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

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

Journal Article · 03 January 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.

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

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

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

OSTI ID:: 2469756

Report Number(s):: LLNL--JRNL-843422

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

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Related Subjects

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

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

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References (67)

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