Long-term Prophylaxis Against Aerosolized Marburg Virus in Nonhuman Primates With an Afucosylated Monoclonal Antibody

Abstract

Marburg virus (MARV) causes a hemorrhagic fever disease in human and non-human primates with high levels of morbidity and mortality. Concerns about weaponization of aerosolized MARV have spurred the development of non-human primate (NHP) models of aerosol exposure. To address the potential threat of aerosol exposure, a monoclonal antibody that binds MARV glycoprotein was tested for its efficacy as a prophylactic. It was expressed with afucosylated N-glycans and two different sets of Fc amino acid mutations to increase serum half-life: MR186YTE and MR186LS. Each variant was tested in guinea pigs for preventing disease from an aerosolized MARV exposure. While both candidates provided significant protection (P<0.005), the observed efficacy conferred by MR186YTE was slightly superior and this version was selected for further testing in NHPs. MR186YTE was administered intramuscularly to NHPs at 15 or 5 mg/kg one month prior to MARV aerosol challenge. Seventy-five percent (3/4) of the 15 mg/kg dose group and fifty percent (2/4) of the 5 mg/kg dose group survived this lethal challenge. Serum analyses of showed that the NHP dosed with 15 mg/kg that succumbed to infection developed an anti-drug antibody response and therefore had no detectable MR186YTE at the time of challenge. Histopathological analyses found that NHPs that succumbed to disease had lesions consistent with previous reports of MARV disease and inflammatory lesions were noted in all lung lobes. In contrast, NHPs that survived aerosolized MARV exposure had background or non-active infiltrates. No evidence of MARV by immunohistochemistry was noted in the survivors. These results suggest that intramuscular dosing of mAbs may be a clinically useful prophylaxis for MARV aerosol exposure.