RSM01, an extended half-life RSV monoclonal antibody with a high barrier to resistance

ABSTRACT Respiratory syncytial virus (RSV) causes substantial infant morbidity and mortality, particularly in low- and middle-income countries (LMICs). RSM01 is a long-acting RSV monoclonal antibody (mAb) in development for LMICs. To date, RSM01 resistant mutants have not been able to be generated in vitro. We systematically assessed the in vitro resistance barrier of RSM01 relative to licensed RSV mAbs and the susceptibility of a panel of global contemporary strains to RSM01. The emergence of mAb-resistant mutant (MARM) was assessed for RSM01, nirsevimab, and palivizumab. Triple plaque-purified RSV-A2 and RSV-B1 were serially passaged under mAb pressure to generate MARMs, which were phenotyped and genotyped. Moderate resistance was defined as > 3-fold and high resistance > 30-fold increase in IC50 compared with parental strains. The susceptibility of contemporary clinical strains from South Africa, Argentina, and the Netherlands to RSM01 was tested in a neutralisation assay. RSV-A and B lab strains developed high resistance to palivizumab and nirsevimab, while RSM01 pressure induced moderate resistance. No MARMs demonstrated a fitness advantage; one RSM01 MARM incurred fitness costs. RSM01 potently neutralized global contemporary RSV-A and B strains. In conclusion, in vitro RSM01 resistance was infrequent and moderate, suggesting a high resistance barrier in vitro. Laboratory-selected MARMs may not directly predict clinical escape, but the confirmation of the high barrier to resistance of RSM01 is encouraging and provides an alternative in the event that resistance is observed with widespread use of current licensed anti-RSV mAbs. One Sentence Summary In vitro RSV resistance to RSM01 is infrequent and moderate, suggesting a high barrier to resistance. Competing Interest Statement UMCU has received major funding (>100,000 euro per industrial partner) for investigator initiated studies from AbbVie, AstraZeneca, the Gates Foundation, Gates Medical Research Institute, the Dutch Lung Foundation, Janssen, MedImmune, MeMed Diagnostics, Moderna, MSD, Pfizer, and Sanofi. UMCU has received major funding as part of the public private partnership IMI-funded RESCEU and PROMISE projects with partners GSK, Novavax, Janssen, AstraZeneca, Pfizer and Sanofi. UMCU has received major funding by Julius Clinical for participating in clinical studies sponsored by MedImmune and Pfizer. UMCU received minor funding (1,000-25,000 euro per industrial partner) for consultation and invited lectures by AbbVie, MedImmune, Ablynx, Bavaria Nordic, MabXience, GSK, Novavax, Pfizer, Moderna, Astrazeneca, MSD, Sanofi, Janssen. LJB and NIM have regular interaction with pharmaceutical and other industrial partners; they have not received personal fees or other personal benefits. LJB is the founding chairman of the ReSViNET Foundation.