Fc-mediated functions of nirsevimab complement direct respiratory syncytial virus neutralization but are not required for optimal prophylactic protection

IntroductionNirsevimab 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.MethodsNirsevimab, MEDI8897* (i.e., nirsevimab without the YTE modification), and MEDI8897*-TM (i.e., MEDI8897* without Fc effector functions) binding to Fc γ receptors (FcγRs) 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.ResultsNirsevimab and MEDI8897* exhibited binding to a range of FcγRs, with expected reductions in FcγR 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.ConclusionNirsevimab 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. Ausführliche Beschreibung

Gespeichert in:

Autor*in:	Tyler Brady [verfasserIn] Corinne Cayatte [verfasserIn] Tiffany L. Roe [verfasserIn] Scott D. Speer [verfasserIn] Hong Ji [verfasserIn] LeeAnn Machiesky [verfasserIn] Tianhui Zhang [verfasserIn] Deidre Wilkins [verfasserIn] Kevin M. Tuffy [verfasserIn] Elizabeth J. Kelly [verfasserIn]

Format:	E-Artikel
Sprache:	Englisch

Erschienen:	2023

Schlagwörter:	nirsevimab respiratory syncytial virus Fc-mediated effector function anti-RSV F protein monoclonal antibodies RSV immunoprophylaxis

Übergeordnetes Werk:	In: Frontiers in Immunology - Frontiers Media S.A., 2011, 14(2023)
Übergeordnetes Werk:	volume:14 ; year:2023

Links:	Link aufrufen Link aufrufen Link aufrufen Journal toc

DOI / URN:	10.3389/fimmu.2023.1283120

Katalog-ID:	DOAJ09832294X

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245	1	0	\|a Fc-mediated functions of nirsevimab complement direct respiratory syncytial virus neutralization but are not required for optimal prophylactic protection
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520			\|a IntroductionNirsevimab 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.MethodsNirsevimab, MEDI8897* (i.e., nirsevimab without the YTE modification), and MEDI8897-TM (i.e., MEDI8897 without Fc effector functions) binding to Fc γ receptors (FcγRs) 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.ResultsNirsevimab and MEDI8897 exhibited binding to a range of FcγRs, with expected reductions in FcγR 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.ConclusionNirsevimab 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.
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650		4	\|a RSV immunoprophylaxis
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700	0		\|a Deidre Wilkins \|e verfasserin \|4 aut
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allfields	10.3389/fimmu.2023.1283120 doi (DE-627)DOAJ09832294X (DE-599)DOAJc72eec9d7aad4feda1ae2f5d53e8d316 DE-627 ger DE-627 rakwb eng RC581-607 Tyler Brady verfasserin aut Fc-mediated functions of nirsevimab complement direct respiratory syncytial virus neutralization but are not required for optimal prophylactic protection 2023 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier IntroductionNirsevimab 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.MethodsNirsevimab, MEDI8897* (i.e., nirsevimab without the YTE modification), and MEDI8897-TM (i.e., MEDI8897 without Fc effector functions) binding to Fc γ receptors (FcγRs) 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.ResultsNirsevimab and MEDI8897 exhibited binding to a range of FcγRs, with expected reductions in FcγR 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.ConclusionNirsevimab 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. nirsevimab respiratory syncytial virus Fc-mediated effector function anti-RSV F protein monoclonal antibodies RSV immunoprophylaxis Immunologic diseases. Allergy Corinne Cayatte verfasserin aut Tiffany L. Roe verfasserin aut Scott D. Speer verfasserin aut Hong Ji verfasserin aut LeeAnn Machiesky verfasserin aut Tianhui Zhang verfasserin aut Deidre Wilkins verfasserin aut Kevin M. Tuffy verfasserin aut Elizabeth J. Kelly verfasserin aut In Frontiers in Immunology Frontiers Media S.A., 2011 14(2023) (DE-627)657998354 (DE-600)2606827-8 16643224 nnns volume:14 year:2023 https://doi.org/10.3389/fimmu.2023.1283120 kostenfrei https://doaj.org/article/c72eec9d7aad4feda1ae2f5d53e8d316 kostenfrei https://www.frontiersin.org/articles/10.3389/fimmu.2023.1283120/full kostenfrei https://doaj.org/toc/1664-3224 Journal toc kostenfrei GBV_USEFLAG_A SYSFLAG_A GBV_DOAJ GBV_ILN_11 GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_39 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_73 GBV_ILN_74 GBV_ILN_95 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_161 GBV_ILN_170 GBV_ILN_206 GBV_ILN_213 GBV_ILN_230 GBV_ILN_285 GBV_ILN_293 GBV_ILN_602 GBV_ILN_2003 GBV_ILN_2014 GBV_ILN_4012 GBV_ILN_4037 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4249 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4700 AR 14 2023
spelling	10.3389/fimmu.2023.1283120 doi (DE-627)DOAJ09832294X (DE-599)DOAJc72eec9d7aad4feda1ae2f5d53e8d316 DE-627 ger DE-627 rakwb eng RC581-607 Tyler Brady verfasserin aut Fc-mediated functions of nirsevimab complement direct respiratory syncytial virus neutralization but are not required for optimal prophylactic protection 2023 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier IntroductionNirsevimab 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.MethodsNirsevimab, MEDI8897* (i.e., nirsevimab without the YTE modification), and MEDI8897-TM (i.e., MEDI8897 without Fc effector functions) binding to Fc γ receptors (FcγRs) 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.ResultsNirsevimab and MEDI8897 exhibited binding to a range of FcγRs, with expected reductions in FcγR 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.ConclusionNirsevimab 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. nirsevimab respiratory syncytial virus Fc-mediated effector function anti-RSV F protein monoclonal antibodies RSV immunoprophylaxis Immunologic diseases. Allergy Corinne Cayatte verfasserin aut Tiffany L. Roe verfasserin aut Scott D. Speer verfasserin aut Hong Ji verfasserin aut LeeAnn Machiesky verfasserin aut Tianhui Zhang verfasserin aut Deidre Wilkins verfasserin aut Kevin M. Tuffy verfasserin aut Elizabeth J. Kelly verfasserin aut In Frontiers in Immunology Frontiers Media S.A., 2011 14(2023) (DE-627)657998354 (DE-600)2606827-8 16643224 nnns volume:14 year:2023 https://doi.org/10.3389/fimmu.2023.1283120 kostenfrei https://doaj.org/article/c72eec9d7aad4feda1ae2f5d53e8d316 kostenfrei https://www.frontiersin.org/articles/10.3389/fimmu.2023.1283120/full kostenfrei https://doaj.org/toc/1664-3224 Journal toc kostenfrei GBV_USEFLAG_A SYSFLAG_A GBV_DOAJ GBV_ILN_11 GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_39 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_73 GBV_ILN_74 GBV_ILN_95 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_161 GBV_ILN_170 GBV_ILN_206 GBV_ILN_213 GBV_ILN_230 GBV_ILN_285 GBV_ILN_293 GBV_ILN_602 GBV_ILN_2003 GBV_ILN_2014 GBV_ILN_4012 GBV_ILN_4037 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4249 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4700 AR 14 2023
allfields_unstemmed	10.3389/fimmu.2023.1283120 doi (DE-627)DOAJ09832294X (DE-599)DOAJc72eec9d7aad4feda1ae2f5d53e8d316 DE-627 ger DE-627 rakwb eng RC581-607 Tyler Brady verfasserin aut Fc-mediated functions of nirsevimab complement direct respiratory syncytial virus neutralization but are not required for optimal prophylactic protection 2023 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier IntroductionNirsevimab 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.MethodsNirsevimab, MEDI8897* (i.e., nirsevimab without the YTE modification), and MEDI8897-TM (i.e., MEDI8897 without Fc effector functions) binding to Fc γ receptors (FcγRs) 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.ResultsNirsevimab and MEDI8897 exhibited binding to a range of FcγRs, with expected reductions in FcγR 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.ConclusionNirsevimab 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. nirsevimab respiratory syncytial virus Fc-mediated effector function anti-RSV F protein monoclonal antibodies RSV immunoprophylaxis Immunologic diseases. Allergy Corinne Cayatte verfasserin aut Tiffany L. Roe verfasserin aut Scott D. Speer verfasserin aut Hong Ji verfasserin aut LeeAnn Machiesky verfasserin aut Tianhui Zhang verfasserin aut Deidre Wilkins verfasserin aut Kevin M. Tuffy verfasserin aut Elizabeth J. Kelly verfasserin aut In Frontiers in Immunology Frontiers Media S.A., 2011 14(2023) (DE-627)657998354 (DE-600)2606827-8 16643224 nnns volume:14 year:2023 https://doi.org/10.3389/fimmu.2023.1283120 kostenfrei https://doaj.org/article/c72eec9d7aad4feda1ae2f5d53e8d316 kostenfrei https://www.frontiersin.org/articles/10.3389/fimmu.2023.1283120/full kostenfrei https://doaj.org/toc/1664-3224 Journal toc kostenfrei GBV_USEFLAG_A SYSFLAG_A GBV_DOAJ GBV_ILN_11 GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_39 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_73 GBV_ILN_74 GBV_ILN_95 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_161 GBV_ILN_170 GBV_ILN_206 GBV_ILN_213 GBV_ILN_230 GBV_ILN_285 GBV_ILN_293 GBV_ILN_602 GBV_ILN_2003 GBV_ILN_2014 GBV_ILN_4012 GBV_ILN_4037 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4249 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4700 AR 14 2023
allfieldsGer	10.3389/fimmu.2023.1283120 doi (DE-627)DOAJ09832294X (DE-599)DOAJc72eec9d7aad4feda1ae2f5d53e8d316 DE-627 ger DE-627 rakwb eng RC581-607 Tyler Brady verfasserin aut Fc-mediated functions of nirsevimab complement direct respiratory syncytial virus neutralization but are not required for optimal prophylactic protection 2023 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier IntroductionNirsevimab 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.MethodsNirsevimab, MEDI8897* (i.e., nirsevimab without the YTE modification), and MEDI8897-TM (i.e., MEDI8897 without Fc effector functions) binding to Fc γ receptors (FcγRs) 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.ResultsNirsevimab and MEDI8897 exhibited binding to a range of FcγRs, with expected reductions in FcγR 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.ConclusionNirsevimab 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. nirsevimab respiratory syncytial virus Fc-mediated effector function anti-RSV F protein monoclonal antibodies RSV immunoprophylaxis Immunologic diseases. Allergy Corinne Cayatte verfasserin aut Tiffany L. Roe verfasserin aut Scott D. Speer verfasserin aut Hong Ji verfasserin aut LeeAnn Machiesky verfasserin aut Tianhui Zhang verfasserin aut Deidre Wilkins verfasserin aut Kevin M. Tuffy verfasserin aut Elizabeth J. Kelly verfasserin aut In Frontiers in Immunology Frontiers Media S.A., 2011 14(2023) (DE-627)657998354 (DE-600)2606827-8 16643224 nnns volume:14 year:2023 https://doi.org/10.3389/fimmu.2023.1283120 kostenfrei https://doaj.org/article/c72eec9d7aad4feda1ae2f5d53e8d316 kostenfrei https://www.frontiersin.org/articles/10.3389/fimmu.2023.1283120/full kostenfrei https://doaj.org/toc/1664-3224 Journal toc kostenfrei GBV_USEFLAG_A SYSFLAG_A GBV_DOAJ GBV_ILN_11 GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_39 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_73 GBV_ILN_74 GBV_ILN_95 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_161 GBV_ILN_170 GBV_ILN_206 GBV_ILN_213 GBV_ILN_230 GBV_ILN_285 GBV_ILN_293 GBV_ILN_602 GBV_ILN_2003 GBV_ILN_2014 GBV_ILN_4012 GBV_ILN_4037 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4249 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4700 AR 14 2023
allfieldsSound	10.3389/fimmu.2023.1283120 doi (DE-627)DOAJ09832294X (DE-599)DOAJc72eec9d7aad4feda1ae2f5d53e8d316 DE-627 ger DE-627 rakwb eng RC581-607 Tyler Brady verfasserin aut Fc-mediated functions of nirsevimab complement direct respiratory syncytial virus neutralization but are not required for optimal prophylactic protection 2023 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier IntroductionNirsevimab 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.MethodsNirsevimab, MEDI8897* (i.e., nirsevimab without the YTE modification), and MEDI8897-TM (i.e., MEDI8897 without Fc effector functions) binding to Fc γ receptors (FcγRs) 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.ResultsNirsevimab and MEDI8897 exhibited binding to a range of FcγRs, with expected reductions in FcγR 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.ConclusionNirsevimab 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. nirsevimab respiratory syncytial virus Fc-mediated effector function anti-RSV F protein monoclonal antibodies RSV immunoprophylaxis Immunologic diseases. Allergy Corinne Cayatte verfasserin aut Tiffany L. Roe verfasserin aut Scott D. Speer verfasserin aut Hong Ji verfasserin aut LeeAnn Machiesky verfasserin aut Tianhui Zhang verfasserin aut Deidre Wilkins verfasserin aut Kevin M. Tuffy verfasserin aut Elizabeth J. Kelly verfasserin aut In Frontiers in Immunology Frontiers Media S.A., 2011 14(2023) (DE-627)657998354 (DE-600)2606827-8 16643224 nnns volume:14 year:2023 https://doi.org/10.3389/fimmu.2023.1283120 kostenfrei https://doaj.org/article/c72eec9d7aad4feda1ae2f5d53e8d316 kostenfrei https://www.frontiersin.org/articles/10.3389/fimmu.2023.1283120/full kostenfrei https://doaj.org/toc/1664-3224 Journal toc kostenfrei GBV_USEFLAG_A SYSFLAG_A GBV_DOAJ GBV_ILN_11 GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_39 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_73 GBV_ILN_74 GBV_ILN_95 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_161 GBV_ILN_170 GBV_ILN_206 GBV_ILN_213 GBV_ILN_230 GBV_ILN_285 GBV_ILN_293 GBV_ILN_602 GBV_ILN_2003 GBV_ILN_2014 GBV_ILN_4012 GBV_ILN_4037 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4249 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4700 AR 14 2023
language	English
source	In Frontiers in Immunology 14(2023) volume:14 year:2023
sourceStr	In Frontiers in Immunology 14(2023) volume:14 year:2023
format_phy_str_mv	Article
institution	findex.gbv.de
topic_facet	nirsevimab respiratory syncytial virus Fc-mediated effector function anti-RSV F protein monoclonal antibodies RSV immunoprophylaxis Immunologic diseases. Allergy
isfreeaccess_bool	true
container_title	Frontiers in Immunology
authorswithroles_txt_mv	Tyler Brady @@aut@@ Corinne Cayatte @@aut@@ Tiffany L. Roe @@aut@@ Scott D. Speer @@aut@@ Hong Ji @@aut@@ LeeAnn Machiesky @@aut@@ Tianhui Zhang @@aut@@ Deidre Wilkins @@aut@@ Kevin M. Tuffy @@aut@@ Elizabeth J. Kelly @@aut@@
publishDateDaySort_date	2023-01-01T00:00:00Z
hierarchy_top_id	657998354
id	DOAJ09832294X
language_de	englisch
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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.MethodsNirsevimab, MEDI8897* (i.e., nirsevimab without the YTE modification), and MEDI8897-TM (i.e., MEDI8897 without Fc effector functions) binding to Fc γ receptors (FcγRs) 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.ResultsNirsevimab and MEDI8897 exhibited binding to a range of FcγRs, with expected reductions in FcγR 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.ConclusionNirsevimab possesses Fc effector activity comparable with the current standard of care, palivizumab. 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callnumber-first	R - Medicine
author	Tyler Brady
spellingShingle	Tyler Brady misc RC581-607 misc nirsevimab misc respiratory syncytial virus misc Fc-mediated effector function misc anti-RSV F protein monoclonal antibodies misc RSV immunoprophylaxis misc Immunologic diseases. Allergy Fc-mediated functions of nirsevimab complement direct respiratory syncytial virus neutralization but are not required for optimal prophylactic protection
authorStr	Tyler Brady
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topic_title	RC581-607 Fc-mediated functions of nirsevimab complement direct respiratory syncytial virus neutralization but are not required for optimal prophylactic protection nirsevimab respiratory syncytial virus Fc-mediated effector function anti-RSV F protein monoclonal antibodies RSV immunoprophylaxis
topic	misc RC581-607 misc nirsevimab misc respiratory syncytial virus misc Fc-mediated effector function misc anti-RSV F protein monoclonal antibodies misc RSV immunoprophylaxis misc Immunologic diseases. Allergy
topic_unstemmed	misc RC581-607 misc nirsevimab misc respiratory syncytial virus misc Fc-mediated effector function misc anti-RSV F protein monoclonal antibodies misc RSV immunoprophylaxis misc Immunologic diseases. Allergy
topic_browse	misc RC581-607 misc nirsevimab misc respiratory syncytial virus misc Fc-mediated effector function misc anti-RSV F protein monoclonal antibodies misc RSV immunoprophylaxis misc Immunologic diseases. Allergy
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title	Fc-mediated functions of nirsevimab complement direct respiratory syncytial virus neutralization but are not required for optimal prophylactic protection
ctrlnum	(DE-627)DOAJ09832294X (DE-599)DOAJc72eec9d7aad4feda1ae2f5d53e8d316
title_full	Fc-mediated functions of nirsevimab complement direct respiratory syncytial virus neutralization but are not required for optimal prophylactic protection
author_sort	Tyler Brady
journal	Frontiers in Immunology
journalStr	Frontiers in Immunology
callnumber-first-code	R
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author_browse	Tyler Brady Corinne Cayatte Tiffany L. Roe Scott D. Speer Hong Ji LeeAnn Machiesky Tianhui Zhang Deidre Wilkins Kevin M. Tuffy Elizabeth J. Kelly
container_volume	14
class	RC581-607
format_se	Elektronische Aufsätze
author-letter	Tyler Brady
doi_str_mv	10.3389/fimmu.2023.1283120
author2-role	verfasserin
title_sort	fc-mediated functions of nirsevimab complement direct respiratory syncytial virus neutralization but are not required for optimal prophylactic protection
callnumber	RC581-607
title_auth	Fc-mediated functions of nirsevimab complement direct respiratory syncytial virus neutralization but are not required for optimal prophylactic protection
abstract	IntroductionNirsevimab 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.MethodsNirsevimab, MEDI8897* (i.e., nirsevimab without the YTE modification), and MEDI8897-TM (i.e., MEDI8897 without Fc effector functions) binding to Fc γ receptors (FcγRs) 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.ResultsNirsevimab and MEDI8897 exhibited binding to a range of FcγRs, with expected reductions in FcγR 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.ConclusionNirsevimab 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.
abstractGer	IntroductionNirsevimab 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.MethodsNirsevimab, MEDI8897* (i.e., nirsevimab without the YTE modification), and MEDI8897-TM (i.e., MEDI8897 without Fc effector functions) binding to Fc γ receptors (FcγRs) 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.ResultsNirsevimab and MEDI8897 exhibited binding to a range of FcγRs, with expected reductions in FcγR 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.ConclusionNirsevimab 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.
abstract_unstemmed	IntroductionNirsevimab 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.MethodsNirsevimab, MEDI8897* (i.e., nirsevimab without the YTE modification), and MEDI8897-TM (i.e., MEDI8897 without Fc effector functions) binding to Fc γ receptors (FcγRs) 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.ResultsNirsevimab and MEDI8897 exhibited binding to a range of FcγRs, with expected reductions in FcγR 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.ConclusionNirsevimab 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.
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title_short	Fc-mediated functions of nirsevimab complement direct respiratory syncytial virus neutralization but are not required for optimal prophylactic protection
url	https://doi.org/10.3389/fimmu.2023.1283120 https://doaj.org/article/c72eec9d7aad4feda1ae2f5d53e8d316 https://www.frontiersin.org/articles/10.3389/fimmu.2023.1283120/full https://doaj.org/toc/1664-3224
remote_bool	true
author2	Corinne Cayatte Tiffany L. Roe Scott D. Speer Hong Ji LeeAnn Machiesky Tianhui Zhang Deidre Wilkins Kevin M. Tuffy Elizabeth J. Kelly
author2Str	Corinne Cayatte Tiffany L. Roe Scott D. Speer Hong Ji LeeAnn Machiesky Tianhui Zhang Deidre Wilkins Kevin M. Tuffy Elizabeth J. Kelly
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doi_str	10.3389/fimmu.2023.1283120
callnumber-a	RC581-607
up_date	2024-07-03T16:39:15.176Z
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Fc-mediated functions of nirsevimab complement direct respiratory syncytial virus neutralization but are not required for optimal prophylactic protection

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