Reversion of Ebolavirus Disease from a Single Intramuscular Injection of a pan-Ebolavirus Immunotherapeutic

Abstract

Intravenous administration (IV) of antiviral monoclonal antibodies (mAbs) is challenging due to limited resources for performing infusions during an ongoing epidemic. An ebolavirus therapeutic administered via intramuscular (IM) injection would reduce these burdens and allow rapid treatment of exposed individuals during an outbreak. Here, we demonstrate how MBP134, a two mAb pan-ebolavirus cocktail, reverses the course of Sudan ebolavirus (SUDV/Gulu) disease with a single IV or IM dose in non-human primates (NHPs) as far as five days post-exposure. Furthermore, we investigated the utility of adding half-life extension mutations to the MBP134 mAbs, ultimately creating a half-life extended cocktail designated MBP431. MBP431 demonstrated an extended serum half-life in vivo and offered complete or significant protection with a single IM dose delivered as a post-exposure prophylactic (PEP) or therapeutic in NHPs challenged with EBOV. These results support the use of MBP431 as a rapidly deployable IM medical countermeasure against every known ebolavirus.

Combination therapy with remdesivir and monoclonal antibodies protects nonhuman primates against advanced Sudan virus disease

“…Drug formulation. CHOK1-AF cells stably expressing the ADI-23774 YTE and ADI-15878 YTE mAbs were generated as previously described (14). Briefly, a dual plasmid system containing expression cassettes for the heavy and light chains of the target mAbs were cotransfected by random integration via chemical means into a modified CHOK1 host cell line (CHOK1-AF), which yielded afucosylated glycans on expressed mAbs.…”

“…Statistics. For statistical comparisons, survival data from 10 historical positive control rhesus macaques from both published (7,14) and unpublished studies, and challenged via the same route with the same virus stock and dose, were added to the in-study control cohorts. All statistical analyses were performed in GraphPad Prism v9.3.1, except for the Hochberg step-up correction for multiple comparisons, which was performed in R (61) using the "p.adjust" function of the included stats v.4.0.2 package.…”

“…Recently, the first pan-ebolavirus mAb cocktail, composed of 2 individual mAbs (MBP134), was demonstrated to confer significant (80%) rescue from lethal SUDV infection in rhesus monkeys when administered as a single dose (i.v.) at 5 days dpi (14). Importantly, in all these studies, therapeutic efficacy was only demonstrated when treatment was initiated by 5 dpi.…”

“…Here, we investigated the therapeutic efficacy of a once-daily 12-dose remdesivir regimen in a near uniformly lethal rhesus macaque model of SUDV infection. We then evaluated the therapeutic benefit of coadministering remdesivir with the pan-ebolavirus mAb cocktail MBP431 (14) during advanced stages of SUDV disease at a point beyond successful therapeutic intervention for remdesivir alone. In congruence with our earlier report on MARV, our findings here further support the development of protocols that utilize therapeutics with complementary mechanisms of action to extend the window of therapeutic intervention in cases of SUDV infection as well as the general treatment of emerging viruses in human populations.…”