Monoclonal Antibodies in Clostridium Difficile Infection (IgAClostridium)

Identification of IgA Monoclonal Antibodies Anti-Clostridium Difficile Surface Proteins

Immunoglobulin A (IgA), the major mucosal antibody, plays a key role in maintaining diversity of the intestinal microbiota and eliminating intestinal pathogens. Dysbiosis is an important risk factor for Clostridium difficile infection, which is the leading cause of nosocomial diarrhea in industrialized countries. This study aims to develop IgA monoclonal antibodies targeting C. difficile surface proteins.

Study Overview

• Status: Completed
• Conditions: Clostridium Infection
• Intervention / Treatment: Other: Collection of peripheral blood mononuclear cells

Detailed Description

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.

• Study Type: Interventional
• Enrollment (Actual): 15
• Phase: Not Applicable

Contacts and Locations

Study Locations

• France
  • Paris, France, 75013
    • Maladies infectieuses et tropicales, Hôpital Pitié-Salpêtrière

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Basic Science
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: CDI	Other: Collection of peripheral blood mononuclear cells; Analysis of specific memory B cells in CDI patients

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Generate C. difficile specific antibodies from circulating memory B lymphocytes of C. difficile patients.	The presence of SlpA and Cwp84 specific memory B cells will be assessed from a single sample per patient. After separation of blood mononuclear cells, specific memory B cells will be selected using microfluidic drop technology. The variable VH and VL fragments of the immunoglobulins, which define the specificity of the antibodies, will be sequenced for each selected B cell. The corresponding antibodies will then be produced in a well-established cell line.	From the blood samples taken between Day 1 and Day 7 after the diagnostic of CDI

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Antibody affinity assessment	The affinity of the antibodies will be evaluated by surface plasmon resonance (Biacore®).	From the blood samples taken between Day1 and Day7 after the diagnostic of CDI
Neutralizing capacity evaluation affinity	The neutralizing activity will be evaluated in vitro: the capacity of the antibodies to decrease the proliferation of the bacteria (in liquid culture), to decrease its mobility (solid culture), to inhibit biofilm formation and to inhibit its adhesion to the surface of intestinal epithelial cells (quantified using the Caco-213 line).	From the blood samples taken between Day1 and Day7 after the diagnostic of CDI

Collaborators and Investigators

• Sponsor: Assistance Publique - Hôpitaux de Paris
• Collaborators: Institut Pasteur
• Investigators: Principal Investigator: Baptiste Hervier, Assistance Publique - Hôpitaux de Paris

Study record dates

Study Major Dates

• Study Start (Actual): November 29, 2021
• Primary Completion (Actual): November 29, 2021
• Study Completion (Actual): September 28, 2022

Study Registration Dates

• First Submitted: September 22, 2020
• First Submitted That Met QC Criteria: April 30, 2021
• First Posted (Actual): May 6, 2021

Study Record Updates

• Last Update Posted (Actual): October 4, 2022
• Last Update Submitted That Met QC Criteria: October 3, 2022
• Last Verified: September 1, 2022

More Information

Terms related to this study

• Keywords: Clostridium difficile infection; Therapeutic monoclonal antibodies
• Additional Relevant MeSH Terms: Bacterial Infections; Bacterial Infections and Mycoses; Gram-Positive Bacterial Infections; Infections; Clostridium Infections
• Other Study ID Numbers: APHP180354

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No