Therapeutic efficacy of a potent anti-Venezuelan equine encephalitis virus antibody is contingent on Fc effector function

Schwedler, Jennifer L.; Stefan, Maxwell A.; Thatcher, Christine E.; McIlroy, Peter R.; Sinha, Anupama; Phillips, Ashlee M.; Sumner, Christopher A.; Courtney, Colleen M.; Kim, Christina Y.; Weilhammer, Dina R.; Harmon, Brooke

doi:10.1080/19420862.2023.2297451

Therapeutic efficacy of a potent anti-Venezuelan equine encephalitis virus antibody is contingent on Fc effector function

Journal Article · Wed Jan 03 04:00:00 EST 2024 · MAbs

DOI:https://doi.org/10.1080/19420862.2023.2297451· OSTI ID:2469756

Schwedler, Jennifer L. ^[1]; Stefan, Maxwell A. ^[1]; Thatcher, Christine E. ^[1]; McIlroy, Peter R. ^[1]; Sinha, Anupama ^[1]; Phillips, Ashlee M. ^[2]; Sumner, Christopher A. ^[1]; Courtney, Colleen M. ^[1]; Kim, Christina Y. ^[1]; Weilhammer, Dina R. ^[2]; ^[1]

Sandia National Laboratories (SNL-CA), Livermore, CA (United States)
Lawrence Livermore National Laboratory (LLNL), Livermore, CA (United States)

The development of specific, safe, and potent monoclonal antibodies (Abs) has led to novel therapeutic options for infectious disease. In addition to preventing viral infection through neutralization, Abs can clear infected cells and induce immunomodulatory functions through engagement of their crystallizable fragment (Fc) with complement proteins and Fc receptors on immune cells. Little is known about the role of Fc effector functions of neutralizing Abs in the context of encephalitic alphavirus infection. To determine the role of Fc effector function in therapeutic efficacy against Venezuelan equine encephalitis virus (VEEV), we compared the potently neutralizing anti-VEEV human IgG F5 (hF5) Ab with intact Fc function (hF5-WT) or containing the loss of function Fc mutations L234A and L235A (hF5-LALA) in the context of VEEV infection. We observed significantly reduced binding to complement and Fc receptors, as well as differential in vitro kinetics of Fc-mediated cytotoxicity for hF5-LALA compared to hF5-WT. The in vivo efficacy of hF5-LALA was comparable to hF5-WT at -24 and + 24 h post infection, with both Abs providing high levels of protection. However, when hF5-WT and hF5-LALA were administered + 48 h post infection, there was a significant decrease in the therapeutic efficacy of hF5-LALA. Together these results demonstrate that optimal therapeutic Ab treatment of VEEV, and possibly other encephalitic alphaviruses, requires neutralization paired with engagement of immune effectors via the Fc region.

View Accepted Manuscript (DOE)

Research Organization:: Lawrence Livermore National Laboratory (LLNL), Livermore, CA (United States)

Sponsoring Organization:: USDOE National Nuclear Security Administration (NNSA); Defense Threat Reduction Agency (DTRA)

Grant/Contract Number:: AC52-07NA27344; NA0003525

OSTI ID:: 2469756

Alternate ID(s):: OSTI ID: 2522863

Journal Information:: MAbs, Journal Name: MAbs Journal Issue: 1 Vol. 16; ISSN 1942-0862

Publisher:: Taylor & FrancisCopyright Statement

Country of Publication:: United States

Language:: English

References (67)

In Vitro Characterization of Five Humanized OKT3 Effector Function Variant Antibodies Xu, Danlin; Alegre, Maria-Luisa; Varga, Sally S. Cellular Immunology, Vol. 200, Issue 1 https://doi.org/10.1006/cimm.2000.1617	journal	February 2000
IgG Fc engineering to modulate antibody effector functions Wang, Xinhua; Mathieu, Mary; Brezski, Randall J. Protein & Cell, Vol. 9, Issue 1 https://doi.org/10.1007/s13238-017-0473-8	journal	October 2017
C3H/HeN mouse model for the evaluation of antiviral agents for the treatment of Venezuelan equine encephalitis virus infection Julander, Justin G.; Skirpstunas, Ramona; Siddharthan, Venkatraman Antiviral Research, Vol. 78, Issue 3 https://doi.org/10.1016/j.antiviral.2008.01.007	journal	June 2008
A humanised murine monoclonal antibody with broad serogroup specificity protects mice from challenge with Venezuelan equine encephalitis virus Goodchild, Sarah A.; O’Brien, Lyn M.; Steven, John Antiviral Research, Vol. 90, Issue 1 https://doi.org/10.1016/j.antiviral.2011.01.010	journal	April 2011
Systematic Analysis of Monoclonal Antibodies against Ebola Virus GP Defines Features that Contribute to Protection Saphire, Erica Ollmann; Schendel, Sharon L.; Fusco, Marnie L. Cell, Vol. 174, Issue 4 https://doi.org/10.1016/j.cell.2018.07.033	journal	August 2018
Human neutralizing antibodies against SARS-CoV-2 require intact Fc effector functions for optimal therapeutic protection Winkler, Emma S.; Gilchuk, Pavlo; Yu, Jinsheng Cell, Vol. 184, Issue 7 https://doi.org/10.1016/j.cell.2021.02.026	journal	April 2021
Pan-protective anti-alphavirus human antibodies target a conserved E1 protein epitope Kim, Arthur S.; Kafai, Natasha M.; Winkler, Emma S. Cell, Vol. 184, Issue 17 https://doi.org/10.1016/j.cell.2021.07.006	journal	August 2021
Therapeutic alphavirus cross-reactive E1 human antibodies inhibit viral egress Williamson, Lauren E.; Reeder, Kristen M.; Bailey, Kevin Cell, Vol. 184, Issue 17 https://doi.org/10.1016/j.cell.2021.07.033	journal	August 2021
Similarities and differences in surface receptor expression by THP-1 monocytes and differentiated macrophages polarized using seven different conditioning regimens Forrester, Megan A.; Wassall, Heather J.; Hall, Lindsay S. Cellular Immunology, Vol. 332 https://doi.org/10.1016/j.cellimm.2018.07.008	journal	October 2018
The mechanistic basis of protection by non-neutralizing anti-alphavirus antibodies Earnest, James T.; Holmes, Autumn C.; Basore, Katherine Cell Reports, Vol. 35, Issue 1 https://doi.org/10.1016/j.celrep.2021.108962	journal	April 2021
A Role for Fc Function in Therapeutic Monoclonal Antibody-Mediated Protection against Ebola Virus Gunn, Bronwyn M.; Yu, Wen-Han; Karim, Marcus M. Cell Host & Microbe, Vol. 24, Issue 2 https://doi.org/10.1016/j.chom.2018.07.009	journal	August 2018
Human mAbs Broadly Protect against Arthritogenic Alphaviruses by Recognizing Conserved Elements of the Mxra8 Receptor-Binding Site Powell, Laura A.; Miller, Andrew; Fox, Julie M. Cell Host & Microbe, Vol. 28, Issue 5 https://doi.org/10.1016/j.chom.2020.07.008	journal	November 2020
Fcγ Receptor Function and the Design of Vaccination Strategies Bournazos, Stylianos; Ravetch, Jeffrey V. Immunity, Vol. 47, Issue 2 https://doi.org/10.1016/j.immuni.2017.07.009	journal	August 2017
Virus entry and replication in the brain precedes blood-brain barrier disruption during intranasal alphavirus infection Cain, Matthew D.; Salimi, Hamid; Gong, Yongfeng Journal of Neuroimmunology, Vol. 308 https://doi.org/10.1016/j.jneuroim.2017.04.008	journal	July 2017
Highly reduced binding to high and low affinity mouse Fc gamma receptors by L234A/L235A and N297A Fc mutations engineered into mouse IgG2a Arduin, E.; Arora, S.; Bamert, P. R. Molecular Immunology, Vol. 63, Issue 2 https://doi.org/10.1016/j.molimm.2014.09.017	journal	February 2015
Dealing with low pH: entry and exit of alphaviruses and flaviviruses Martín, Claudia Sánchez-San; Liu, Catherine Y.; Kielian, Margaret Trends in Microbiology, Vol. 17, Issue 11 https://doi.org/10.1016/j.tim.2009.08.002	journal	November 2009
Encephalitic alphaviruses Zacks, Michele A.; Paessler, Slobodan Veterinary Microbiology, Vol. 140, Issue 3-4 https://doi.org/10.1016/j.vetmic.2009.08.023	journal	January 2010
Treatment of mice with human monoclonal antibody 24h after lethal aerosol challenge with virulent Venezuelan equine encephalitis virus prevents disease but not infection Hunt, Ann R.; Bowen, Richard A.; Frederickson, Shana Virology, Vol. 414, Issue 2 https://doi.org/10.1016/j.virol.2011.03.016	journal	June 2011
Fc receptor but not complement binding is important in antibody protection against HIV Hessell, Ann J.; Hangartner, Lars; Hunter, Meredith Nature, Vol. 449, Issue 7158 https://doi.org/10.1038/nature06106	journal	September 2007
Structural changes of envelope proteins during alphavirus fusion Li, Long; Jose, Joyce; Xiang, Ye Nature, Vol. 468, Issue 7324 https://doi.org/10.1038/nature09546	journal	December 2010
Broadly neutralizing hemagglutinin stalk–specific antibodies require FcγR interactions for protection against influenza virus in vivo DiLillo, David J.; Tan, Gene S.; Palese, Peter Nature Medicine, Vol. 20, Issue 2 https://doi.org/10.1038/nm.3443	journal	January 2014
Beyond binding: antibody effector functions in infectious diseases Lu, Lenette L.; Suscovich, Todd J.; Fortune, Sarah M. Nature Reviews Immunology, Vol. 18, Issue 1 https://doi.org/10.1038/nri.2017.106	journal	October 2017
Human antibodies targeting Zika virus NS1 provide protection against disease in a mouse model Bailey, Mark J.; Duehr, James; Dulin, Harrison Nature Communications, Vol. 9, Issue 1 https://doi.org/10.1038/s41467-018-07008-0	journal	November 2018
Beyond neutralization: Fc-dependent antibody effector functions in SARS-CoV-2 infection Zhang, Ali; Stacey, Hannah D.; D’Agostino, Michael R. Nature Reviews Immunology, Vol. 23, Issue 6 https://doi.org/10.1038/s41577-022-00813-1	journal	December 2022
A molecular understanding of alphavirus entry and antibody protection Kim, Arthur S.; Diamond, Michael S. Nature Reviews Microbiology, Vol. 21, Issue 6 https://doi.org/10.1038/s41579-022-00825-7	journal	December 2022
Structural basis of Chikungunya virus inhibition by monoclonal antibodies Zhou, Qun Fei; Fox, Julie M.; Earnest, James T. Proceedings of the National Academy of Sciences, Vol. 117, Issue 44 https://doi.org/10.1073/pnas.2008051117	journal	October 2020
Effector-attenuating Substitutions That Maintain Antibody Stability and Reduce Toxicity in Mice Lo, Megan; Kim, Hok Seon; Tong, Raymond K. Journal of Biological Chemistry, Vol. 292, Issue 9 https://doi.org/10.1074/jbc.M116.767749	journal	January 2017
Affinity of human IgG subclasses to mouse Fc gamma receptors Dekkers, Gillian; Bentlage, Arthur E. H.; Stegmann, Tamara C. mAbs, Vol. 9, Issue 5 https://doi.org/10.1080/19420862.2017.1323159	journal	May 2017
Neutralizing antibodies against Mayaro virus require Fc effector functions for protective activity Earnest, James T.; Basore, Katherine; Roy, Vicky Journal of Experimental Medicine, Vol. 216, Issue 10 https://doi.org/10.1084/jem.20190736	journal	July 2019
Neutralizing antibodies protect mice against Venezuelan equine encephalitis virus aerosol challenge Kafai, Natasha M.; Williamson, Lauren E.; Binshtein, Elad Journal of Experimental Medicine, Vol. 219, Issue 4 https://doi.org/10.1084/jem.20212532	journal	March 2022
Novel human IgG1 and IgG4 Fc-engineered antibodies with completely abolished immune effector functions Schlothauer, Tilman; Herter, Sylvia; Koller, Claudia Ferrara Protein Engineering Design and Selection, Vol. 29, Issue 10 https://doi.org/10.1093/protein/gzw040	journal	August 2016
Early activation of the host complement system is required to restrict central nervous system invasion and limit neuropathology during Venezuelan equine encephalitis virus infection Brooke, Christopher B.; Schäfer, Alexandra; Matsushima, Glenn K. Journal of General Virology, Vol. 93, Issue 4 https://doi.org/10.1099/vir.0.038281-0	journal	April 2012
A humanized murine monoclonal antibody protects mice either before or after challenge with virulent Venezuelan equine encephalomyelitis virus Hunt, A. R. Journal of General Virology, Vol. 87, Issue 9 https://doi.org/10.1099/vir.0.81925-0	journal	September 2006
Divergent Immunoglobulin G Subclass Activity Through Selective Fc Receptor Binding Nimmerjahn, F. Science, Vol. 310, Issue 5753 https://doi.org/10.1126/science.1118948	journal	December 2005
Antigen-specific antibody Fc glycosylation enhances humoral immunity via the recruitment of complement Lofano, Giuseppe; Gorman, Matthew J.; Yousif, Ashraf S. Science Immunology, Vol. 3, Issue 26 https://doi.org/10.1126/sciimmunol.aat7796	journal	August 2018
Optimal therapeutic activity of monoclonal antibodies against chikungunya virus requires Fc-FcγR interaction on monocytes Fox, Julie M.; Roy, Vicky; Gunn, Bronwyn M. Science Immunology, Vol. 4, Issue 32 https://doi.org/10.1126/sciimmunol.aav5062	journal	February 2019
Antibody Fc characteristics and effector functions correlate with protection from symptomatic dengue virus type 3 infection Dias, Antonio G.; Atyeo, Caroline; Loos, Carolin Science Translational Medicine, Vol. 14, Issue 651 https://doi.org/10.1126/scitranslmed.abm3151	journal	June 2022
Analysis of the Fc Gamma Receptor-Dependent Component of Neutralization Measured by Anthrax Toxin Neutralization Assays Verma, Anita; Ngundi, Miriam M.; Meade, Bruce D. Clinical and Vaccine Immunology, Vol. 16, Issue 10 https://doi.org/10.1128/CVI.00194-09	journal	October 2009
Long-Lasting Protective Antiviral Immunity Induced by Passive Immunotherapies Requires both Neutralizing and Effector Functions of the Administered Monoclonal Antibody Nasser, Roudaina; Pelegrin, Mireia; Michaud, Henri-Alexandre Journal of Virology, Vol. 84, Issue 19 https://doi.org/10.1128/JVI.00568-10	journal	October 2010
Locking and Blocking the Viral Landscape of an Alphavirus with Neutralizing Antibodies Porta, J.; Jose, J.; Roehrig, J. T. Journal of Virology, Vol. 88, Issue 17 https://doi.org/10.1128/JVI.01286-14	journal	June 2014
Effector Function Activities of a Panel of Mutants of a Broadly Neutralizing Antibody against Human Immunodeficiency Virus Type 1 Hezareh, M.; Hessell, A. J.; Jensen, R. C. Journal of Virology, Vol. 75, Issue 24 https://doi.org/10.1128/JVI.75.24.12161-12168.2001	journal	December 2001
Antibodies against West Nile Virus Nonstructural Protein NS1 Prevent Lethal Infection through Fc Receptor-Dependent and -Independent Mechanisms Chung, K. M.; Nybakken, G. E.; Thompson, B. S. Journal of Virology, Vol. 80, Issue 3 https://doi.org/10.1128/JVI.80.3.1340-1351.2006	journal	January 2006
Attenuation of Venezuelan equine encephalitis virus strain TC-83 is encoded by the 5'-noncoding region and the E2 envelope glycoprotein. Kinney, R. M.; Chang, G. J.; Tsuchiya, K. R. Journal of Virology, Vol. 67, Issue 3 https://doi.org/10.1128/jvi.67.3.1269-1277.1993	journal	January 1993
Monoclonal Antibodies against Zika Virus NS1 Protein Confer Protection via FcγReceptor-Dependent and -Independent Pathways Yu, Lei; Liu, Xinglong; Ye, Xianmiao mBio, Vol. 12, Issue 1 https://doi.org/10.1128/mBio.03179-20	journal	February 2021
V ENEZUELAN E QUINE E NCEPHALITIS Weaver, Scott C.; Ferro, Cristina; Barrera, Roberto Annual Review of Entomology, Vol. 49, Issue 1 https://doi.org/10.1146/annurev.ento.49.061802.123422	journal	January 2004
Replication of Alphaviruses: A Review on the Entry Process of Alphaviruses into Cells Leung, Jason Yat-Sing; Ng, Mary Mah-Lee; Chu, Justin Jang Hann Advances in Virology, Vol. 2011 https://doi.org/10.1155/2011/249640	journal	January 2011
Fc-Receptor Interactions Regulate Both Cytotoxic and Immunomodulatory Therapeutic Antibody Effector Functions DiLillo, David J.; Ravetch, Jeffrey V. Cancer Immunology Research, Vol. 3, Issue 7 https://doi.org/10.1158/2326-6066.CIR-15-0120	journal	July 2015
Fc functional antibodies in humans with severe H7N9 and seasonal influenza Vanderven, Hillary A.; Liu, Lu; Ana-Sosa-Batiz, Fernanda JCI Insight, Vol. 2, Issue 13 https://doi.org/10.1172/jci.insight.92750	journal	July 2017
REVIEW PAPER: Pathology of Animal Models of Alphavirus Encephalitis Steele, K. E.; Twenhafel, N. A. Veterinary Pathology, Vol. 47, Issue 5 https://doi.org/10.1177/0300985810372508	journal	June 2010
The First Human Epitope Map of the Alphaviral E1 and E2 Proteins Reveals a New E2 Epitope with Significant Virus Neutralizing Activity Hunt, Ann R.; Frederickson, Shana; Maruyama, Toshiaki PLoS Neglected Tropical Diseases, Vol. 4, Issue 7 https://doi.org/10.1371/journal.pntd.0000739	journal	July 2010
Isolation and Characterisation of a Human-Like Antibody Fragment (scFv) That Inactivates VEEV In Vitro and In Vivo Rülker, Torsten; Voß, Luzie; Thullier, Philippe PLoS ONE, Vol. 7, Issue 5 https://doi.org/10.1371/journal.pone.0037242	journal	May 2012
Measuring Cytotoxicity by Bioluminescence Imaging Outperforms the Standard Chromium-51 Release Assay Karimi, Mobin A.; Lee, Eric; Bachmann, Michael H. PLoS ONE, Vol. 9, Issue 2 https://doi.org/10.1371/journal.pone.0089357	journal	February 2014
Fc-engineered antibodies with immune effector functions completely abolished Wilkinson, Ian; Anderson, Stephen; Fry, Jeremy PLOS ONE, Vol. 16, Issue 12 https://doi.org/10.1371/journal.pone.0260954	journal	December 2021
Development of a Highly Protective Combination Monoclonal Antibody Therapy against Chikungunya Virus Pal, Pankaj; Dowd, Kimberly A.; Brien, James D. PLoS Pathogens, Vol. 9, Issue 4 https://doi.org/10.1371/journal.ppat.1003312	journal	April 2013
A cross-reactive antibody protects against Ross River virus musculoskeletal disease despite rapid neutralization escape in mice Fox, Julie M.; Huang, Ling; Tahan, Stephen PLOS Pathogens, Vol. 16, Issue 8 https://doi.org/10.1371/journal.ppat.1008743	journal	August 2020
A structural and functional perspective of alphavirus replication and assembly Jose, Joyce; Snyder, Jonathan E.; Kuhn, Richard J. Future Microbiology, Vol. 4, Issue 7 https://doi.org/10.2217/fmb.09.59	journal	September 2009
IgG Subclasses and Allotypes: From Structure to Effector Functions Vidarsson, Gestur; Dekkers, Gillian; Rispens, Theo Frontiers in Immunology, Vol. 5 https://doi.org/10.3389/fimmu.2014.00520	journal	October 2014
Fc-Mediated Antibody Effector Functions During Respiratory Syncytial Virus Infection and Disease van Erp, Elisabeth A.; Luytjes, Willem; Ferwerda, Gerben Frontiers in Immunology, Vol. 10 https://doi.org/10.3389/fimmu.2019.00548	journal	March 2019
New roles for Fc receptors in neurodegeneration-the impact on Immunotherapy for Alzheimer's Disease Fuller, James P.; Stavenhagen, Jeffrey B.; Teeling, Jessica L. Frontiers in Neuroscience, Vol. 8 https://doi.org/10.3389/fnins.2014.00235	journal	August 2014
Human-Like Neutralizing Antibodies Protect Mice from Aerosol Exposure with Western Equine Encephalitis Virus Burke, Crystal; Froude, Jeffrey; Miethe, Sebastian Viruses, Vol. 10, Issue 4 https://doi.org/10.3390/v10040147	journal	March 2018
Current Understanding of the Molecular Basis of Venezuelan Equine Encephalitis Virus Pathogenesis and Vaccine Development Sharma, Anuj; Knollmann-Ritschel, Barbara Viruses, Vol. 11, Issue 2 https://doi.org/10.3390/v11020164	journal	February 2019
Requirement of Fc-Fc Gamma Receptor Interaction for Antibody-Based Protection against Emerging Virus Infections Keeler, Shamus P.; Fox, Julie M. Viruses, Vol. 13, Issue 6 https://doi.org/10.3390/v13061037	journal	May 2021
Development of a Macrophage-Based ADCC Assay Uccellini, Melissa B.; Aslam, Sadaf; Liu, Sean T. H. Vaccines, Vol. 9, Issue 6 https://doi.org/10.3390/vaccines9060660	journal	June 2021
Crosstalk between Human IgG Isotypes and Murine Effector Cells Overdijk, Marije B.; Verploegen, Sandra; Ortiz Buijsse, Antonio The Journal of Immunology, Vol. 189, Issue 7 https://doi.org/10.4049/jimmunol.1200356	journal	September 2012
Mapping of the C1q Binding Site on Rituxan, a Chimeric Antibody with a Human IgG1 Fc Idusogie, Esohe E.; Presta, Leonard G.; Gazzano-Santoro, Helene The Journal of Immunology, Vol. 164, Issue 8 https://doi.org/10.4049/jimmunol.164.8.4178	journal	April 2000
Development and validation of an antibody-dependent cell-mediated cytotoxicity-reporter gene assay Parekh, Bhavin S.; Berger, Elaine; Sibley, Sharon mAbs, Vol. 4, Issue 3 https://doi.org/10.4161/mabs.19873	journal	May 2012
Human-like antibodies neutralizing Western equine encephalitis virus Hülseweh, Birgit; Rülker, Torsten; Pelat, Thibaut mAbs, Vol. 6, Issue 3 https://doi.org/10.4161/mabs.28170	journal	February 2014

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59 BASIC BIOLOGICAL SCIENCES
Antibody dependent cell-mediated cytotoxicity (ADCC)
Fc effector function
Fc-engineering
Research & Experimental Medicine
Venezuelan equine encephalitis virus (VEEV)
antibody therapy
complement
complement dependent cytotoxicity (CDC)
neutralizing antibody

Therapeutic efficacy of a potent anti-Venezuelan equine encephalitis virus antibody is contingent on Fc effector function

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