Multi-specific nanobody-Fc fusions against TcdB protect in vivo from diverse Clostridioides difficile strains

Multi-specific nanobody-Fc fusions targeting TcdB neutralize multiple clinically relevant Clostridioides difficile subtypes and improve CDI outcomes in mice, outperforming bezlotoxumab.

• Why it matters: CDI remains a major antibiotic-associated threat with frequent recurrence, and bezlotoxumab was discontinued; TcdB sequence variation across twelve subtypes limits pan-neutralization.
• What they did: The study generated three bi-specific and one tri-specific nanobody-Fc fusions against TcdB, testing in vitro neutralization across clinically relevant subtypes and in vivo prophylactic and therapeutic mouse CDI models using three diverse strains.
• The result: Several fusions improved infection outcomes over bezlotoxumab with prophylactic dosing, and one fusion improved survival in a therapeutic mouse model, supporting translation despite TcdB sequence variation.

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