The kidney is often a target of autoimmune diseases, including lupus. But little is known about how immune cells adapt to the low oxygen level in renal tissue to wreak havoc.
A group of scientists at Yale University identified a transcription factor that they say mediates the functioning of T cells in an oxygen-deprived environment. Then they found that an experimental cancer drug being developed by Seattle Genetics helped reverse kidney damage in mouse models of lupus nephritis. They published the results in Science Translational Medicine.
The drug, called PX-478, inhibits hypoxia-inducible factor 1-alpha (HIF-1alpha). Seattle Genetics picked up PX-478 in its 2018 acquisition of Cascadian Therapeutics. The drug had shown promise in some patients with advanced solid tumors in a phase 1 clinical trial.
HIFs play a key role in allowing cells to sense and adapt to hypoxia, or low oxygen levels. Three scientists earned the 2019 Nobel Prize in Physiology or Medicine for their work shedding light on that mechanism.
Normally, the kidney is physiologically more hypoxic than other organs. In lupus nephritis, the availability of oxygen is further decreased, causing inflammation of the kidney. The Yale team found that even under low oxygen levels, T cells infiltrating the kidney are functional and contribute to tissue damage in lupus nephritis.
"Kidney damage affects about half of the patients with lupus, sometimes leading to renal failure with a requirement for dialysis or transplantation," explained Joe Craft, M.D., the new study’s senior author, in a statement. "Finding what causes that damage is extremely important."
RNA sequencing of CD4+ and CD8+ T cells from nephritic kidneys revealed that it was HIF-1 that mediated these cells’ adaptation to hypoxia, and that HIF-1alpha was the dominant form of HIF that accumulated. The adaptation promoted T-cell survival and triggered the inflammation that damaged kidney tissue.
Craft and colleagues reasoned that blocking HIF-1 might reduce tissue damage from kidney-infiltrating T cells in lupus nephritis. So they tested PX-478, a known HIF-1alpha, in mice models of lupus. The drug did decrease HIF-1alpha in the animals.
Four weeks after treatment, the quantity of renal-infiltrating T cells fell significantly in mice that got PX-478 compared to control animals, the researchers observed. Kidney function, as measured by the amount of protein in the urine, also recovered in the treated mice, indicating the damage had been reversed. The drug was well tolerated over 12 weeks, and it helped preserve renal function and improved survival.
Much of the recent research on HIF inhibitors has focused on their potential to treat cancer. Other than SeaGen’s HIF-1alpha inhibitor, Merck & Co. recently bought Peloton Therapeutics and took control of an experimental HIF-2alpha inhibitor, PT2977, which is in a late-phase trial in metastatic renal cell carcinoma.
Nobel laureate William Kaelin Jr. of Harvard Medical School showed that the VHL gene encodes a protein that prevents the onset of cancer, and that cancer cells lacking a functional VHL gene express high levels of hypoxia-related genes. And Sir Peter Ratcliffe, another Nobel winner, linked VHL to HIF-1alpha.
Drug development efforts in the lupus space have been disappointing for companies such as Biogen and Xencor, but a few pieces of good news emerged recently. AstraZeneca is planning to file for approval of its anti-IFNAR1 antibody anifrolumab later this year after a tweaked phase 3 returned positive results. Aurinia Pharmaceuticals’ calcineurin inhibitor voclosporin also achieved a higher renal response rate in lupus nephritis patients than did standard immunosuppressants.
Craft and his teammates at Yale believe their findings suggest HIF-1 blockade—and PX-478 specifically—could find a role in ameliorating kidney inflammation in lupus. "Since this drug and others that block HIF-1 function have been used in humans with cancer, they could be used for treatment of patients with lupus," Craft said in a statement.
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