New Lupus Therapy Targets T Cells
A drug derived from sea anemone venom demonstrates the potential to suppress inflammation without the severe side effects of existing therapies.
Stichodactyla helianthus is a simple but sinister creature. The innocently swaying tentacles of this Caribbean sea anemone carry venom that stuns passing fish and turns them into dinner.
Dr. Anne Stevens of Seattle Children’s worked with two Seattle biotech companies, KPI Therapeutics and Kineta, and found that a drug derived from the venom has the potential to treat lupus and other autoimmune disorders without the severe side effects of existing therapies – which could mean a giant leap forward in patient care.
The drug, called dalazatide, targets overactive effector memory T cells. Effector memory T cells play an essential role in directing the body’s immune system, but autoimmune disorders cause them to spiral out of control, spreading painful and damaging inflammation throughout the body.
Stevens made two key findings using tissue and urine samples from pediatric patients with lupus nephritis. She confirmed the presence of elevated levels of a T-cell activator (the Kv1.3 potassium channel) in lupus nephritis patients and demonstrated that dalazatide can block the Kv1.3 channel to inhibit T-cell activation and, in theory, suppress inflammation.
“We were concerned that the lupus T cells could overcome the blockade, but they didn’t,” Stevens says.
She presented her findings at an international conference last year. “We demonstrated dalazatide inhibits cell activation in a laboratory dish. Now we need to show that it can suppress inflammation in humans,” says Stevens, a rheumatologist and researcher whose lab focuses on the role of T cells in autoimmune disorders.
Parallel pediatric trial
Step one to bring dalazatide to patients is already complete. The drug was proven safe in a phase 1 clinical trial of adult psoriasis patients based on a study completed by KPI Therapeutics in 2016.
Stevens is now collaborating with KPI Therapeutics to develop a protocol and lead a phase 2 clinical trial to determine the efficacy of dalazatide in patients with lupus. The trial is planned to start at Seattle Children’s in lupus patients age 18 and older. Other clinical centers will also participate. Once safety is demonstrated in a group of adult and young adult patients, the trial will open enrollment to pediatric patients – beginning with the oldest.
“We don’t need to complete a full adult trial before beginning to enroll children. We only need to double-check – out of an abundance of caution – that dalazatide is safe in patients with lupus,” Stevens says.
This novel approach accelerates the normal process for developing pediatric applications for new drugs. “Trials typically are completed first for adults and five or 10 years later there may or may not be pediatric trials,” Stevens says. “As far as I know, ours will be the first adult/pediatric study for lupus – or any other disease.”
The cause of lupus is a mystery, but it is thought to develop in response to a combination of hormones, genetics and environment. An estimated 1.5 million people in the U.S. are living with some form of this disease. There currently are no treatments specifically approved for pediatric lupus patients, underscoring the importance of the dalazatide trial.
“Children process medications differently than adults,” Stevens says. “Pediatric trials help us accurately dose and safely treat kids. We can also determine whether medications that weren’t effective in adults might work in children, who haven’t lived with the disease as long as adults.”
If all goes well, dalazatide could be ready for FDA approval within five years.
Less toxic option
Current autoimmune disease treatments attack overactive T cells with heavy doses of steroids and chemotherapy, but those medicines also weaken the rest of the immune system, leaving patients vulnerable to infection. Children using steroids may experience additional side effects that range from stunted growth to osteoporosis to depression. Chemotherapy adds nausea, diarrhea and fatigue.
“Patients currently must endure years and years of toxic treatment to control their disease because there is no cure for lupus and many other autoimmune diseases,” Stevens says. “Kids really suffer with steroids and chemotherapy. My goal is to give them a less toxic option.”
Newly diagnosed patients still would need steroids and chemotherapy to tamp down the disease, but dalazatide could gradually replace those therapies with twice weekly injections to control the disease going forward.
“As far as I know, ours will be the first parallel adult/pediatric study for lupus – or any other disease.”
– Dr. Anne Stevens
From peptide to drug
Dalazatide is the result of research by University of California–Irvine scientists who were aware that the sting of Caribbean sea anemones causes numbness in humans and were searching the venom for peptides that affect nerve cells. “They didn’t have a specific outcome in mind. It was very basic science,” Stevens says.
After finding that ShK (the parent molecule to dalazatide) blocks various potassium channels in nerve cells, they discovered it also blocks the Kv1.3 channel in white blood cells – including effector memory T cells – that patrol the bloodstream for previously encountered viruses and other foreign invaders. Once activated, they multiply and produce hormones called cytokines that cause inflammation.
While inflammation is a normal immune response, autoimmune diseases cause effector memory T cells to multiply and produce cytokines at a virulent rate. Blocking the Kv1.3 channel halts an essential step in cell activation and stifles cytokine production. The problem with the original ShK molecule is that it also blocks other potassium channels. Dalazatide is a modified version specific to the Kv1.3 channel, which limits toxicity.
Collaborating with industry
KPI Therapeutics and Kineta enlisted Stevens to help study dalazatide’s therapeutic potential after licensing the drug from UC-Irvine. Funding for the lupus/dalazatide project comes from Alliance for Children’s Therapeutics, Kineta, KPI Therapeutics and a grant from the National Institutes of Health.
The collaboration is a win-win for patients who need better treatments and for healthcare providers that are looking for new alternatives.
“By lending our expertise, we can help private industry develop pediatric applications for new drugs like dalazatide that normally would not be developed for children until long after they were developed for adults – if at all,” Stevens says. “It is an exciting time to be collaborating with KPI and I look forward to advancing this study."
Published in the Academic Annual Report, March 2017.