PMID- 37901217 OWN - NLM STAT- MEDLINE DCOM- 20231031 LR - 20231105 IS - 1664-3224 (Electronic) IS - 1664-3224 (Linking) VI - 14 DP - 2023 TI - Fc-mediated functions of nirsevimab complement direct respiratory syncytial virus neutralization but are not required for optimal prophylactic protection. PG - 1283120 LID - 10.3389/fimmu.2023.1283120 [doi] LID - 1283120 AB - INTRODUCTION: Nirsevimab is an extended half-life (M252Y/S254T/T256E [YTE]-modified) monoclonal antibody to the pre-fusion conformation of the respiratory syncytial virus (RSV) Fusion protein, with established efficacy in preventing RSV-associated lower respiratory tract infection in infants for the duration of a typical RSV season. Previous studies suggest that nirsevimab confers protection via direct virus neutralization. Here we use preclinical models to explore whether fragment crystallizable (Fc)-mediated effector functions contribute to nirsevimab-mediated protection. METHODS: Nirsevimab, MEDI8897* (i.e., nirsevimab without the YTE modification), and MEDI8897*-TM (i.e., MEDI8897* without Fc effector functions) binding to Fc gamma receptors (FcgammaRs) was evaluated using surface plasmon resonance. Antibody-dependent neutrophil phagocytosis (ADNP), antibody-dependent cellular phagocytosis (ADCP), antibody-dependent complement deposition (ADCD), and antibody-dependent cellular cytotoxicity (ADCC) were assessed through in vitro and ex vivo serological analyses. A cotton rat challenge study was performed with MEDI8897* and MEDI8897*-TM to explore whether Fc effector functions contribute to protection from RSV. RESULTS: Nirsevimab and MEDI8897* exhibited binding to a range of FcgammaRs, with expected reductions in FcgammaR binding affinities observed for MEDI8897*-TM. Nirsevimab exhibited in vitro ADNP, ADCP, ADCD, and ADCC activity above background levels, and similar ADNP, ADCP, and ADCD activity to palivizumab. Nirsevimab administration increased ex vivo ADNP, ADCP, and ADCD activity in participant serum from the MELODY study (NCT03979313). However, ADCC levels remained similar between nirsevimab and placebo. MEDI8897* and MEDI8897*-TM exhibited similar dose-dependent reduction in lung and nasal turbinate RSV titers in the cotton rat model. CONCLUSION: Nirsevimab possesses Fc effector activity comparable with the current standard of care, palivizumab. However, despite possessing the capacity for Fc effector activity, data from RSV challenge experiments illustrate that nirsevimab-mediated protection is primarily dependent on direct virus neutralization. CI - Copyright (c) 2023 Brady, Cayatte, Roe, Speer, Ji, Machiesky, Zhang, Wilkins, Tuffy and Kelly. FAU - Brady, Tyler AU - Brady T AD - Translational Medicine, Vaccines and Immune Therapies, BioPharmaceuticals R&D, AstraZeneca, Gaithersburg, MD, United States. FAU - Cayatte, Corinne AU - Cayatte C AD - Early Oncology ICA, Oncology R&D, AstraZeneca, Gaithersburg, MD, United States. FAU - Roe, Tiffany L AU - Roe TL AD - Translational Medicine, Vaccines and Immune Therapies, BioPharmaceuticals R&D, AstraZeneca, Gaithersburg, MD, United States. FAU - Speer, Scott D AU - Speer SD AD - Virology and Vaccine Discovery, Vaccines and Immune Therapies, BioPharmaceuticals R&D, AstraZeneca, Gaithersburg, MD, United States. FAU - Ji, Hong AU - Ji H AD - Translational Medicine, Vaccines and Immune Therapies, BioPharmaceuticals R&D, AstraZeneca, Gaithersburg, MD, United States. FAU - Machiesky, LeeAnn AU - Machiesky L AD - Process and Analytical Sciences, BioPharmaceuticals R&D, AstraZeneca, Gaithersburg, MD, United States. FAU - Zhang, Tianhui AU - Zhang T AD - Discovery Sciences, BioPharmaceuticals R&D, AstraZeneca, Gaithersburg, MD, United States. FAU - Wilkins, Deidre AU - Wilkins D AD - Translational Medicine, Vaccines and Immune Therapies, BioPharmaceuticals R&D, AstraZeneca, Gaithersburg, MD, United States. FAU - Tuffy, Kevin M AU - Tuffy KM AD - Translational Medicine, Vaccines and Immune Therapies, BioPharmaceuticals R&D, AstraZeneca, Gaithersburg, MD, United States. FAU - Kelly, Elizabeth J AU - Kelly EJ AD - Translational Medicine, Vaccines and Immune Therapies, BioPharmaceuticals R&D, AstraZeneca, Gaithersburg, MD, United States. LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20231011 PL - Switzerland TA - Front Immunol JT - Frontiers in immunology JID - 101560960 RN - VRN8S9CW5V (nirsevimab) RN - DQ448MW7KS (Palivizumab) RN - 0 (Antibodies, Viral) RN - 9007-36-7 (Complement System Proteins) SB - IM MH - Infant MH - Humans MH - Animals MH - Palivizumab/therapeutic use MH - Antibodies, Viral MH - *Respiratory Syncytial Virus, Human MH - *Respiratory Syncytial Virus Infections MH - Complement System Proteins/therapeutic use MH - Sigmodontinae PMC - PMC10600457 OTO - NOTNLM OT - Fc-mediated effector function OT - RSV immunoprophylaxis OT - anti-RSV F protein monoclonal antibodies OT - nirsevimab OT - respiratory syncytial virus COIS- The authors of this manuscript are current or former employees of AstraZeneca and may hold AstraZeneca stock or stock options. The authors declare that this study received funding from AstraZeneca and Sanofi. The funders had the following involvement with the study: study design; collection, analysis and interpretation of data; the writing of this article and the decision to submit it for publication. EDAT- 2023/10/30 06:46 MHDA- 2023/10/31 06:42 PMCR- 2023/01/01 CRDT- 2023/10/30 04:47 PHST- 2023/08/25 00:00 [received] PHST- 2023/09/25 00:00 [accepted] PHST- 2023/10/31 06:42 [medline] PHST- 2023/10/30 06:46 [pubmed] PHST- 2023/10/30 04:47 [entrez] PHST- 2023/01/01 00:00 [pmc-release] AID - 10.3389/fimmu.2023.1283120 [doi] PST - epublish SO - Front Immunol. 2023 Oct 11;14:1283120. doi: 10.3389/fimmu.2023.1283120. eCollection 2023.