Treatment with Monoclonal Antibodies against<i>Clostridium difficile</i>Toxins

Lowy, Israel; Molrine, Deborah C.; Leav, Brett; Blair, Barbara M.; Baxter, Roger; Gerding, Dale N.; Nichol, G.; Thomas, William D.; Leney, Mark D.; Sloan, Susan; Hay, Catherine A.; Ambrosino, Donna M.

doi:10.1056/nejmoa0907635

Cited by 689 publications

(502 citation statements)

References 26 publications

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“…Further, its half-life extending variant that includes the YTE mutation has also been studied in mice, monkeys and humans. Motavizumab has a half-life of 19–34 days 18 in humans and actoxumab has a half-life of 26 ± 8.4 days 34 in humans. Two different approaches were employed: recombinant (His) 6 -tagged FcRn capture on NiNTA biosensors with IgG as the analyte, and IgG captured on anti-CH1 biosensors with recombinant FcRn as the analyte.…”

Section: Resultsmentioning

confidence: 99%

Extending human IgG half-life using structure-guided design

Booth

Ramakrishnan

Narayan

et al. 2018

mAbs

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Engineering of antibodies for improved pharmacokinetics through enhanced binding to the neonatal Fc receptor (FcRn) has been demonstrated in transgenic mice, non-human primates and humans. Traditionally, such approaches have largely relied on random mutagenesis and display formats, which fail to address related critical attributes of the antibody, such as effector functions or biophysical stability. We have developed a structure- and network-based framework to interrogate the engagement of IgG with multiple Fc receptors (FcRn, C1q, TRIM21, FcγRI, FcγRIIa/b, FcγRIIIa) simultaneously. Using this framework, we identified features that govern Fc-FcRn interactions and identified multiple distinct pathways for enhancing FcRn binding in a pH-specific manner. Network analysis provided a novel lens to study the allosteric impact of half-life-enhancing Fc mutations on FcγR engagement, which occurs distal to the FcRn binding site. Applying these principles, we engineered a panel of unique Fc variants that enhance FcRn binding while maintaining robust biophysical properties and wild type-like binding to activating receptors. An antibody harboring representative Fc designs demonstrates a half-life improvement of > 9 fold in transgenic mice and > 3.5 fold in cynomolgus monkeys, and maintains robust effector functions such as antibody-dependent cell-mediated cytotoxicity and complement-dependent cytotoxicity.

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Section: Resultsmentioning

confidence: 99%

Extending human IgG half-life using structure-guided design

Booth

Ramakrishnan

Narayan

et al. 2018

mAbs

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“…In a phase II clinical trial, a monoclonal antibody to toxins A and B used as an adjunct to antibiotics was shown to decrease recurrence rates in patients with CDI (7 % compared with 38 % ); in patients with a previous episode of CDI, the recurrence rate was 7 % compared with 18 % in the control group ( P = 0.07) ( 127 ). Th is product is only available in phase III trials.…”

Section: Other Investigational Treatmentsmentioning

confidence: 99%

Guidelines for Diagnosis, Treatment, and Prevention of Clostridium difficile Infections

Surawicz

Brandt

Binion

et al. 2013

American Journal of Gastroenterology

1,477

1,408

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Clostridium diffi cile infection (CDI) is a leading cause of hospital-associated gastrointestinal illness and places a high burden on our health-care system. Patients with CDI typically have extended lengths-of-stay in hospitals, and CDI is a frequent cause of large hospital outbreaks of disease. This guideline provides recommendations for the diagnosis and management of patients with CDI as well as for the prevention and control of outbreaks while supplementing previously published guidelines. New molecular diagnostic stool tests will likely replace current enzyme immunoassay tests. We suggest treatment of patients be stratifi ed depending on whether they have mild-to-moderate, severe, or complicated disease. Therapy with metronidazole remains the choice for mildto-moderate disease but may not be adequate for patients with severe or complicated disease. We propose a classifi cation of disease severity to guide therapy that is useful for clinicians. We review current treatment options for patients with recurrent CDI and recommendations for the control and prevention of outbreaks of CDI. Am J Gastroenterol 2013; 108:478-498; doi: 10.1038/ajg.2013 12. In patients in whom oral antibiotics cannot reach a segment of the colon, such as with Hartman's pouch, ileostomy, or colon diversion, vancomycin therapy delivered via enema should be added to treatments above until the patient improves. (Conditional recommendation, low-quality evidence)13. The use of anti-peristaltic agents to control diarrhea from confi rmed or suspected CDI should be limited or avoided, as they may obscure symptoms and precipitate complicated disease. Use of anti-peristaltic agents in the setting of CDI must always be accompanied by medical therapy for CDI. (Strong recommendation, low-quality evidence) Management of severe and complicated CDI14. Supportive care should be delivered to all patients and includes intravenous fl uid resuscitation, electrolyte replacement, and pharmacological venous thromboembolism prophylaxis. Furthermore, in the absence of ileus or signifi cant abdominal distention, oral or enteral feeding should be continued. 17. Vancomycin delivered orally (500 mg four times per day) and per rectum (500 mg in a volume of 500 ml four times a day) plus intravenous metronidazole (500 mg three times a day) is the treatment of choice for patients with complicated CDI with ileus or toxic colon and / or signifi cant abdominal distention. (Strong recommendation, low-quality evidence)18. Surgical consult should be obtained in all patients with complicated CDI. Surgical therapy should be considered in patients with any one of the following attributed to CDI: hypotension requiring vasopressor therapy; clinical signs of sepsis and organ dysfunction (renal and pulmonary); mental status changes; white blood cell count ≥ 50,000 cells / μ l, lactate ≥ 5 mmol / l; or failure to improve on medical therapy after 5 days. (Strong recommendation, moderate-quality evidence) Management of recurrent CDI (RCDI)19. The fi rst recurrence of CDI can be treated ...

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“…The use of animal serum containing antibodies that target bacterial antigens was a common therapeutic approach pre-dating the development of small molecule antibiotics, 7 but technological advances in antibody discovery, including B-cell cloning from human patients, 8 has invigorated research into monoclonal antibody (mAb)-based antibiotics. Anti-infective biologics with novel mechanisms of action targeting S. aureus alpha toxin, 9,10 protective antigen of Bacillus anthracis , 11 toxins A and B from Clostridium difficile , 12 and Pseudomonas aeruginosa cell wall components 13,14 are currently approved or in clinical development. The presence of cell wall glycopolymers, particularly in Gram-positive bacteria, shields many epitopes that might confer bactericidal activity from antibodies and other host-defense molecules, 15 but these cell wall polysaccharides also represent a potential target for mAb therapeutics.…”

Section: Introductionmentioning

confidence: 99%

Structural investigation of humanS. aureus-targeting antibodies that bind wall teichoic acid

Fong¹,

Kajihara²,

Chen³

et al. 2018

mAbs

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Infections caused by methicillin-resistant Staphylococcus aureus (MRSA) are a growing health threat worldwide. Efforts to identify novel antibodies that target S. aureus cell surface antigens are a promising direction in the development of antibiotics that can halt MRSA infection. We biochemically and structurally characterized three patient-derived MRSA-targeting antibodies that bind to wall teichoic acid (WTA), which is a polyanionic surface glycopolymer. In S. aureus, WTA exists in both α- and β-forms, based on the stereochemistry of attachment of a N-acetylglucosamine residue to the repeating phosphoribitol sugar unit. We identified a panel of antibodies cloned from human patients that specifically recognize the α or β form of WTA, and can bind with high affinity to pathogenic wild-type strains of S. aureus bacteria. To investigate how the β-WTA specific antibodies interact with their target epitope, we determined the X-ray crystal structures of the three β-WTA specific antibodies, 4462, 4497, and 6078 (Protein Data Bank IDs 6DWI, 6DWA, and 6DW2, respectively), bound to a synthetic WTA epitope. These structures reveal that all three of these antibodies, while utilizing distinct antibody complementarity-determining region sequences and conformations to interact with β-WTA, fulfill two recognition principles: binding to the β-GlcNAc pyranose core and triangulation of WTA phosphate residues with polar contacts. These studies reveal the molecular basis for targeting a unique S. aureus cell surface epitope and highlight the power of human patient-based antibody discovery techniques for finding novel pathogen-targeting therapeutics.

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Treatment with Monoclonal Antibodies againstClostridium difficileToxins

Abstract: The addition of monoclonal antibodies against C. difficile toxins to antibiotic agents significantly reduced the recurrence of C. difficile infection. (ClinicalTrials.gov number, NCT00350298.)

Cited by 689 publications

References 26 publications

Extending human IgG half-life using structure-guided design

Extending human IgG half-life using structure-guided design

Guidelines for Diagnosis, Treatment, and Prevention of Clostridium difficile Infections

Structural investigation of humanS. aureus-targeting antibodies that bind wall teichoic acid

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