January 4, 2022—(BRONX, NY)—Albert Einstein College of Medicine researchers and their colleagues have found a key cause of severe kidney complications that affects many lupus patients and are now conducting a clinical trial to evaluate a promising treatment aimed at preventing those complications.
The Burden of Lupus
Systemic lupus erythematosus, more commonly referred to as lupus, is an inflammatory autoimmune disease that affects more than 300,000 Americans, 90% of them women. There is no cure, and all drugs for treating the disease can cause serious adverse effects. Inflammation from lupus can ravage organs throughout the body, leading to complications involving the skin, brain, heart, and, notoriously, the kidneys.
Up to half of all lupus patients—and nearly 70% of Hispanic and African American patients with the disease—will develop lupus-related kidney inflammation known as lupus nephritis. Left unchecked, lupus nephritis can cause irreversible kidney scarring that can result in organ failure and death.
Uncovering Key Driver of Lupus-Associated Kidney Disease
Lupus and other autoimmune diseases occur when the body’s immune system—including its immune cells and antibodies—aberrantly attack healthy tissues. Major contributors to lupus kidney damage are immune cells known as T cells, which infiltrate and inflame kidney tissue. T cells are activated by molecules that bind to antenna-like receptor proteins projecting from the surface of T cells.
Researchers have long known that various tissues of the body express ALCAM, a molecule that binds to a T cell receptor called CD6. T cells activated in this way have been implicated in numerous autoimmune diseases including psoriasis, multiple sclerosis, and rheumatoid arthritis—but never, until now, in lupus.
In a study that published online on January 4 in the Journal of Clinical Investigation (JCI), senior author Chaim Putterman, M.D., professor of medicine and of microbiology & immunology at Einstein and associate dean for research at the Azrieli Faculty of Medicine at Bar-Ilan University, together with senior authors Cherie Ng, Ph.D., of Equillium, Inc., and Chandra Mohan, M.D., Ph.D., of the University of Texas and colleagues, found that ALCAM’s interaction with T cells bearing CD6 receptors is a key driver of lupus nephritis.
The scientists examined urine levels of ALCAM in more than 1,000 ethnically diverse lupus patients. For all ethnic groups examined, patients with active nephritis had significantly elevated urinary ALCAM levels compared with other lupus patients, with ALCAM levels correlating with disease severity in lupus patients with nephritis. In addition, renal biopsies of 24 patients with lupus nephritis and 9 healthy controls revealed that lupus nephritis patients had increased numbers of CD6-expressing T cells in their kidney tissue as well as increased numbers of ALCAM-expressing cells.
Evaluating a Potential Therapy
Could lupus nephritis be curbed by interfering with the CD6 T-cell/ALCAM pathway? In experiments involving mouse models of lupus, the researchers found that administering antibodies that blocked CD6 T-cell receptors prolonged survival, decreased the number of immune cells that invaded kidney tissue, improved kidney function, and reduced kidney pathology.
In a phase 1 clinical trial now underway, Dr. Putterman and colleagues are treating lupus patients with itolizumab, a novel monoclonal antibody that binds specifically to CD6 receptors on T cells. Itolizumab may be able to treat lupus and lupus nephritis by preventing CD6-T cells from interacting with ALCAM. Phase 2 trials are expected to begin in the coming months.
Itolizumab could potentially serve as a targeted, personalized drug benefiting those lupus nephritis patients who have elevated urinary ALCAM levels indicating that the CD6-ALCAM pathways is operating in this patient group. Elevated urinary ALCAM levels can also potentially be used to make an earlier diagnosis of patients at risk for developing nephritis.
Additional Einstein authors are: Samantha Chalmers, Sayra Garcia, Evan Der, and Nicole Jordan. Other authors include: Rajalakshmy Ayilam Ramachandran and Ting Zhang from the University of Houston in Texas; Leal Herlitz from the Cleveland Clinic in Ohio; Jeanette Ampudia, Krishna Polu, Stephen Connelly, and Dalena Chu, from Equillium, Inc., in California; Ioannis Parodis, and Iva Gunnarsson, from the Karolinska University Hospital in Sweden; Huihua Ding and Nan Shen, from the Shanghai Jiao Tong University School of Medicine in China; Michelle Petri from Johns Hopkins University School of Medicine in Maryland; Chi Chiu Mok from Tuen Men Hospital in Hong Kong; and Ramesh Saxena from the University of Texas Southwestern Medical Center at Dallas in Texas.
The paper is titled, “The CD6/ALCAM pathway promotes lupus nephritis via T cell–mediated responses.” This study was supported in part by funding from the Accelerating Medicines Partnership (AMP) in Rheumatoid Arthritis and Lupus Network. Funding was also provided through grants from the National Institutes of Health (UH2-AR067676, UH2-AR067677, UH2-AR067679, UH2AR067681, UH2-AR067685, UH2-AR067688, UH2-AR067689, UH2-AR067690, UH2-AR067691, UH2-AR067694, and UM2AR067678); the Lupus Research Alliance and the NIH (AR NIH R01 AR074096 to CM); the NIH (R01-AR069572 and UH2AR067679 to MP); the George M. O’Brien Kidney Research Core Center (NIH grant P30DK079328 to RS); and the Swedish Rheumatism Association (R-932236), the King Gustaf V’s 80-year Foundation (FAI-2019-0635), the Professor Nanna Svartz Foundation (201900290), the Ulla and Roland Gustafsson Foundation (2019-12), Region Stockholm, and Karolinska Institute.