In Vivo Efficacy of SYN023, an Anti-Rabies Monoclonal Antibody Cocktail, in Post-Exposure Prophylaxis Animal Models

Abstract

Rabies immune globulin (RIG) is an indispensable component of rabies post-exposure prophylaxis (PEP) because it provides passive immunity to prevent this otherwise inescapably fatal disease in Category III exposed patients. Even with decades of development, RIG products are still criticized for their high cost, lot-to-lot variation, and potential safety issues. They remain largely unattainable in most developing regions of the world, where demand is highest. In recent years, monoclonal antibodies (MAbs) have become widely accepted as safer and more cost-effective alternatives to RIG products. As an example, SYN023 is a 1:1 cocktail of two humanized anti-rabies MAbs previously shown to display extensive neutralizing capabilities. Here, we further assessed the efficacy of SYN023 in animal models of rabies, and found that SYN023 afforded protection equal to a standard dose of human RIG (HRIG) at 0.03 mg/kg in Syrian hamsters and 0.1 mg/kg in beagles. Potential interference with vaccine-induced immunity was analyzed for the MAbs at these concentrations. While individual MAbs did not interfere with vaccine response, SYN023 at dosages of 0.1 mg/kg and above resulted in reduced neutralizing antibody titers similar to HRIG. Thus, the in vivo characterization of SYN023 supports its utility in human rabies PEP as an efficacious alternative to RIG products.

Keywords: monoclonal antibody; post-exposure prophylaxis; rabies; rabies immune globulin.

Conflict of interest statement

The authors declare no conflict of interest. The funders had no role in the design of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript, or in the decision to publish the results.

Figures

Figure 1

In vivo efficacy of SYN023 in a Syrian hamster post-exposure prophylaxis (PEP) model. Human rabies immune globulin (HRIG) at 20 IU/kg or SYN023 at 0.003, 0.01, 0.03, 0.1, 0.3, and 1 mg/kg were administered in conjunction with rabies vaccine to rabies virus (RABV) (BD06)-infected Syrian hamsters at 24 h post infection. Vaccine was administered on Days 0, 3, 7, 14, and 28. Hamster mortality and morbidity were monitored daily. Vaccine only and untreated groups were included as negative controls. * indicates p < 0.05.

Figure 2

Changes of serum anti-rabies antibody titers in non-challenged Syrian hamsters. (A) CTB011 (0.05, 0.15, 0.5 mg/kg), (B) CTB012 (0.05, 0.15, 0.5 mg/kg), (C) SYN023 (0.003, 0.01, 0.03, 0.1, 0.33, 1 mg/kg), or HRIG (20 IU/kg) were administered to the opposite site of vaccination on Day 0. Serum RVNA levels were monitored by performing a rapid fluorescence focus inhibition test (RFFIT) on blood samples.

Figure 3

In vivo efficacy of SYN023 in a beagles PEP model. HRIG at 20 IU/kg or SYN023 at 0.03, 0.1, 0.3, and 1 mg/kg were administered in conjunction with rabies vaccine to RABV (BD06)-infected Syrian hamsters at 24 h post infection. Two doses of vaccine were administered on Day 0, followed by one dose each on Days 7 and 21. Animal mortality and morbidity were monitored daily. Saline group was included as negative control. * indicates p < 0.05.