A phase 1 trial of lipid-encapsulated mRNA encoding a monoclonal antibody with neutralizing activity against Chikungunya virus

Allison August,Leon M Ptaszek,Marjie Hard,Husain Z Attarwala,Shiva Kalidindi,Joanne E Tomassini,Sophia Lu,Tal Zaks,Sunny Himansu,Rolando Pajon,Jean-Michel Lecerf,James E Crowe,Shu Han

doi:10.1038/s41591-021-01573-6

Abstract

Chikungunya virus (CHIKV) infection causes acute disease characterized by fever, rash and arthralgia, which progresses to severe and chronic arthritis in up to 50% of patients. Moreover, CHIKV infection can be fatal in infants or immunocompromised individuals and has no approved therapy or prevention. This phase 1, first-in-human, randomized, placebo-controlled, proof-of-concept trial conducted from January 2019 to June 2020 evaluated the safety and pharmacology of mRNA-1944, a lipid nanoparticle-encapsulated messenger RNA encoding the heavy and light chains of a CHIKV-specific monoclonal neutralizing antibody, CHKV-24 (NCT03829384). The primary outcome was to evaluate the safety and tolerability of escalating doses of mRNA-1944 administered via intravenous infusion in healthy participants aged 18–50 years. The secondary objectives included determination of the pharmacokinetics of mRNA encoding for CHKV-24 immunoglobulin heavy and light chains and ionizable amino lipid component and the pharmacodynamics of mRNA-1944 as assessed by serum concentrations of mRNA encoding for CHKV-24 immunoglobulin G (IgG), plasma concentrations of ionizable amino lipid and serum concentrations of CHKV-24 IgG. Here we report the results of a prespecified interim analysis of 38 healthy participants who received intravenous single doses of mRNA-1944 or placebo at 0.1, 0.3 and 0.6 mg kg−1, or two weekly doses at 0.3 mg kg−1. At 12, 24 and 48 h after single infusions, dose-dependent levels of CHKV-24 IgG with neutralizing activity were observed at titers predicted to be therapeutically relevant concentrations (≥1 µg ml−1) across doses that persisted for ≥16 weeks at 0.3 and 0.6 mg kg−1 (mean t1/2 approximately 69 d). A second 0.3 mg kg−1 dose 1 week after the first increased CHKV-24 IgG levels 1.8-fold. Adverse effects were mild to moderate in severity, did not worsen with a second mRNA-1944 dose and none were serious. To our knowledge, mRNA-1944 is the first mRNA-encoded monoclonal antibody showing in vivo expression and detectable ex vivo neutralizing activity in a clinical trial and may offer a treatment option for CHIKV infection. Further evaluation of the potential therapeutic use of mRNA-1944 in clinical trials for the treatment of CHIKV infection is warranted.

Highlights

Chikungunya virus (CHIKV) infection causes acute disease characterized by fever, rash and arthralgia, which progresses to severe and chronic arthritis in up to 50% of patients
We recently reported that a lipid nanoparticle (LNP)-encapsulated mRNA encoding the light and heavy chains of a human monoclonal antibody (CHKV-24 immunoglobulin G (IgG)) targeting the CHIKV E2 glycoprotein elicited high levels of biologically relevant neutralizing antibodies when administered by infusion into mice or cynomolgus macaques[54]
Between 22 January 2019 and 18 June 2020, all 38 were randomized to treatment with a single dose of mRNA-1944 at 0.1 mg kg−1, 0.3 mg kg−1, 0.6 mg kg−1 or 0.6 mg kg−1 preadministered with a steroid to assess its impact on infusion-related reactions (0.6 mg kg−1 with a steroid) or placebo, or 2 weekly doses at 0.3 mg kg−1 or placebo administered on days 1 and 8 (Fig. 1)