A cocktail of human monoclonal antibodies broadly neutralizes North American rabies virus variants as a promising candidate for rabies post-exposure prophylaxis

Abstract

Human rabies remains a globally significant public health problem. Replacement of polyclonal anti-rabies immunoglobulin (RIG), a passive component of rabies post-exposure prophylaxis (PEP), with a monoclonal antibody (MAb), would eliminate the cost and availability constraints associated with RIG. Our team has developed and licensed a human monoclonal antibody RAB1 (Rabishield©), as the replacement for RIG where canine rabies is enzootic. However, for the highly diverse rabies viruses of North America, a cocktail containing two or more MAbs targeting different antigenic sites of the rabies glycoprotein should be included to ensure neutralization of all variants of the virus. In this study, two MAb cocktails, R172 (RAB1-RAB2) and R173 (RAB1-CR57), were identified and evaluated against a broad range of rabies variants from North America. R173 was found to be the most potent cocktail, as it neutralized all the tested North American RABV isolates and demonstrated broad coverage of isolates from both terrestrial and bat species. R173 could be a promising candidate as an alternative or replacement for RIG PEP in North America.

Development of a novel bispecific antibody GR1801 for rabies

“…This implies the potential limitations of using a single mAb to cover diverse antigenic variations of RABV G protein. Thus, cocktails of mAbs have been developed to achieve broad‐spectrum neutralization, such as Rabimabs (M777‐16‐3 and 62‐71‐3), SYN023 (CTB011 and CTB012), CL184 (CR57 and CR4098), and R173 (RAB1 and CR57) 2,20 . However, compared to cocktails of mAbs, bispecific antibodies are more cost‐effective.…”

“…However, due to the mono-specificity of RAB1 for the conformational epitope containing antigenic site III, neutralization-escape mutants of RAB1 emerged. [18][19][20] As a result, the WHO advocates using cocktails of at least two different antibodies targeting nonoverlapping epitopes to achieve broad coverage for various RABV strains and prevent viral escape mutants. 5 Bispecific antibodies can simultaneously bind two different antigens or two nonoverlapping epitopes, providing therapeutic effects unattainable by mAb or cocktails of mAbs, as well as safety and efficiency advantages.…”

“…2,20 However, compared to cocktails of mAbs, bispecific antibodies are more cost-effective. Cocktails of mAbs are prepared by producing each mAb product separately using different engineered cell lines, and then mixing them at the final formulation stage.…”

Uses and Challenges of Antiviral Polyclonal and Monoclonal Antibody Therapies

“…They target non-overlapping spike epitopes, neutralize virus, and did not mediate Fc effector functions in cell culture. In addition, mAb combinations are currently under development for many other viruses, including CMV, HIV-1, influenza virus, and rabies virus 48,[193][194][195][196] . For general regulatory advice on the codevelopment of mAbs, we encourage readers to refer to the appropriate guidance document, which applies only to drugs and biologics regulated by CDER 197 .…”

“…Thus, mAb combinations are often designed to target non-overlapping epitopes on the same viral protein, leading to broader activity against different virus types, genotypes, subtypes, and/or variants than individual mAbs. For example, the anti-rabies virus mAbs R172 and R173, which target non-overlapping sites on the viral glycoprotein, are being developed in combination to ensure sufficient breadth of activity against viral variants circulating in North America 193 . However, mAb combinations have also been developed that target different viral proteins or overlapping epitopes on the same viral protein.…”