Medicine and Health Sciences Commons^™

Development And Characterization Of A Severe Acute Respiratory Syndrome-Associated Coronavirus-Neutralizing Human Monoclonal Antibody That Provides Effective Immunoprophylaxis In Mice, Thomas Greenough, Gregory Babcock, Anjeanette Roberts, Hector Hernandez, William Thomas, Jennifer Coccia, Robert Graziano, Mohan Srinivasan, Israel Lowy, Robert Finberg, Kanta Subbarao, Leatrice Vogel, Mohan Somasundaran, Katherine Luzuriaga, John Sullivan, Donna Ambrosino

William D Thomas Jr

BACKGROUND: Severe acute respiratory syndrome (SARS) remains a significant public health concern after the epidemic in 2003. Human monoclonal antibodies (MAbs) that neutralize SARS-associated coronavirus (SARS-CoV) could provide protection for exposed individuals. METHODS: Transgenic mice with human immunoglobulin genes were immunized with the recombinant major surface (S) glycoprotein ectodomain of SARS-CoV. Epitopes of 2 neutralizing MAbs derived from these mice were mapped and evaluated in a murine model of SARS-CoV infection. RESULTS: Both MAbs bound to S glycoprotein expressed on transfected cells but differed in their ability to block binding of S glycoprotein to Vero E6 cells. Immunoprecipitation analysis revealed …

Treatment With Monoclonal Antibodies Against Clostridium Difficile Toxins, Israel Lowy, Deborah Molrine, Brett Leav, Barbara Blair, Roger Baxter, Dale Gerding, Geoffrey Nichol, William Thomas, Mark Leney, Susan Sloan, Catherine Hay, Donna Ambrosino

William D Thomas Jr

BACKGROUND: New therapies are needed to manage the increasing incidence, severity, and high rate of recurrence of Clostridium difficile infection.

METHODS: We performed a randomized, double-blind, placebo-controlled study of two neutralizing, fully human monoclonal antibodies against C. difficile toxins A (CDA1) and B (CDB1). The antibodies were administered together as a single infusion, each at a dose of 10 mg per kilogram of body weight, in patients with symptomatic C. difficile infection who were receiving either metronidazole or vancomycin. The primary outcome was laboratory-documented recurrence of infection during the 84 days after the administration of monoclonal antibodies or placebo.

RESULTS: …

Human Monoclonal Antibodies Directed Against Toxins A And B Prevent Clostridium Difficile-Induced Mortality In Hamsters, Gregory Babcock, Teresa Broering, Hector Hernandez, Robert Mandell, Katherine Donahue, Naomi Boatright, Anne Stack, Israel Lowy, Robert Graziano, Deborah Molrine, Donna Ambrosino, William Thomas

William D Thomas Jr

Clostridium difficile is the leading cause of nosocomial antibiotic-associated diarrhea, and recent outbreaks of strains with increased virulence underscore the importance of identifying novel approaches to treat and prevent relapse of Clostridium difficile-associated diarrhea (CDAD). CDAD pathology is induced by two exotoxins, toxin A and toxin B, which have been shown to be cytotoxic and, in the case of toxin A, enterotoxic. In this report we describe fully human monoclonal antibodies (HuMAbs) that neutralize these toxins and prevent disease in hamsters. Transgenic mice carrying human immunoglobulin genes were used to isolate HuMAbs that neutralize the cytotoxic effects of either toxin …

Amino Acids 270 To 510 Of The Severe Acute Respiratory Syndrome Coronavirus Spike Protein Are Required For Interaction With Receptor, Gregory Babcock, Diana Esshaki, William Thomas, Donna Ambrosino

William D Thomas Jr

A novel coronavirus, severe acute respiratory syndrome coronavirus (SARS-CoV), has recently been identified as the causative agent of severe acute respiratory syndrome (SARS). SARS-CoV appears similar to other coronaviruses in both virion structure and genome organization. It is known for other coronaviruses that the spike (S) glycoprotein is required for both viral attachment to permissive cells and for fusion of the viral envelope with the host cell membrane. Here we describe the construction and expression of a soluble codon-optimized SARS-CoV S glycoprotein comprising the first 1,190 amino acids of the native S glycoprotein (S(1190)). The codon-optimized and native S glycoproteins …

Therapy With A Severe Acute Respiratory Syndrome-Associated Coronavirus-Neutralizing Human Monoclonal Antibody Reduces Disease Severity And Viral Burden In Golden Syrian Hamsters, Anjeanette Roberts, William Thomas, Jeannette Guarner, Elaine Lamirande, Gregory Babcock, Thomas Greenough, Leatrice Vogel, Norman Hayes, John Sullivan, Sherif Zaki, Kanta Subbarao, Donna Ambrosino

William D Thomas Jr

BACKGROUND: Immunotherapy with monoclonal antibodies (MAbs) offers safe interventions for the prevention of infection in patients after organ transplantation and for the treatment of cancers and autoimmune diseases. MAb 201 is a severe acute respiratory syndrome-associated coronavirus (SARS-CoV)-specific MAb that prevents establishment of viral replication in vitro and prevents viral replication in vivo when administered prophylactically. The efficacy of MAb 201 in the treatment of SARS was evaluated in golden Syrian hamsters, an animal model that supports SARS-CoV replication to high levels and displays severe pathological changes associated with infection, including pneumonitis and pulmonary consolidation. METHODS: Golden Syrian hamsters that …