Raxibacumab: potential role in the treatment of inhalational anthrax

Kummerfeldt, Carlos E.

doi:10.2147/idr.s47305

Cited by 67 publications

(59 citation statements)

References 28 publications

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“…MAbs directed against nonhuman targets and as a class of therapeutics in general have an excellent safety record and are well tolerated in the clinic (unlike therapy with serum). To date, there are two licensed MAb products against infectious targets (35,36) and many more in the clinical phase of testing or under preclinical development (37,38).…”

Section: Discussionmentioning

confidence: 99%

Bactericidal Monoclonal Antibodies Specific to the Lipopolysaccharide O Antigen from Multidrug-Resistant Escherichia coli Clone ST131-O25b:H4 Elicit Protection in Mice

Szijártó

Guachalla

Visram

et al. 2015

Antimicrob Agents Chemother

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The Escherichia coli sequence type 131 (ST131)-O25b:H4 clone has spread worldwide and become responsible for a significant proportion of multidrug-resistant extraintestinal infections. We generated humanized monoclonal antibodies (MAbs) that target the lipopolysaccharide O25b antigen conserved within this lineage. These MAbs bound to the surface of live bacterial cells irrespective of the capsular type expressed. In a serum bactericidal assay in vitro, MAbs induced >95% bacterial killing in the presence of human serum as the complement source. Protective efficacy at low antibody doses was observed in a murine model of bacteremia. The mode of action in vivo was investigated by using aglycosylated derivatives of the protective MAbs. The significant binding to live E. coli cells and the in vitro and in vivo efficacy were corroborated in assays using bacteria grown in human serum to mimic relevant clinical conditions. Given the dry pipeline of novel antibiotics against multidrug-resistant Gram-negative pathogens, passive immunization with bactericidal antibodies offers a therapeutic alternative to control infections caused by E. coli ST131-O25b:H4. Escherichia coli is a member of the intestinal commensal flora. Certain variants (pathotypes) of the species, however, can cause either intestinal or extraintestinal infections, such as urinary tract infection, meningitis, or bacteremia (1). Extraintestinal pathogenic E. coli (ExPEC) strains harbor a large array of virulence traits that enable them to cause disease outside the intestinal tract. ExPEC strains have been evolving antibiotic resistance, often a combined resistance against most of the clinically relevant antibiotics, such as fluoroquinolones, aminoglycosides, and ␤-lactam antibiotics. Typically, multidrug-resistant (MDR) strains are compromised in their fitness and virulence, which restricts their prevalence to a nosocomial setting and conversely limits their spread in the community. Some successful MDR clonal lineages do, however, retain high virulence potential (2, 3). The E. coli clonal lineage sequence type 131 (ST131)-O25b:H4, first described in 2008 (4, 5), has spread globally not only in hospitals (as do most other MDR clones) but also in the community (6-9). This clone is responsible for ϳ15% (up to 25% [10,11]) of all extraintestinal E. coli infections and represents the majority of fluoroquinolone-resistant isolates (12) and about half of the extended-spectrum ␤-lactamase (ESBL)-producing isolates (13). The progressive acquisition of additional resistance phenotypes in ST131-O25b:H4 strains leaves very few effective antibiotics for treatment of patients infected by members of this lineage (14). Even more alarming is the recent appearance of carbapenem-resistant ST131 isolates (15-17). Recently, ST131-O25b:H4 strains were shown to predominate among carbapenem-resistant E. coli isolates (18). A major clinical concern is the lack of development of novel antibiotics against Gram-negative pathogens, again leaving very limited treatment options (19). The p...

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Section: Discussionmentioning

confidence: 99%

Bactericidal Monoclonal Antibodies Specific to the Lipopolysaccharide O Antigen from Multidrug-Resistant Escherichia coli Clone ST131-O25b:H4 Elicit Protection in Mice

Szijártó

Guachalla

Visram

et al. 2015

Antimicrob Agents Chemother

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“…One such study utilized a glycomimetic approach to inhibit Shiga toxin's recognition of the host receptor, globotriaosylceramide, which has proven to be effective in vitro and in animal models of enterohemorrhagic Escherichia coli infections (21,22). Similarly, the monoclonal antibody raxibacumab targets the protective antigen component of anthrax toxin (23) and was approved by the FDA in 2012 for protection against and treatment of inhaled anthrax (23)(24)(25). Despite this great promise, however, only a handful of antivirulence therapeutics have made it to human clinical trials to date.…”

Section: Antivirulence Therapiesmentioning

confidence: 99%

Innovative Solutions to Sticky Situations: Antiadhesive Strategies for Treating Bacterial Infections

2016

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Bacterial adherence to host tissue is an essential process in pathogenesis, necessary for invasion and colonization and often required for the efficient delivery of toxins and other bacterial effectors. As existing treatment options for common bacterial infections dwindle, we find ourselves rapidly approaching a tipping point in our confrontation with antibiotic-resistant strains and in desperate need of new treatment options. Bacterial strains defective in adherence are typically avirulent and unable to cause infection in animal models. The importance of this initial binding event in the pathogenic cascade highlights its potential as a novel therapeutic target. This article seeks to highlight a variety of strategies being employed to treat and prevent infection by targeting the mechanisms of bacterial adhesion. Advancements in this area include the development of novel antivirulence therapies using small molecules, vaccines, and peptides to target a variety of bacterial infections. These therapies target bacterial adhesion through a number of mechanisms, including inhibition of pathogen receptor biogenesis, competition-based strategies with receptor and adhesin analogs, and the inhibition of binding through neutralizing antibodies. While this article is not an exhaustive description of every advancement in the field, we hope it will highlight several promising examples of the therapeutic potential of antiadhesive strategies.

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“…For example, the treatment regimen of raxibacumab (humanized mAb against inhalational anthrax, recently approved by the FDA) is 40 mg/kg [44]. Such an amount of mAb has to be administered by intravenous infusion, which takes at least 2 hours.…”

Section: Antibody Efficacymentioning

confidence: 99%

Opportunities and Challenges of Therapeutic Monoclonal Antibodies as Medical Countermeasures for Biodefense

Hu¹,

Nagata²

2016

J Bioterror Biodef

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Antibodies, naturally produced in the body as part of the immune response to infectious agents, can also be introduced artificially to treat infectious diseases. Advances in biotechnology in the last decades have made human or humanized monoclonal antibodies (mAbs) as therapeutics possible. These therapeutic mAbs currently enjoy unprecedented success and recognition of their potential. Unlike vaccines, therapeutic mAbs can confer instant and consistent protection against bio-threat agents when administered regardless of the recipient's immune status. Therapeutic mAbs can be administered in higher levels than those elicited by vaccines, and thus provide a higher level of protection or treatment that is necessary in a biological attack where people are exposed to a higher exposure of agent concentration than that found in nature. Furthermore, therapeutic mAbs have substantial advantages over antimicrobial drugs, such as high specificity, low systemic toxicity, relatively long half-life, and no concerns over disrupting the body's microbiome. Therapeutic mAbs can be used for both pre-and post-exposure protection; therefore, they have great value as effective medical countermeasures (MedCMs) against bio-threat agents. However, there are still some challenges to be overcome before therapeutic mAbs become ideal MedCMs against bio-threat agents. In this review, both opportunities and challenges in development of therapeutic mAbs are discussed.

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Raxibacumab: potential role in the treatment of inhalational anthrax

Cited by 67 publications

References 28 publications

Bactericidal Monoclonal Antibodies Specific to the Lipopolysaccharide O Antigen from Multidrug-Resistant Escherichia coli Clone ST131-O25b:H4 Elicit Protection in Mice

Bactericidal Monoclonal Antibodies Specific to the Lipopolysaccharide O Antigen from Multidrug-Resistant Escherichia coli Clone ST131-O25b:H4 Elicit Protection in Mice

Innovative Solutions to Sticky Situations: Antiadhesive Strategies for Treating Bacterial Infections

Opportunities and Challenges of Therapeutic Monoclonal Antibodies as Medical Countermeasures for Biodefense

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