Monoclonal Antibodies in Clostridium Difficile Infection

Immunoglobulin A (IgA), the major mucosal antibody, plays a key role in maintaining the diversity of the intestinal microbiota and eliminating intestinal pathogens. They modulate microbiota composition and also commensal bacteria homeostasis, thus promoting a symbiotic relationship. These observations, derived from mouse studies, open promising therapeutic perspectives: IgA could be used to restore or maintain a healthy microbiota in individuals suffering from intestinal dysbiosis. Specific to a pathogen, IgA can also be considered as an alternative to antibiotics by mimicking a physiological elimination.

Abnormalities in microbial diversity (i.e. dysbiosis) have been associated in humans with various diseases such as Clostridium difficile infection, which is the leading cause of nosocomial diarrhea in industrialized countries. The incidence of CDI has dramatically raised since the early 2000s, with an increasing severity. Current treatments are limited to the administration of antibiotics that unbalance the intestinal microbiota, a risk factor for relapse. These frequent relapses contribute to the severity and chronicity of the infection.

This study aims to generate human IgA-type antibodies targeting C. difficile surface proteins with neutralizing and/or protective activity. These antibodies will be selected against surface proteins involved in the early stages of colonization. After injection or ingestion, these IgA antibodies should reproduce physiological mucosal immunity, treat severe forms and prevent the occurrence of C. difficile relapses while limiting deleterious effects on the intestinal microbiota.

C. difficile-specific B cells will be selected from infected patients. After selection of the most neutralizing IgA antibodies in vitro, these will be administered to C. difficile infected mice.

Inclusion criteria

• adult patient, 18 years of age
• diarrhea and/or abdominal pain.
• Presence of C. difficile toxins in feces
• Patient having dated and signed informed consent.

Exclusion criteria

• pregnant or nursing women
• adult under guardianship
• Ileus
• Peritonitis
• Pseudomembranous colitis
• Hemodynamic instability
• Fever ≥ 38.5°C
• Shivers
• Respiratory failure
• Leukocytosis > 15x109/L
• Serum creatinin >50% reference values)
• Serum lactate > 5mM
• Serum Albumine < 30g/l
• Other diarrhea cause
• Humoral immunodeficiency