Sunday, October 13, 2024
10/13/2024
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.
HHS’ Tracking Accountability in Government Grants System (TAGGS) website provides access to detailed descriptions of grants, loans, aggregated direct payments and other types of financial assistance awarded by the HHS Operating Divisions (OPDIVs) and the Office of the Secretary Staff Divisions (STAFFDIVs).
