# Directing Antibody Effector Activity via Controlled IgG Subclass Switching

> **NIH NIH R01** · DARTMOUTH COLLEGE · 2020 · $647,344

## Abstract

Abstract
Antibody subclass has been critically linked to variable potency in the anti-viral activity of polyclonal antibodies:
variation in IgG subclass switching has been associated with variable vaccine efficacy; and in natural infection,
subclass switching has been associated with variable viral suppression. Furthermore, in a number of studies,
subclass switched variants of bnAbs have strongly modulated not only their effector function via tuning of
interactions with Fc receptors, but neutralization breadth and potency. These observations suggest that
antibody subclass may be a key parameter of antibody activity in vivo—contributing both to enhanced viral
recognition, neutralization capacity, as well as innate immune recognition via Fc receptors, suggesting that
better understanding of both the signals associated with and the significance of subclass switching will
contribute to the development of a protective HIV vaccine. We hypothesize that IgG subclass composition
contributes significantly to antiviral protection and can be rationally modulated by vaccination. We propose a 3-
pronged approach to generalize our understanding of the significance of subclass switching to protections from
HIV infection. First, we will evaluate diverse monoclonal HIV-specific antibodies across a variety of in vitro anti-
viral antibody activities in IgG1, IgG2, IgG3, and IgG4 forms. Second, we will evaluate whether the unique
IgG3 hinge topology imparts a general enhancement in neutralization potency by comparing the activity of
monovalent Fab and bivalent Fab'2 fragments from polyclonal donor serum. Lastly, we will compare the
efficacy of subclass switched monoclonal antibodies in in vivo viral challenge experiments in a humanized
mouse model. Additionally, the signals associated with subclass-specific class switch recombination in human
B cells are poorly defined in comparison with mouse B cells. A greater understanding of the stimuli and their
downstream molecular regulators that promote IgG3 responses would help guide the design of vaccine
formulations that would bias HIV responses towards IgG subclasses that are protective and away from those
that are ineffective or detrimental. To determine the mechanisms controlling IgG subclass selection, first, we
will identify and characterize the cytokines and co-stimulatory signals that promote optimal class switching to
IgG3 in purified B cell cultures. Second, we will specifically as well as systematically target intracellular
regulators of class switch recombination to and away from IgG3.

## Key facts

- **NIH application ID:** 9970403
- **Project number:** 5R01AI131975-04
- **Recipient organization:** DARTMOUTH COLLEGE
- **Principal Investigator:** Margaret E Ackerman
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $647,344
- **Award type:** 5
- **Project period:** 2017-08-18 → 2022-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9970403

## Citation

> US National Institutes of Health, RePORTER application 9970403, Directing Antibody Effector Activity via Controlled IgG Subclass Switching (5R01AI131975-04). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9970403. Licensed CC0.

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