# Novel Therapeutic Approaches for Lupus Nephritis

> **NIH NIH R01** · UNIVERSITY OF COLORADO DENVER · 2020 · $440,908

## Abstract

Systemic lupus erythematosus (SLE) is a severe autoimmune disease that can affect multiple organs
throughout the body. Unfortunately, the currently available drugs are not effective for all patients, and the drugs
can have significant side effects. The complement system is integrally involved with several aspects of SLE.
The classical pathway protects against the development of SLE. On the other hand, evidence suggests that
C3d covalently bound to antigens lowers the threshold for developing autoimmunity through its interaction with
complement receptor 2 (CR2). Complement activation is also a critical downstream mediator of target organ
injury in SLE. We developed a monoclonal antibody, designated mAb 3d8b, that binds C3d and blocks
autoantigen complex from ligating CR2. Furthermore, mAb 3d8b targets sites of complement activation and
C3d fixation in vivo. We generated unique chimeric proteins that link 3d8b to molecules that inhibit the
complement effector functions. These chimeric molecules are able to block the two key pathologic roles of
complement in the development of SLE: they prevent the development of high affinity autoantibodies, and they
inhibit pro-inflammatory complement activation in target organs. Because the drugs do not block the classical
pathway, however, they do not interfere with complement's protective effects. Furthermore, the risk of infection
with tissue-targeted drugs is expected to be less than with untargeted complement inhibitors. Based on these
considerations, the overall hypothesis of this project is that the 3d8b-targeted complement inhibitors will be
more protective in a model of SLE than untargeted complement inhibitors, through both modulation of
autoantibody production and inhibition of the downstream pro-inflammatory effects. To test this hypothesis, the
following specific aims will be pursued. Aim 1) Examine the effects of C3d-targeted complement inhibitors on
autoimmunity in the (NZBxNZW)F1 model of lupus. We will determine the pharmacokinetics and
pharmacodynamics of the targeted drugs compared to untargeted complement inhibitors, and we will test the
effects of these drugs on systemic autoimmunity. Aim 2) Compare the efficacy of single and combined
therapeutic complement inhibitors for treating kidney disease in the (NZBxNZW)F1 model of lupus. In this aim
we will test the efficacy of the different strategies for preventing the pathologic effects of complement in lupus
nephritis. Aim 3) Characterize the systemic immunomodulatory effects of single and combined therapeutic
complement inhibitors. In this aim we will examine the effects of the targeted and untargeted complement
inhibitors on myeloid and lymphoid cell populations from spleen, peripheral blood, and bone marrow of
(NZBxNZW)F1 mice. The studies in this proposal are innovative, because they test novel molecules designed
to block multiple mechanisms of autoimmunity and tissue injury in SLE. This project is significant, because it
develops a new class...

## Key facts

- **NIH application ID:** 10033331
- **Project number:** 1R01DK125823-01
- **Recipient organization:** UNIVERSITY OF COLORADO DENVER
- **Principal Investigator:** Vernon Michael Holers
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $440,908
- **Award type:** 1
- **Project period:** 2020-07-01 → 2024-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10033331

## Citation

> US National Institutes of Health, RePORTER application 10033331, Novel Therapeutic Approaches for Lupus Nephritis (1R01DK125823-01). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10033331. Licensed CC0.

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