# Translating oral CD11b agonist as a novel therapeutic for lupus nephritis

> **NIH NIH R01** · UNIVERSITY OF TEXAS MED BR GALVESTON · 2024 · $746,829

## Abstract

Project Summary
 Lupus nephritis (LN) is a highly debilitating disease associated with Systemic Lupus Erythematosus
(SLE, lupus). >40% of lupus patients develop LN and many progress to end stage kidney disease (ESKD).
Thus, LN remains the strongest predictor of morbidity and mortality in lupus patients. LN is currently
managed with aggressive immunosuppressive and cytotoxic agents that have considerable side effects
and long-term toxicity. Therefore improved, targeted new treatments are urgently needed. Uncontrolled
toll-like receptor (TLR) signaling in myeloid cells results in their overactivity and produces a feed-forward
cycle of pro-inflammatory mediators, such as type I interferon (IFN I), IL-6, IL-1b and soluble uPAR
(suPAR). IFN I is increased in sera of LN patients, and suPAR is a circulating risk factor for glomerular
diseases, including LN. Three single nucleotide polymorphisms (SNPs) in ITGAM gene (coding for integrin
CD11b) are found in ~20% of LN patients and produce dysfunctional CD11b. We found that 1) these SNPs
not only show strong correlation with the incidence of LN (and SLE), but are also associated with
significantly higher levels of IFN I and suPAR in LN patient sera; and that 2) CD11b is a natural regulator
of uncontrolled TLR signaling, and the variant CD11b is especially ineffective in controlling the TLR
pathways in myeloid cells. To address this deficiency, we developed a novel, highly selective CD11b
agonist small molecule, termed ONTEGIMOD, that activates both wildtype and mutant CD11b and
reduces uncontrolled TLR-signaling in vitro and in vivo. It also reduces myeloid infiltration in inflamed
kidneys. New data in multiple LN murine models also shows that oral ONTEGIMOD therapeutically
reduces serum IFN I, anti-dsDNA antibody and suPAR levels, reduces myeloid influx in kidneys,
decreases albuminuria and protects against kidney injury in LN. Therefore, we propose that CD11b
activation, by rescuing the functional deficit in CD11b and thereby suppressing TLR-dependent
inflammatory signaling, will provide us with a new therapeutic for LN. Direct proof of ONTEGIMOD’s
potential as a LN therapeutic requires a new clinical trial in LN patients. Here, we propose such a pilot,
mechanistic clinical trial and propose three aims. First, we plan to use ex vivo assays to identify LN
patients most likely to respond to CD11b activator ONTEGIMOD, especially patients homozygous for
ITGAM SNPs, thereby developing a personalized therapeutic approach. We also plan to perform a Phase
I/II clinical trial to generate preliminary evidence of safety, tolerability and efficacy of ONTEGIMOD in LN
patients. Finally, we plan to define molecular changes in sera and in circulating immune cells from
ONTEGIMOD treated LN patients. Successful completion of our pilot trial will generate crucial preliminary
evidence for a larger, placebo-controlled efficacy trial in the future to help develop it as a novel, first-in-
class, oral LN therapeutic.

## Key facts

- **NIH application ID:** 10980058
- **Project number:** 2R01DK084195-13
- **Recipient organization:** UNIVERSITY OF TEXAS MED BR GALVESTON
- **Principal Investigator:** VINEET GUPTA
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $746,829
- **Award type:** 2
- **Project period:** 2011-09-20 → 2029-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10980058

## Citation

> US National Institutes of Health, RePORTER application 10980058, Translating oral CD11b agonist as a novel therapeutic for lupus nephritis (2R01DK084195-13). Retrieved via AI Analytics 2026-05-27 from https://api.ai-analytics.org/grant/nih/10980058. Licensed CC0.

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