# Regulation of antibody-mediated effector functions

> **NIH NIH U19** · STANFORD UNIVERSITY · 2024 · $347,463

## Abstract

PROJECT SUMMARY 
lgG perform immunomodulatory signaling via lgG Fe-Fey receptor (FcyR) interactions that trigger different 
effector functions according to the balance of activating to inhibitory (A/I) signals. Non-neutralizing, FcyR- 
mediated effector functions can be critical for optimal protection in many infectious diseases, including both 
influenza viruses and SARS-CoV-2. Studies over the past decade have shown tremendous heterogeneity in 
lgG Fe domains across individuals, with Fe domain structure (both protein and glycan components) being 
one key determinant of effector functions that are engaged during an infection. Yet, it is clear from clinical 
studies showing variable efficacy of monoclonal antibody (mAb) therapeutics with homogenous Fe 
domains that Fe domain 
structure is not the sole determinant of antibody effector function in vivo. The functional capacity of effector 
cells is almost certainly a critical determinant of lgG activity in vivo, but this has not been defined. This 
proposal addresses key unanswered questions in immunity mediated by broad, FcyR-dependent antibodies 
against influenza viruses and SARS-CoV-2: 1) how much heterogeneity exists in the functional capacity 
of human 
effector cells and is function altered by influenza virus or SARS-CoV-2 vaccination or infection, 2) how do 
obesity and diabetes - states that confer high risk during influenza virus or SARS-CoV-2 infections - impact 
effector cell function 3) can the functional capacity of hypo- or hyperresponsive effector cells be "tuned" using 
lgG engineering strategies. We will address these questions in experiments that include key collaborations 
with Project 2 (Barnes), Project 3 (Khatri) and the Technology Project (Davis). Designed immunogen baits via 
Project 2 will be used to pull out broadly reactive, anti-influenza and SARS-CoV-2 lgG from polyclonal 
antisera to study the effector functions recruited by these antibodies. Effector cells will furthermore be 
subject to transcriptomics before and after treatment with lgG immune complexes to define correlates for 
responses through collaboration with Project 3. In collaboration with the Technology Project we will use 
spleen, tonsil, and lung organoids to test the hypothesis that effector cell functions can be "tuned" using 
engineered lgG immune complexes. Finally, to follow up on our observation from humans that effector cell 
function is heterogeneous across individuals, we will use different collaborative cross mouse strains to test 
the hypothesis that the ability of broad, non-neutralizing anti-influenza mAbs to protect is correlated with the 
functional capacity of their effector cells (collaboration between Dr. Taia Wang and Dr. David Schneider). 
Collectively, this work, alongside the other projects proposed, helps to establish a rigorous immunological 
foundation for factors underlying protection against influenza virus and SARS-CoV-2.

## Key facts

- **NIH application ID:** 10825315
- **Project number:** 2U19AI057229-21
- **Recipient organization:** STANFORD UNIVERSITY
- **Principal Investigator:** Taia Wang
- **Activity code:** U19 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $347,463
- **Award type:** 2
- **Project period:** 2003-09-01 → 2029-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10825315

## Citation

> US National Institutes of Health, RePORTER application 10825315, Regulation of antibody-mediated effector functions (2U19AI057229-21). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10825315. Licensed CC0.

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