In 1999, lupus research needed a shot in the arm. The Food and Drug Administration hadn’t approved a new drug for treating the disease in more than 40 years. And the death rate from lupus, which fell earlier in the century, had been rising for the previous two decades.

Now, 20 years later, the outlook for lupus patients and lupus treatment is much brighter. A new drug belimumab (Benlysta), developed by the biotech firm Human Genome Sciences and the pharmaceutical company GlaxoSmithKline, was approved in 2011, and more than 40 other potential treatments are in clinical trials. The Lupus Research Alliance and its heritage organizations—the Alliance for Lupus Research (ALR), the Lupus Research Institute (LRI), and the S.L.E. Lupus Foundation—helped spur this turnaround by funding researchers who have been unraveling the mechanisms that drive lupus and discovering new ways to stop them.

Two scientists funded by then ALR helped set the stage for development of belimumab and helped researchers better understand and target the molecular pathway affected by belimumab. The immune cells known as B cells malfunction in lupus. B cells produce proteins called antibodies that attack patients’ own DNA. In the late 1990s, researchers discovered that the protein BLyS stimulates B cells and helps them survive.

When BLyS first came to light, however, researchers were more interested in identifying ways to boost levels of the proteins to treat patients who have too few B cells, according to Dr. William Stohl of the University of Southern California in Los Angeles.

With his 2000 Target Identification in Lupus grant, Dr. Stohl and colleagues, including researchers from Human Genome Sciences, helped provide a rationale for blocking the molecule. Like patients with lupus, some patients infected with HIV produce antibodies that target their own cells. The researchers determined that these individuals had higher levels of BLyS, furnishing some of the first evidence that inhibiting BLyS could be beneficial in people [1]. In another ALR-funded study, the scientists tracked patients with lupus for more than a year and found that half of them had increased levels of BLyS at least part of the time, suggesting that the protein has a role in lupus [2].

“Thanks to the ALR grant, we were able to demonstrate that BLyS levels were frequently and chronically elevated in SLE patients, so the primary translational focus turned from replacement in diseases with inadequate B cell function to neutralization in diseases with excessive B cell function,” says Dr. Stohl. That means researchers began to focus on how to interfere with BLyS in diseases such as lupus, and their work led to belimumab, which blocks BLyS and causes B cells to die.

Dr. Robert Carter now Acting Director of the National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS) also received our Target Identification in Lupus grant in 2000 and helped further clarify the effects of blocking BLyS. Using mouse models of lupus, he and colleagues demonstrated that blocking BLyS decreased the levels of antibodies that targeted the animals’ own cells and reduced some of their lupus symptoms [3].  BLyS stimulates B cells by attaching to a receptor molecule on the cells’ surface. Dr. Carter and his team also found that these receptors usually have molecules of BLyS stuck to them, suggesting that any treatment that targets BLyS would need to bump it from its position [4].

The two LRA grants to Drs. Stohl and Carter helped change researchers’ thinking about BLyS and gave them a clearer sense of how Benlysta works.

References:

1. W. Stohl, et al. 2002. Clinical Immunology 104: 115–122.
2. W. Stohl, et al. 2003. Arthritis & Rheumatism 48: 3475–3486.
3. W. Liu, et al. 2004. Arthritis & Rheumatism 50: 1884–1896.
4. R.H. Carter, et al. 2005. Arthritis & Rheumatism 52: 3943–3954.