# Antibody therapy of MRSA colonization and infection

> **NIH NIH R01** · UNIVERSITY OF CHICAGO · 2024 · $540,443

## Abstract

ABSTRACT
Methicillin-resistant Staphylococcus aureus (MRSA) colonize the nasopharynx and GI tract of healthy
individuals and of patients admitted to hospitals. Colonization is the key risk factor for community-acquired and
hospital-acquired MRSA invasive diseases. MRSA infection is associated with treatment failure, increased
morbidity, and increased mortality. Prior attempts to develop vaccines or immune therapeutics that can prevent
MRSA colonization or invasive disease or that improve the outcome of MRSA infections have failed. Infected
individuals cannot develop protective antibody responses (immunity), which enables MRSA to persist within
host tissues and to cause recurrent disease. MRSA immune escape is based on immunoglobulinbinding
proteins, specifically staphylococcal protein A (SpA) and staphylococcal binder of immunoglobulin (Sbi). SpA
and Sbi block effector functions of human IgG by binding to the Fcγ domain of antibodies. SpA also binds to
the variant heavy chains of VH3-idiotypic immunoglobulin and crosslinks IgM B cell receptors, thereby
activating B cell proliferation and the secretion of VH3-clonal antibodies that fail to recognize MRSA. This B cell
superantigen activity (BCSA) of SpA is essential for the diversion of antibody responses during MRSA
colonization and invasive disease. Here we describe a monoclonal antibody, MAb 3F6, that binds and
neutralizes SpA and Sbi. We show that MAb 3F6 galactosylation at Fcγ promotes C1q binding, MAb 3F6-
dependent opsonophagocytic killing (OPK) of MRSA and protection of mice against MRSA bloodstream
infection. Further, we isolated amino acid substitutions in Fcγ that abolish SpA and Sbi binding and enhance
the OPK activity of variant MAb 3F6. We also report that SpA is essential for suppression of antibody
responses (BCSA) against bacterial colonization factors, thereby enabling S. aureus persistence in the
nasopharynx and GI tract. Intravenous administration of MAb 3F6 into mice neutralizes circulating SpA and
blocks its BCSA, thereby promoting antibody responses against bacterial surface antigens and the removal of
S. aureus from the nasopharynx and GI tract. Here, we will test the hypotheses that intravenous administration
of glyco- and Fcγ-engineered human 3F6-IgG1 in preclinical models a) elicits broad spectrum antibody
responses against S. aureus, b) promotes decolonization of MSSA and MRSA, c) induces immunity to prevent
re-colonization as well as invasive MSSA and MRSA disease, and d) improves the outcome of MRSA
bloodstream infections. Glyco- and Fcγengineered 3F6 antibodies that achieve such product profile can be
developed further for clinical testing to prevent and treat MRSA infections in American hospitals.

## Key facts

- **NIH application ID:** 10734064
- **Project number:** 5R01AI148543-05
- **Recipient organization:** UNIVERSITY OF CHICAGO
- **Principal Investigator:** Dominique Missiakas
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $540,443
- **Award type:** 5
- **Project period:** 2019-12-13 → 2024-11-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10734064

## Citation

> US National Institutes of Health, RePORTER application 10734064, Antibody therapy of MRSA colonization and infection (5R01AI148543-05). Retrieved via AI Analytics 2026-06-14 from https://api.ai-analytics.org/grant/nih/10734064. Licensed CC0.

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