neutralizing anti-PA antibodies. This immune response was long lasting (at least 12 months) and provided protection against a lethal challenge of virulent (Vollum) anthrax spores. The recombinant B. anthracis spore vaccine appears to be more efficacious than the vegetative cell vaccine. Furthermore, while results clearly suggest a direct correlation between the level of expression of PA and the potency of the vaccine, they also suggest that some B. anthracisspore-associated antigen(s) may contribute in a significant manner to protective immunity.

scholarly journals Efficient Neutralization of Antibody-Resistant Forms of Anthrax Toxin by a Soluble Receptor Decoy Inhibitor

2008 ◽  
Vol 53 (3) ◽  
pp. 1210-1212 ◽  
Author(s):  
Shilpi Sharma ◽  
Diane Thomas ◽  
John Marlett ◽  
Marianne Manchester ◽  
John A. T. Young
Keyword(s):  
Monoclonal Antibody ◽  
Bacillus Anthracis ◽  
Protective Antigen ◽  
Anthrax Toxin ◽  
Soluble Receptor ◽  
Antibody Neutralization

ABSTRACT A soluble receptor decoy inhibitor (RDI), comprised of the extracellular I domain of ANTXR2, is a candidate anthrax therapeutic. Here we show that RDI can effectively neutralize altered forms of the protective antigen toxin subunit that are resistant to 14B7 monoclonal antibody neutralization. These data highlight the potential of RDI to act as an adjunct to existing antibody-based therapies and indicate that inhibitors based on RDI might be useful as a stand-alone treatment against specifically engineered strains of Bacillus anthracis.

scholarly journals Establishment of a New Zealand White Rabbit Model for Lethal Toxin (LT) Challenge and Efficacy of Monoclonal Antibody 5E11 in the LT-Challenged Rabbit Model

Toxins ◽  
2018 ◽  
Vol 10 (7) ◽  
pp. 289 ◽  
Author(s):  
Duanyang Zhang ◽  
Weicen Liu ◽  
Zhonghua Wen ◽  
Bing Li ◽  
Shuling Liu ◽  
...  
Keyword(s):  
Monoclonal Antibody ◽  
Protective Antigen ◽  
Lethal Dose ◽  
Rabbit Model ◽  
Zealand White Rabbit ◽  
Lethal Toxin ◽  
Anthrax Spores ◽  
Level 3 ◽  
Anthrax Protective Antigen ◽  
Biosafety Level

Anthrax caused by Bacillus anthracis is a lethal infectious disease, especially when inhaled, and the mortality rate approaches 100% without treatment. The anthrax antitoxin monoclonal antibody (MAb) 5E11 is a humanized antibody that targets the anthrax protective antigen (PA). The efficacy of 5E11 needs proper animal models. However, anthrax spores are extremely dangerous, so experiments must be conducted under Biosafety Level 3 conditions. Considering the critical effects of lethal toxin (LT) on hosts during infection, we report the establishment of a LT-challenged rabbit model, which caused 100% mortality with a dose of 2 mg PA + 1 mg LF, while a 4 mg PA + 2 mg LF challenge could limit death to within three days. Then, we evaluated 5E11 efficacy against LT. A prophylactic study showed that the i.v. administration of 40 mg/kg 5E11 four days before lethal dose LT challenge could lead to 100% survival. In therapeutic studies, the i.v. administration of 40 mg/kg 5E11 10 min after lethal dose LT challenge could provide complete protection. Overall, we developed a new LT-challenged rabbit model, and our results indicate that 5E11 shows potential for the clinical application in anthrax treatment.

scholarly journals A Monoclonal Antibody to Bacillus anthracis Protective Antigen Defines a Neutralizing Epitope in Domain 1

2006 ◽  
Vol 74 (7) ◽  
pp. 4149-4156 ◽  
Author(s):  
Johanna Rivera ◽  
Antonio Nakouzi ◽  
Nareen Abboud ◽  
Ekaterina Revskaya ◽  
David Goldman ◽  
...  
Keyword(s):  
Monoclonal Antibody ◽  
Monoclonal Antibodies ◽  
Bacillus Anthracis ◽  
Protective Antigen ◽  
Lethal Factor ◽  
Proteolytic Digestion ◽  
Potential Mechanism ◽  
Host Protection ◽  
Edema Toxin

ABSTRACT Antibody (Ab) responses to Bacillus anthracis toxins are protective, but relatively few protective monoclonal antibodies (MAbs) have been reported. Protective antigen (PA) is essential for the action of B. anthracis lethal toxin (LeTx) and edema toxin. In this study, we generated two MAbs to PA, MAbs 7.5G and 10F4. These MAbs did not compete for binding to PA, consistent with specificities for different epitopes. The MAbs were tested for their ability to protect a monolayer of cultured macrophages against toxin-mediated cytotoxicity. MAb 7.5G, the most-neutralizing MAb, bound to domain 1 of PA and reduced LeTx toxicity in BALB/c mice. Remarkably, MAb 7.5G provided protection without blocking the binding of PA or lethal factor or the formation of the PA heptamer complex. However, MAb 7.5G slowed the proteolytic digestion of PA by furin in vitro, suggesting a potential mechanism for Ab-mediated protection. These observations indicate that some Abs to domain 1 can contribute to host protection.

scholarly journals Development of Protective Immunity in New Zealand White Rabbits Challenged with Bacillus anthracis Spores and Treated with Antibiotics and Obiltoxaximab, a Monoclonal Antibody against Protective Antigen

2017 ◽  
Vol 62 (2) ◽  
Author(s):  
Lisa N. Henning ◽  
Sarah Carpenter ◽  
Gregory V. Stark ◽  
Natalya V. Serbina
Keyword(s):  
Monoclonal Antibody ◽  
New Zealand ◽  
Bacillus Anthracis ◽  
Protective Immunity ◽  
Protective Antigen ◽  
Lethal Dose ◽  
Survival Rates ◽  
Anamnestic Response ◽  
Content Type ◽  
Treatment Regimens

ABSTRACT The recommended management of inhalational anthrax, a high-priority bioterrorist threat, includes antibiotics and antitoxins. Obiltoxaximab, a chimeric monoclonal antibody against anthrax protective antigen (PA), is licensed under the U.S. Food and Drug Administration's (FDA's) Animal Rule for the treatment of inhalational anthrax. Because of spore latency, disease reemergence after treatment cessation is a concern, and there is a need to understand the development of endogenous protective immune responses following antitoxin-containing anthrax treatment regimens. Here, acquired protective immunity was examined in New Zealand White (NZW) rabbits challenged with a targeted lethal dose of Bacillus anthracis spores and treated with antibiotics, obiltoxaximab, or a combination of both. Survivors of the primary challenge were rechallenged 9 months later and monitored for survival. Survival rates after primary and rechallenge for controls and animals treated with obiltoxaximab, levofloxacin, or a combination of both were 0, 65, 100, and 95%, and 0, 100, 95, and 89%, respectively. All surviving immune animals had circulating antibodies to PA and serum toxin-neutralizing titers prior to rechallenge. Following rechallenge, systemic bacteremia and toxemia were not detected in most animals, and the levels of circulating anti-PA IgG titers increased starting at 5 days postrechallenge. We conclude that treatment with obiltoxaximab, alone or combined with antibiotics, significantly improves the survival of rabbits that received a lethal inhalation B. anthracis spore challenge dose and does not interfere with the development of immunity. Survivors of primary challenge are protected against reexposure, have rare incidents of systemic bacteremia and toxemia, and have evidence of an anamnestic response.

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