Potential Inhibitor Shows Superiority to Benlysta in Early Study in Mice
A new approach to treating lupus, based on attacking a wide array of disease-implicated molecular pathways, showed promise in a new study in mice.
The target is NF-κB-inducing kinase (NIK), which mediates the function of proteins in the tumor necrosis factor (TNF) family. Members of the family are known to be implicated in the development of systemic lupus erythematosus (SLE). Inhibiting NIK improved survival and reduced kidney damage in a mouse model of the disease.
The study, “NF-κB inducing kinase is a therapeutic target for systemic lupus erythematosus,” was published in the journal Nature Communications.
One member of the TNF family, the B cell-activating factor (BAFF), is key for the survival and differentiation of the B-cells that produce auto-antibodies. The only new therapy approved for lupus in more than 50 years, Benlysta (belimumab), works by blocking BAFF — but it is only partially effective in treating the condition.
That’s because multiple other TNF-related proteins, like TWEAK and OX40, are also involved in the disease. The TWEAK protein, for example, has been implicated in the chronic kidney inflammation characteristic of lupus. The OX40 receptor may take part in the development of lupus – blocking its activity was found to delay disease progression in mice.
“Combined inhibition of all of these pathways, for example through targeting a common downstream signaling pathway, therefore holds the promise of superior efficacy compared to existing treatments in SLE,” the researchers wrote in the study.
NIK is a common element in the pathways of those TNF family members. Studies have shown that mice without any NIK are severely immunocompromised, and lack most B-cells – including those that produce lupus autoantibodies.
Based on that information, Genentech researchers developed a potent and highly selective small molecule inhibitor to target NIK.
The inhibitor effectively blocked BAFF signals in human and mouse B-cells, which reduced B-cell survival in a dose-dependent manner — the more inhibitor the researchers used, the more B-cells died.
The inhibitor also blocked TWEAK and OX40 signals, preventing their pro-inflammatory and immune-activating signals in lab-grown cells.
When used in mice with a lupus-like condition, the drug also reduced B-cell numbers and autoantibody production. The effects, particularly on autoantibody productions, may be stronger than those that result from BAFF inhibitors like belimumab, reported the researchers.
The animals also had reduced kidney inflammation, and a significant improvement in protein levels in the urine, which is a measure of kidney function. Treatment with the NIK inhibitor decreased mouse mortality by 50%.
“These data position NIK inhibition as potentially superior to BAFF blockade, which has only limited efficacy in human SLE,” the investigators wrote. “Given the absence of significant side effects at an efficacious dose, the evaluation of NIK inhibitors in the clinical setting is warranted.”