title: A mixture of functionally oligoclonal humanized monoclonal antibodies that neutralize Clostridium difficile TcdA and TcdB with high levels of in vitro potency shows in vivo protection in a hamster infection model.
abstract: Clostridium difficile infections are a major cause of antibiotic-associated diarrhea in hospital and care facility patients. In spite of the availability of effective antibiotic treatments, C. difficile infection (CDI) is still a major cause of patient suffering, death, and substantial health care costs. Clostridium difficile exerts its major pathological effects through the actions of two protein exotoxins, TcdA and TcdB, which bind to and disrupt gut tissue. Antibiotics target the infecting bacteria but not the exotoxins. Administering neutralizing antibodies against TcdA and TcdB to patients receiving antibiotic treatment might modulate the effects of the exotoxins directly. We have developed a mixture of three humanized IgG1 monoclonal antibodies (MAbs) which neutralize TcdA and TcdB to address three clinical needs: reduction of the severity and duration of diarrhea, reduction of death rates, and reduction of the rate of recurrence. The UCB MAb mixture showed higher potency in a variety of in vitro binding and neutralization assays (∼10-fold improvements), higher levels of protection in a hamster model of CDI (82% versus 18% at 28 days), and higher valencies of toxin binding (12 versus 2 for TcdA and 3 versus 2 for TcdB) than other agents in clinical development. Comparisons of the MAb properties also offered some insight into the potential relative importance of TcdA and TcdB in the disease process.
authors: Discovery Biology, UCB Pharma Slough, Slough, Berkshire, United Kingdom.
authors: Nicola L
authors: NL
authors: Davies
authors: Joanne E
authors: JE
authors: Compson
authors: Brendon
authors: B
authors: Mackenzie
authors: Victoria L
authors: VL
authors: O'Dowd
authors: Amanda K F
authors: AK
authors: Oxbrow
authors: James T
authors: JT
authors: Heads
authors: Alison
authors: A
authors: Turner
authors: Kaushik
authors: K
authors: Sarkar
authors: Sarah L
authors: SL
authors: Dugdale
authors: Mark
authors: M
authors: Jairaj
authors: Louis
authors: L
authors: Christodoulou
authors: David E O
authors: DE
authors: Knight
authors: Amanda S
authors: AS
authors: Cross
authors: Karine J M
authors: KJ
authors: Hervé
authors: Kerry L
authors: KL
authors: Tyson
authors: Hanna
authors: H
authors: Hailu
authors: Carl B
authors: CB
authors: Doyle
authors: Mark
authors: M
authors: Ellis
authors: Marco
authors: M
authors: Kriek
authors: Matthew
authors: M
authors: Cox
authors: Matthew J T
authors: MJ
authors: Page
authors: Adrian R
authors: AR
authors: Moore
authors: Daniel J
authors: DJ
authors: Lightwood
authors: David P
authors: DP
authors: Humphreys
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology / Q000302:isolation & purification / Q000627:therapeutic use*; D057134:Antibodies, Neutralizing / Q000276:immunology / Q000302:isolation & purification / Q000627:therapeutic use*; D001426:Bacterial Proteins / Q000037:antagonists & inhibitors* / Q000276:immunology; D001427:Bacterial Toxins / Q000037:antagonists & inhibitors* / Q000276:immunology; D003015:Clostridium Infections / Q000628:therapy*; D006224:Cricetinae; D004195:Disease Models, Animal; D004768:Enterotoxins / Q000037:antagonists & inhibitors* / Q000276:immunology; D007074:Immunoglobulin G / Q000276:immunology / Q000302:isolation & purification / Q000627:therapeutic use; D007155:Immunologic Factors / Q000276:immunology / Q000302:isolation & purification / Q000627:therapeutic use*; D016896:Treatment Outcome
chemical_list: D000911:Antibodies, Monoclonal; D057134:Antibodies, Neutralizing; D001426:Bacterial Proteins; D001427:Bacterial Toxins; D004768:Enterotoxins; D007074:Immunoglobulin G; D007155:Immunologic Factors; C041348:tcdA protein, Clostridium difficile; C031815:toxB protein, Clostridium difficile