Eldon Hard, PhD
Albert Einstein College of Medicine
Design and Characterization of Crimean-Congo Hemorrhagic Fever Virus Bispecific Antibodies
Crimean-Congo hemorrhagic fever virus (CCHFV) is a widespread tick-borne nairovirus in the bunyavirales order. The CCHF virus is an enveloped negative-sense RNA virus with case fatality rates ranging from ~5-30%, causing the World Health Organization (WHO) to categorize CCHF as a priority pathogen. There are currently no approved vaccines or therapeutics for CCHF, and most antibody-based therapeutics target the surface glycoproteins Gc and Gn, which are responsible for viral attachment and membrane fusion of the virus to host cells. Another glycoprotein, GP38 is exclusive to Nairoviridae and is a target of protective antibodies from human survivors of infection. Previous studies have identified Gc-specific neutralizing antibodies and GP38-specific non-neutralizing antibodies that show protection in infected animal models. Further studies have characterized Gc-Gc bispecific antibodies (bsAbs) and demonstrated synergistic virus neutralization. Here, we generate and characterize novel Gc-GP38 bsAbs in order to combine the neutralization capabilities of the Gc-specific antibodies with the protective propensity of the GP38-specific antibodies. A panel of 120 Gc-GP38 bsAbs were generated in three different configurations, the dual variable domain format (DVD), single chain fragment variable (SC), and hinge single chain fragment variable (hSC). We found synergistic effects within the Gc-GP38 bsAbs that resulted in potent neutralization and protection in mice models.
Crimean-Congo hemorrhagic fever virus (CCHFV) is a widespread tick-borne nairovirus in the bunyavirales order. The CCHF virus is an enveloped negative-sense RNA virus with case fatality rates ranging from ~5-30%, causing the World Health Organization (WHO) to categorize CCHF as a priority pathogen. There are currently no approved vaccines or therapeutics for CCHF, and most antibody-based therapeutics target the surface glycoproteins Gc and Gn, which are responsible for viral attachment and membrane fusion of the virus to host cells. Another glycoprotein, GP38 is exclusive to Nairoviridae and is a target of protective antibodies from human survivors of infection. Previous studies have identified Gc-specific neutralizing antibodies and GP38-specific non-neutralizing antibodies that show protection in infected animal models. Further studies have characterized Gc-Gc bispecific antibodies (bsAbs) and demonstrated synergistic virus neutralization. Here, we generate and characterize novel Gc-GP38 bsAbs in order to combine the neutralization capabilities of the Gc-specific antibodies with the protective propensity of the GP38-specific antibodies. A panel of 120 Gc-GP38 bsAbs were generated in three different configurations, the dual variable domain format (DVD), single chain fragment variable (SC), and hinge single chain fragment variable (hSC). We found synergistic effects within the Gc-GP38 bsAbs that resulted in potent neutralization and protection in mice models.
