# MASPs as therapeutic targets in complement-mediated diseases

> **NIH NIH R01** · UNIVERSITY OF PENNSYLVANIA · 2020 · $580,145

## Abstract

Complement is a humoral innate immune system that plays an important role in host defense and in bridging
adaptive immunity. Under certain conditions, complement activation can also cause significant autologous
tissue injury leading to complement-mediated diseases. Complement is activated via three different pathways;
one of which is by the lectin pathway (LP) which is triggered by collagen-like soluble pattern recognition
molecules (PRMs). Upon binding of PRMs to sugar molecules on microbes or altered self-tissues, a specific
group of proteases called MASPs are activated. Activation of MASPs is the key step in LP complement
activation and the ensuing host defense response or tissue injury consequence. The mechanism of action of
MASPs in vivo has not been well understood and recent studies have revealed a surprising link between
MASP3 and the alternative pathway (AP) complement activation. It has been shown that MASP3 plays an
essential role in converting pro-factor D (FD) to mature active FD. The objectives of this proposal are two fold,
1) to understand whether MASP2 and MASP3 play significant roles in complement-mediated pathologies, and
if so, whether targeting these enzyme represents a feasible therapeutic approach; and 2) to understand how
FD activity is regulated in vivo by MASP3 and a putative serine protease inhibitor(s). To this end, we propose
three specific aims in this project. Specific aim 1. To use MASP2 KO mice and blocking mAbs and test the role
of MASP2 and LP in complement-mediated diseases. Specific aim 2. To use MASP3 KO mice and blocking
mAbs and test the role of MASP3 in regulating AP complement activity and as a therapeutic target in AP
complement-dependent diseases. Specific aim 3. To test the hypothesis that maturation of pro-FD by MASP3
is not a default reaction, but rather a regulated process, and that constitutive, unregulated mature FD activity
leads to AP complement consumption via Factor B cleavage which can be exploited therapeutically. These
studies will provide proof of concept for therapeutically targeting MASP2 and MASP3, as well as add new
fundamental knowledge on how FD and AP complement activity is regulated in vivo.

## Key facts

- **NIH application ID:** 9973779
- **Project number:** 1R01AI146162-01A1
- **Recipient organization:** UNIVERSITY OF PENNSYLVANIA
- **Principal Investigator:** Wenchao Song
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $580,145
- **Award type:** 1
- **Project period:** 2020-03-18 → 2025-02-28

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9973779

## Citation

> US National Institutes of Health, RePORTER application 9973779, MASPs as therapeutic targets in complement-mediated diseases (1R01AI146162-01A1). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9973779. Licensed CC0.

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