Developing SR-878, a novel monoclonal antibody drug candidate targeting inflammation

SR-878, which builds upon foundational basic research discoveries made in the lab of Carl P. Blobel, MD, PhD, director of the Arthritis and Tissue Degeneration Program at the HSS Research Institute, is a monoclonal antibody drug candidate that targets inflammation in a new way.  More specifically, SR-878 targets a complex consisting of inactive Rhomboid 2 (iRhom2) and TACE/ADAM17 (ADAM17), a “master switch” for regulating the inflammatory response that is overactive in many autoimmune diseases.

ADAM17 is an enzyme involved in accelerating the body’s immune response, which has long held the interest of researchers due to its close association with an already proven target in the treatment of rheumatoid arthritis and other inflammatory diseases, the molecule TNF-alpha.

Researchers hypothesized that going after ADAM17 could prove even more effective than targeting TNF-alpha alone. “Beginning in the late 90s, there was an interest in targeting ADAM17 as another way to reduce TNF-alpha,” Dr. Blobel explains, “but it turns out, on its own, it wasn’t an optimal target because ADAM17 holds other important functions — such as protecting the skin and intestinal barrier.”

However, studies at HSS have since revealed that ADAM17 is regulated by its binding partner iRhom2. When iRhom2 is inactivated, those studies have demonstrated that the related iRhom1 can still protect against the problems observed when ADAM17 is blocked.  This research suggested that iRhom2 could be a safer and more effective target for drugs than ADAM17.

Collaborations with HSS rheumatologist Jane E. Salmon, MD, HSS Chief Scientific Officer Lionel B. Ivashkiv, MD, and HSS Physician-in-Chief Emerita Mary K. (Peggy) Crow, MD further supported this notion.  Those studies explored the effects of knocking out iRhom2 in preclinical mouse models with inflammatory arthritis as well as an autoimmune kidney disease called lupus glomerulonephritis. Their research demonstrated that the mouse models were protected from disease by blocking the TNF-alpha pathway and, in the case of lupus glomerulonephritis, also by inhibiting another pathway that contributes to inflammation, called the EGFR pathway. “We eventually realized that iRhom2 could be a very exciting target,” Dr. Blobel says.

The development of SR-878 underscores the importance of doing basic science research at academic institutions like HSS,” says Michael P. Ast, MD, orthopedic surgeon and Chief Medical Innovation Officer at HSS. “Scientific breakthroughs uncovered in the lab can be used to shape further studies that advance our understanding of complex diseases. Through the knowledge and expertise of investigators at HSS and SciRhom, we can build on the insights made together to ultimately benefit patients worldwide.”

Co-Founding & Advancing SciRhom

During a visiting professorship in 2015 in Munich, Germany, Dr. Blobel met two researchers, Drs. Jens Ruhe and Matthias Schneider, who have extensive experience in preclinical development of early to clinical stage antibody projects.

Together, HSS, the three researchers, and other experienced biotech entrepreneurs and investors, co-founded SciRhom in 2016 to translate Dr. Blobel’s scientific findings into novel therapies for autoimmune diseases.

Proof of concept studies performed by HSS scientist Gisela Weskamp, PhD, have since strongly supported the notions that targeting iRhom2 with SR-878 in a preclinical model of inflammatory arthritis is more effective than targeting TNF-alpha alone and is at least as effective as blocking both TNF-alpha and the EGFR pathway together. In addition, treatment with SR-878 also has potential to block another target of existing therapies, the interleukin-6 receptor. “We anticipate that SR-878 will simultaneously block multiple disease-causing pathways and therefore has potential for superior efficacy relative to current monotherapies,” she adds.

Following on the footsteps of its pre-clinical findings, SciRhom has since expanded its board and management ranks with former executives from the global pharmaceutical industry, including Chief Executive Officer Dr. Jan Poth, former Therapeutic Area Head Immunology at Boehringer Ingelheim, and board member Dr. Wolfgang Baiker, former CEO of Boehringer Ingelheim USA.

“SciRhom’s recent Series A financing and its approval to start clinical trials are pivotal milestones in the company’s journey towards commercialization” says Vijay Nair, Managing Director at the HSS Innovation Institute. “Bringing a discovery from the lab to patients requires immense dedication and collaboration across HSS and with the biotech entrepreneurial and investment communities. Their leadership and external validation have been critical in launching the company, securing funding, attracting world-class talent, pursuing pre-clinical development, and reaching this inflection point.”

“There is a lot of enthusiasm for this approach among members of the medical and investment communities. We are tremendously excited that we can now advance the study of this drug to human trials,” says Dr. Blobel.

Dr. Niewold is currently the Editor-in-Chief of the Journal of Immunological Methods, serves on the Board of Directors of the Lupus Research Foundation and the Sjögren’s Syndrome Foundation, and is a standing member of the U.S. Department of Defense’s Peer Reviewed Medical Research Program. He has recently served as a standing member of the National Institutes of Health (NIH) Arthritis, Connective Tissue, and Skin (ACTS) Study Section. He is a former Chair of the Scientific Advisory Council of the Rheumatology Research Foundation, and a past President of the Central Society for Clinical and Translational Research.

“We are delighted that Dr. Niewold will help lead the next generation of groundbreaking translational and clinical research for the Department of Medicine at HSS,” said S. Louis Bridges, Jr., MD, PhD, physician-in-chief and chair of the Department of Medicine at HSS. “We are at a historic intersection of knowledge, cutting edge technology and patient need. We are poised to accelerate impactful patient oriented research that will improve the lives of our patients.”

Dr. Niewold returns to HSS from the New York University Grossman School of Medicine, where he served as Judith and Stewart Colton Professor of Medicine and Director of the Colton Center for Autoimmunity.

Dr. Niewold, a world leader in lupus research, moves to HSS together with outstanding rheumatology investigators Theresa Wampler Muskardin, MD; Ruth Fernandez-Ruiz, MD; and Ashira Blazer, MD. At HSS Dr. Niewold and his colleagues will continue their current research, including three studies supported by the NIH, and one supported by the Centers for Disease Control and Prevention (CDC).

“Research is foundational to HSS excellence, and scientific leadership in rheumatic diseases is among the ways we achieve reliably better outcomes for patients with any musculoskeletal condition,” said Bryan T. Kelly, MD, MBA, HSS surgeon-in-chief and medical director. “Dr. Niewold and I both had the privilege of training at HSS, and I’m very happy to now share with him also the privilege of leading HSS to improve quality of life for future generations.”

“HSS has the privilege and responsibility to help people get back to what they need and love to do better than any other place in the world,” added HSS President & CEO Louis A. Shapiro. “Since our founding 158 years ago, that begins and ends with the most talented, most committed specialists, and so we are especially pleased to welcome Dr. Niewold home and support his leadership forward.”

SLE, commonly just called lupus, is an autoimmune disease that affects as many as 500,000 people in the United States. In people with the condition, the immune system malfunctions and, instead of attacking infections like it’s supposed to, it attacks healthy tissues. The organs and systems, most commonly affected by lupus include the skin, joints, kidneys and lungs.

“There are not many drugs that are currently effective against lupus, and many of those that are used tend to have a lot of side effects,” says Mary K. “Peggy” Crow, MD, Physician-in-Chief Emerita at HSS, Director of the Autoimmunity and Inflammation Research Program and Co-Director of the Mary Kirkland Center for Lupus Research at the HSS Research Institute. “I think the approval of this drug will be met with a lot of excitement, both by patients and the doctors who treat this disease.”

Anifrolumab is a monoclonal antibody that works by blocking the receptor for a family of molecules called type I interferon. These molecules are essential for the body’s natural defense against viral infections: When they detect an invader, they bind to the interferon receptor, which turns on a number of genes that rally the immune system to fight the infection. In lupus, however, this receptor is activated even when no infection is present, causing the immune system to instead attack its host.

The link between interferon and lupus was made thanks to decades of research. “There were observations going back to the 1970s that interferon was elevated in certain autoimmune diseases, including lupus,” Dr. Crow says. “But it wasn’t until the availability of gene microarrays in about 2000 that my lab was able to begin figuring out exactly what interferon’s role is in the disease.”

In the lab, Dr. Crow and her team began studying the blood of people with lupus and comparing it to the blood of healthy individuals. They looked at which genes were being transcribed in each group, and when they compared the lists they saw that there were substantial differences. “It was like a puzzle, trying to figure out what the data meant,” she remembers. “But as we took a closer look, it became clear that many of the differences between patients and healthy donors were genes that were regulated by type I interferon.”

In 2003, Dr. Crow and her HSS team were one of three groups to publish research confirming interferon’s pivotal role in lupus. Additional important findings came from mouse models of lupus. “The mouse studies helped to make the case that this type I interferon pathway really is contributing to disease pathogenesis,” she says. “They confirmed that this was an appropriate therapeutic target.”

One of the members of Dr. Crow’s lab who worked on this research was physician-scientist Kyriakos A. Kirou, MD, DSc, FACP, an Associate Attending Physician at HSS. Dr. Kirou now leads clinical trials for lupus at HSS and was involved in the anifrolumab trial. “Lupus is a very heterogeneous disease, and it’s difficult to bring it under control,” he says. “One of things that makes anifrolumab so promising is that it appears to work particularly well for patients whose disease is more severe. It was especially effective against the skin rashes that are common in lupus patients.”

He added that because the drug is targeted only at the type I interferon receptor, it appears to have relatively few side effects compared to drugs with more wide-ranging effects like steroids. But because it acts on the immune system, it does appear to increase the risk of upper respiratory infections. People who got the drug were also more likely to develop shingles, so it may be recommended that people get the shingles vaccine before starting the drug.

Dr. Crow says that because interferon is also implicated in other autoimmune diseases, it’s possible that anifrolumab may work in them as well. She adds that there are other promising drugs for lupus currently under investigation. “As an investigator who focuses on translational research, my goal is always to discover something that can benefit patients,” she says. “It’s very gratifying when your research can have a positive impact on people’s lives.”

The study, published online-first in Arthritis & Rheumatology today, was led by Iris Navarro-Millán, MD, MSPH, a rheumatologist at HSS. At the height of the pandemic in New York City, Dr. Navarro-Millán was working as a hospitalist on a COVID-19 unit. She observed indicators that signified a patient was about to worsen quickly and hypothesized that these measures could suggest the best time to intervene with additional medication.

“In rheumatology, we take a very measured approach to treating each patient,” said Dr. Navarro-Millán. “I applied those methods to develop specific criteria and determine markers that suggested patients were in this window of opportunity where they were most likely to benefit from an immune-suppressing drug.”

“At the height of the pandemic, I was following the literature that was coming out about COVID-19 so that I could understand what was going on from an immunological point of view,” explained senior author Mary K. Crow, MD, physician-in-chief and chair of the Department of Medicine at HSS. “We were all aware that people who needed ventilators were at high risk for fatality, so preventing them from getting to that point seemed like an important goal.”

The two criteria identified as signals that a patient would soon require mechanical ventilation were acute hypoxic respiratory failure (AHRF) and cytokine storm syndrome (CSS). CSS, in which the immune system floods the body with proteins that promote inflammation and tissue damage, has been identified as the most dangerous consequence leading to fatality in people with COVID-19. AHRF was defined as an increased need for supplemental oxygen. Elevated levels of a blood marker called ferritin were used as an indicator of CSS.

In the paper, the investigators report that of the 11 patients who received anakinra after exhibiting signs of being close to requiring intubation and mechanical ventilation, those seven patients who received anakinra within 36 hours of increasing oxygen requirements were able to avoid mechanical ventilation and were later discharged home. In the four who did not receive anakinra until four or more days after the onset of respiratory failure, all were placed on ventilators, three were eventually extubated, with two of those patients discharged and one remaining hospitalized. One fatality was reported, of a patient who received anakinra and later went on a ventilator.

Since the COVID-19 pandemic began, a number of immunosuppressive drugs have been evaluated in patients experiencing CSS. Some of these drugs, including anakinra, inhibit a protein called interleukin-1. Other drugs being investigated inhibit different proteins in the interleukin family.

Dr. Navarro-Millán chose to study anakinra in part because the drug has a shorter half-life than other immunosuppressive drugs, enabling her to more readily customize the amount of the drug in the body. “We know that once someone does go on a ventilator, their risk of other infections, especially bacterial infections, goes way up,” she said. “At that point, suppressing the immune system is not the best approach. When we stop anakinra, the immune system rebounds much more quickly than it does with other immunosuppressive drugs.”

“This is a small study, but we think it could provide guidance to other doctors to help them identify which patients might benefit from anakinra treatment,” Dr. Crow added. “For those showing evidence of CSS and increasing oxygen requirements, the timing of the intervention is essential in avoiding the need for intubation. We thought it was important to publish our experiences and get this information out and available, especially as the pandemic is worsening in other parts of the country.”

Dr. Navarro-Millán is now developing a controlled study of anakinra in patients with COVID-19 who fit the criteria she developed.

“Research identifying the role of type I interferon in autoimmune disease, particularly lupus, is progressing. The study by Kim et al. provides data on one of the mechanisms that might explain why interferon is being made in excess in lupus. It also supports therapeutic targeting of the interferon pathway in lupus,” said Dr. Crow, who is also chief of the Division of Rheumatology at HSS and NewYork-Presbyterian/Weill Cornell Medical Center.

Previous research has shown that the IFN-I family of innate immune cytokines contributes to the aberrant immune functions of SLE and several other autoimmune diseases. White blood cells from SLE patients demonstrate an IFN-I signature characterized by increased expression of hundreds of IFN-regulated genes. Sustained activation of the IFN pathway supports differentiation of T follicular helper cells, development of autoantibody-producing plasma cells and recruitment of inflammatory cells that produce tissue damage. Previous research has also shown that toll-like receptors, when stimulated by immune complexes, induce production of IFN-I in patients with SLE.

The study by Kim et al. describes a new mechanism for IFN-I production and identifies a role for mitochondrial stress in inducing oligomerization of VDAC, a molecule in the outer mitochondrial membrane that controls entry and exit of metabolites. Oligomerization of a protein refers to the interaction of more than one polypeptide chain. The researchers showed that interaction of amino-terminal amino acids of the protein VDAC1 with mitochondrial DNA (mtDNA) initiates pore creation. Mitochondria with increased mitochondrial reactive oxygen species (mROS) release small fragments of mtDNA into the cytosol, the aqueous component of the cytoplasm of a cell, through the VDAC pore, and this triggers induction of IFN-I. The transfer of mtDNA to the cytosol occurred under relatively benign conditions of mitochondrial stress, suggesting that induction of IFN-I through sensing of mtDNA could involve different environmental triggers.

“In a disease like lupus, there are many kinds of stressors that can trigger the disease or flares of the disease, such as ultraviolet light or excessive fatigue,” explained Dr. Crow. “There are many potential triggers that can make lupus worse.”

Kim et al. also demonstrated that inhibiting VDAC oligomerization in SLE mice reduced accumulation of cytosolic mtDNA, decreased expression of type I IFN-regulated genes and abrogated features of autoimmune disease in mice with SLE.

“Overall, this study points to this important cell structure, the mitochondria, which we typically think of as producing energy, as also having the role of sensing cell stress that leads to changes that allow the formation of this pore, the leakage of mitochondrial DNA, and activation of the immune response, as measured by production of interferon,” said Dr. Crow. “The study by Kim et al. suggests a novel mechanism that could account for the production of type I IFN.”

Dr. Crow pointed out that in this week’s New England Journal of Medicine, the TULIP-2 (Treatment of Uncontrolled Lupus via the Interferon Pathway–2) trial reported positive results for anifrolumab, an antibody that inhibits signaling through the type I IFN receptor in patients with SLE. “There is progress in developing therapies to inhibit interferon’s impact on the immune system and improve outcomes for patients with lupus,” said Dr. Crow.

Mary K. Crow, MD, physician-in-chief and chief of Rheumatology at HSS, was this year's recipient of the Presidential Gold Metal, the highest award the ACR can bestow.

"My experience in ACR leadership roles has taught me a lot about how to be a good leader," says Dr. Crow. "I learned how to move a group of individuals forward, build consensus, achieve a goal by shaping the conversation and getting people all on the same page and in a productive way."

At the awards ceremony, Dr. Crow commented on the impact that rheumatologists can make on the illnesses that affect up to 10 times more women than men.

Read the full article at The-Rheumatologist.org.

Recognizing outstanding career achievements in rheumatology, the Presidential Gold Medal is the highest honor that ACR presents to one individual each year. Winners have made important contributions to clinical medicine, research, education and administration.

Dr. Crow is the second woman as well as the second HSS physician, following physician-in-chief emeritus Charles L. Christian, MD, to receive this distinction. 

"It’s a tremendous honor to receive this award,” said Dr. Crow. “Throughout my career, I have worked to improve the understanding and treatment of autoimmune rheumatic diseases to increase the quality of patient care."

A member of the ACR for 35 years, Dr. Crow is a rheumatologist and physician scientist who investigates the cellular and molecular mechanisms of systemic lupus erythematosus and rheumatoid arthritis.

Her research efforts have contributed to identification of new targets for therapy, and her work has established the rationale for drug development programs testing new treatments for lupus patients. Specifically, she identified the autologous mixed lymphocyte reaction, characterized the role of CD40-CD40 ligand in lupus, and defined the type I interferon pathway as a critical disease mechanism in lupus. Additionally, her characterization of gene expression in patients with lupus nephritis holds promise of designing precision medicine strategies for the disease.

After being appointed physician-in-chief in 2010, Dr. Crow led an initiative to establish a perioperative medicine program at HSS to optimize outcomes of patients with rheumatic disease who undergo orthopedic surgery procedures. HSS perioperative medicine guidelines have since been applied to more than 30,000 surgeries at HSS.

"HSS is a world leader in orthopedics and rheumatology, and physicians across all specialties have the incredible opportunity to collaborate," said Todd J. Albert, MD, surgeon-in-chief at HSS. "By working with Dr. Crow and her team, we are able to transform and personalize care delivery, improve patient care and outcomes, and implement advances in treatment for numerous conditions."

During Dr. Crow’s tenure as chief, the Department of Rheumatology at HSS has recruited 12 new adult and pediatric rheumatologists, along with infectious disease and metabolic bone disease specialists, and has established a dedicated team of perioperative medicine internists. The department’s physicians evaluate and manage the full spectrum of rheumatic diseases, with more than 40,000 patient visits in 2017.

Dr. Crow is also passionate about mentoring women working in rheumatology. She is devoted to growing the number of women in the field and supporting the development of clinical investigators.

"Her dedication to advancing the careers of the next generation is second to none. She is the iconic role model for women in our field. She has inspired, mentored and paved the way for many women in rheumatology," said Jane E. Salmon, MD, rheumatologist at HSS.

Dr. Crow plays an integral role in creating and expanding centers of excellence at the Hospital, serving as director of the Autoimmunity and Inflammation Research Program and co-director of the Mary Kirkland Center for Lupus Research. She is also currently the co-chair of the Scientific Advisory Board for the Lupus Research Alliance.

She has published 15 book chapters and 154 peer-reviewed articles, and continues to publish in leading rheumatic disease journals including Arthritis & Rheumatism and Lancet.

In 2017, Dr. Crow was named an honorary member of the European League Against Rheumatism (EULAR) based on her service in improving the treatment, prevention and rehabilitation of musculoskeletal diseases. In past years, she has served as president of the American College of Rheumatology and President of the Henry Kunkel Society and has been an invited speaker at numerous national and international medical conferences.

According to the article, the Presidential Gold Medal is the highest award that the ACR bestows.  

"My overwhelming reaction is gratitude for experiences that are meaningful in so many ways," said Dr. Crow.

"We are proud that we prioritize diseases that especially affect women including many from minority groups, many of whom are disadvantaged by their socioeconomic situation," she added.

Read the full article at healio.com.

Founded in 1947, EULAR’s mission is to reduce the burden of rheumatic conditions and to improve the treatment, prevention and rehabilitation of musculoskeletal diseases. EULAR represents the scientific societies of rheumatology in all the European nations, health professional associations, and organizations for people with rheumatism.

As a mark of distinction, EULAR elects honorary members based on their outstanding service in accomplishing the organization’s objectives and in 2017, began nominating its first overseas individuals. Dr. Crow is among the first two Americans honored in 2017, and Dr. Salmon is the third American recognized.

About Dr. Crow

As physician-in-chief and chief of Rheumatology, Dr. Crow leads 66 full-time physicians including both adult and pediatric rheumatologists. Additionally, Dr. Crow’s academic and research career has focused on the molecular mechanisms that underlie systemic autoimmune diseases with a focus systemic lupus erythematosus and rheumatoid arthritis.

About Dr. Salmon

At HSS, Dr. Salmon is the director of the Lupus and APS Center of Excellence, co-director of the Mary Kirkland Center for Lupus Research, and director of the FOCIS Center of Excellence. Dr. Salmon’s research has focused on the mechanisms of tissue injury in lupus and other autoimmune conditions.