Development of Human Monoclonal Antibodies With Broad Reactivity for Rabies Postexposure Prophylaxis.

Area of Science:

• Immunology and Virology
• Development of novel biologics for infectious disease treatment

Background:

• Rabies is a lethal neurotropic viral disease requiring prompt postexposure prophylaxis (PEP).
• Current rabies immune globulin (RIG) products face challenges related to cost, stability, and safety.
• There is a need for improved and accessible rabies PEP alternatives.

Purpose of the Study:

• To develop a novel, fully human monoclonal antibody (mAb) cocktail for enhanced rabies PEP.
• To evaluate the neutralizing potential and efficacy of the mAb cocktail against rabies virus (RABV).

Main Methods:

• Screening of neutralizing fully human mAbs using a fully humanized antibody mouse model (CAMouse^HG).
• Selection of mAbs 26-12 G and 5-7 G based on fluorescent antibody virus neutralization test (FAVN) and binding to RABV-glycoprotein (RABV-G) antigenic sites I and III.
• Identification of key amino acid residues involved in binding using cross-linking and mass spectrometry; assessment of mAb conservation across RABV strains and in vivo protection studies in mice.

Main Results:

• Two noncompeting fully human mAbs, 26-12 G and 5-7 G, were identified with potent neutralizing activity against RABV.
• These mAbs bind to distinct antigenic sites (I and III) on RABV-G, targeting specific key amino acid residues.
• The mAbs demonstrated broad-spectrum activity across diverse RABV strains and protected mice from lethal RABV challenge in vivo.

Conclusions:

• A novel fully human mAb cocktail, CAM001, was successfully generated by mixing mAbs 26-12 G and 5-7 G.
• CAM001 exhibits high-potency and broad-spectrum neutralization, offering a promising alternative to current RIG products.
• The cocktail has the potential to serve as an efficacious and affordable option for rabies PEP, especially in endemic regions.