Treatment of Lassa virus infection in outbred guinea pigs with first-in-class human monoclonal antibodies

Abstract

Lassa fever is a significant health threat to West African human populations with hundreds of thousands of annual cases. There are no approved medical countermeasures currently available. Compassionate use of the antiviral drug ribavirin or transfusion of convalescent serum has resulted in mixed success depending on when administered or the donor source, respectively. We previously identified several recombinant human monoclonal antibodies targeting the glycoprotein of Lassa virus with strong neutralization profiles in vitro. Here, we demonstrate remarkable therapeutic efficacy using first-in-class human antibodies in a guinea pig model of Lassa infection thereby presenting a promising treatment alternative.

Figure 1. Correlation of IC50 and IC80 values among leading huMAb candidates in LASV neutralization assay platforms

Averaged, log10 transformed IC50 (A.) and IC80 (B.) values for therapeutic candidate huMAbs derived in LASV/HIV-1pp, LASV/LCMVpp, and PRNT assays. Antibodies segregated into two distinct clusters of IC50 and IC80 values. (C.) FACS binding profiles of NAbs (Red) to 293T cell surface-expressed LASV GPC (Josiah) versus irrelevant human IgG antibody isotype control (Black). LASV NAbs did not bind significantly to mock transfected 293T cells (data not shown). A potential therapeutic cocktail comprised of NAbs 8.9F, 12.1F, and 37.2D bound to 293T cells expressing GPC from clade III (D.) and clade II (E.) strains of LASV, highlighting their relevance as potential Pan Lassa therapeutics.

Figure 2. Protective efficacy profile of LASV GPC huMAbs in a Hartley GP model of LF

(A.) Pooled survival plots for treated and control GPs challenged with LASV from multiple independent experiments, as noted. Control GPs succumbed to LF between 14 and 22 PI (median = 15 days). In these studies a single GP survived infection through the 28-day study endpoint (1/18). Hartley GPs challenged with GPA LASV strain Josiah on day 0 () were treated with LASV huMAbs, at 30 mg/kg of body weight on the same day (↓). Additional therapeutic antibody was administered at the same dose on days 3 and 6 PI (↓). Animals were monitored for clinical signs of LF throughout the 28-day study timeline. (B.) Viremia data from treated and control GP plasma on days 7 and 14 PI. Viremia levels for day 7 treatment groups 37.7H, 12.1F, and 25.6A as well as day 14 12.1F, 37.2D, 19.7E, and 10.4B were below the limit of detection (LOD). Error bars represent standard deviation from mean values. * denotes P≤0.05. ** denotes P≤0.001. *** denotes P≤0.0001.