Human C. difficile-specific memory B cells encode protective IgG1 despite predominance of non-neutralizing antibodies

Area of Science:

• Immunology
• Infectious Diseases
• Microbiology

Background:

• Clostridioides difficile infection (CDI) is a significant healthcare-associated infection with limited treatment and no vaccine.
• Clostridioides difficile Toxin B (TcdB)-specific IgG is a key marker for protection against severe and recurrent CDI.
• Few fully human monoclonal antibodies (hmAbs) targeting TcdB have demonstrated therapeutic efficacy.

Purpose of the Study:

• To investigate the potential of memory B cells (Bmem) from recovered individuals as a source for protective anti-TcdB therapeutic antibodies.
• To identify and characterize high-affinity, TcdB-neutralizing hmAbs from a Bmem-derived IgG1 sequence library.

Main Methods:

• Generation of a library of fully human monoclonal antibodies (hmAbs) from IgG1 sequences of memory B cells (Bmem) from recovered patients.
• In vitro assessment of TcdB-specific hmAbs for binding affinity and neutralization capacity.
• In vivo efficacy studies in C57Bl/6 and Tg32 mice to evaluate protection against C. difficile-induced disease.

Main Results:

• The Bmem-derived antibody library contained both low-affinity, non-neutralizing and high-affinity, TcdB-neutralizing hmAbs.
• High-affinity, TcdB-neutralizing hmAbs demonstrated moderate protection in mouse models of C. difficile infection.
• Efficacy was observed in both standard and human FcRn transgenic mice, suggesting gut delivery was not a limiting factor.

Conclusions:

• Despite the dominance of non-protective sequences, human Bmem cells represent a viable source for identifying potent therapeutic hmAbs against C. difficile.
• Targeting TcdB with high-affinity neutralizing antibodies derived from the Bmem compartment holds therapeutic potential for treating C. difficile infections.