# Harnessing the anti-inflammatory activity of extracellular sialylation of IgG.

> **NIH NIH R01** · MASSACHUSETTS GENERAL HOSPITAL · 2022 · $549,715

## Abstract

Project Summary/Abstract.
Despite the tremendous clinical success of immunotheraputics, little is known regarding IgG2-4 biology relative
to IgG1. Our long-term goal is to understand how glycosylation of antibodies regulates, and is regulated, by
immune responses. The overall objective of this application is to examine the regulation of extracellular
sialylation of IgG, and understand how IgG sialylation exerts anti-inflammatory activity. Studies over the last
decade have illuminated the importance of IgG1 glycosylation, little is known about the contribution of
glycosylation to other IgG subclasses or the regulation of IgG sialylation. We recently demonstrated sialylation
of IgG during inflammation occurs extracellularly in situ following administration of soluble glycosyltransferases,
termed B4ST6Fc. Our central hypothesis is that extracellular sialylation by B4ST6Fc conveys type II FcγR binding
and anti-inflammatory activity selectively to IgG1 and IgG3. Our hypothesis is informed by preliminary data
shown here in the Approach subsection of the Research Strategy section. Extracellular sialylation in situ of
pathogenic mouse IgG in the kidneys or paws during autoantibody-induced disease attenuates two distinct
models of autoimmune disease. Further, we show sialylation of IgG1 and IgG3 results in anti-inflammatory
activity in vivo, and DC-SIGN binding in vitro. The rationale that underlies the proposed research is understanding
the contribution of Fc glycosylation to all IgG subclasses will enable new insights into IgG biology, and may lead
to development of innovative antibody-based therapies. We will test our central hypothesis and, thereby, attain
the objective of this application by pursuing the following specific aims using a combination of biophysical
experiments, and in vitro and in vivo functional assays.
1) Define the regulation of extracellular IgG sialylation during autoimmune disease. Hypothesis: B4ST6Fc
reduces SLE nephritis by sialylation of pathogenic IgG1 and IgG3 with the aid of nucleotide-sugar substrates
released by deposited platelets.
2) Identify the molecular determinants of sialylated IgG anti-inflammatory activity. Hypothesis: a specific
amino acid sequence that is unique to IgG1 and IgG3 and absent from IgG2 and IgG4, in combination with N297
sialylation, results in DC-SIGN binding ability and anti-inflammatory activity.

## Key facts

- **NIH application ID:** 10394191
- **Project number:** 5R01AI155662-02
- **Recipient organization:** MASSACHUSETTS GENERAL HOSPITAL
- **Principal Investigator:** Robert McCullough Anthony
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $549,715
- **Award type:** 5
- **Project period:** 2021-04-16 → 2026-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10394191

## Citation

> US National Institutes of Health, RePORTER application 10394191, Harnessing the anti-inflammatory activity of extracellular sialylation of IgG. (5R01AI155662-02). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10394191. Licensed CC0.

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