A potent broadly neutralizing human RSV antibody targets conserved site IV of the fusion glycoprotein

Abstract

Respiratory syncytial virus (RSV) infection is the leading cause of hospitalization and infant mortality under six months of age worldwide; therefore, the prevention of RSV infection in all infants represents a significant unmet medical need. Here we report the isolation of a potent and broadly neutralizing RSV monoclonal antibody derived from a human memory B-cell. This antibody, RB1, is equipotent on RSV A and B subtypes, potently neutralizes a diverse panel of clinical isolates in vitro and demonstrates in vivo protection. It binds to a highly conserved epitope in antigenic site IV of the RSV fusion glycoprotein. RB1 is the parental antibody to MK-1654 which is currently in clinical development for the prevention of RSV infection in infants.

Challenges and opportunities for antiviral monoclonal antibodies as COVID-19 therapy

“…Unfortunately, nearly all such efforts to develop mAb as therapy for ARIs have been met with disappointing results. Some human or humanized mAbs developed as antivirals that have advanced past Phase 1 studies include MEDI-8852 (influenza; IC 50 ~ 41–4050 ng/mL; 750 or 3000 mg) [ 155 , 156 ], MHAA4549 (influenza; IC 50 ~ 195–6765 ng/mL; 3600 or 8400 mg) [ 44 , 157 ], CR8020 (influenza; IC 50 ~ 9–500 ng/mL; 30 mg/kg) [ 158 ], CT-P27 (influenza; IC 50 ~ 15 μg/mL; 10–20 mg/kg) [ 136 ], diridavumab (influenza; IC 50 ~ 18–2200 ng/mL; 30 mg/kg) [ 159 , 160 ], VIS-410 (influenza; IC 50 ~ 30–7000 ng/mL; 2000 or 4000 mg) [ 161 , 162 ], Motavizumab (RSV; IC 50 ~ 20 ng/mL; 15 mg/kg [ 163 ]), and palivizumab (RSV; IC 50 ~ 163–360 ng/mL; 15 mg/kg) [ [163] , [164] , [165] ]. None of these mAbs were noted to have major safety concerns, which supports the anticipated safe use of mAbs against SARS-CoV-2.…”

“…Indeed, the majority of the current anti-SARS-COV-2 mAbs in active preclinical and clinical development have exceptional potencies (IC 50 values <10 ng/mL range) ( Table 1 ). These potencies substantially exceed nearly all of the antiviral mAbs that were previously advanced into clinical studies and failed, including palivizumab against RSV (Synagis; IC 50 ~ 163–360 ng/mL [ [163] , [164] , [165] ]), MEDI8852 against influenza (IC 50 ~ 41–4050 ng/mL [ 155 , 156 ]), and MHAA4549 against influenza (IC 50 ~ 195–6765 ng/mL [ 44 , 157 ]). Theoretically, assuming the concentrations of these anti-SARS-CoV-2 mAbs in BALF can reach ~0.1–0.2% of the mAb concentration in plasma, consistent with prior non-human primate studies, the local concentration should substantially exceed the IC 50 of these mAbs.…”

Antibody Epitopes of Pneumovirus Fusion Proteins

“…The structure of the R4.C6 Fab-post-fusion RSV F complex obtained by cryo-EM showed that the antibody binds to a cross-protomer area in between site II and IV. Recently, a site IV human antibody, RB1, was co-crystallized in complex with pre-fusion RSV F, and a half-life extended variant of this antibody is in clinical development (74).…”

Strategies for active and passive pediatric RSV immunization

“…108 , 109 In a similar endeavor to extend the half-life and reduce the number of injections required to protect infants during the RSV season, MK-1654, a broadly neutralizing human RSV antibody that targets the conserved site IV of the RSV F protein is being tested. 110 A double-blind, randomized, placebo controlled study is currently recruiting healthy pre-term and full-term infants to evaluate the safety, tolerability, pharmacokinetics, and incidence of anti-drug antibodies following a single dose of MK-1654. 111 Early studies show that the parent compound of MK-164, RB1 is approximately 50-fold more potent in vitro than palivizumab against both RSV A and B subtypes.…”