# Mechanisms of IgM mediated activation of the complement system

> **NIH NIH R01** · UNIVERSITY OF WASHINGTON · 2021 · $484,415

## Abstract

SUMMARY
 Immunglobulin µ (IgM) is an evolutionary old class of antibody that is the first antibody
produced in response to an infection. Several IgMs are present as natural antibodies and are vital
for immunity during the early stages of development. Unlike any other class of antibody, a single
copy is sufficient for activating the classical complement system, and several monoclonal IgMs
have shown massive potential for the treatment of cancers. The large size, high degree of
glycosylation, and structural heterogeneity of IgM has rendered them refractory to structural
studies and to date the molecular mechanisms of how antigen binding activates IgM to initiate the
complement cascade remain murky. In contrast, a detailed understanding of the structure and
various interactions of immunoglobulin g (IgG) have been fundamental to their advancement as
the premier molecular platform for biotherapeutics. Accordingly, a similar level of understanding
of IgM will be critical for their development as a new class of biotherapeutics.
 This proposal aims to apply structural mass spectrometry techniques, electron microscopy
with complementary structural approaches, and biophysical tools to study the structural changes
within IgM that govern activation of the complement cascade. Various types of IgM-antigen
complexes will be prepared and analyzed using hydrogen/deuterium exchange and X-ray foot
printing with mass spectrometry to track the local structural changes within IgM upon binding
different presentations of antigen (Aim 1). Electron microscopy and small angle X-ray scattering
will be used to visualize and track large-scale structural transitions in the antigen-IgM complexes
(Aim 2). The full combination of techniques will be used to study how IgM recruits and activates
the initial component, C1, of the complement cascade (Aim 3). The molecular mechanisms of
how IgM recognizes antigen and recruits complement will provide a foundation for modulating the
immune system for a new paradigm in biotherapeutics.

## Key facts

- **NIH application ID:** 10296558
- **Project number:** 1R01AI153191-01A1
- **Recipient organization:** UNIVERSITY OF WASHINGTON
- **Principal Investigator:** Miklos Guttman
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $484,415
- **Award type:** 1
- **Project period:** 2021-06-02 → 2026-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10296558

## Citation

> US National Institutes of Health, RePORTER application 10296558, Mechanisms of IgM mediated activation of the complement system (1R01AI153191-01A1). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10296558. Licensed CC0.

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