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.

Findings indicated that the protein ADAM17 plays a key role in inflammatory disorders, and iRhom2 regulates the production of the ADAM17 protein.

"They separate out the protective and pro-inflammatory functions of the gene. iRhom2 is meant to immediately respond to bacterial invaders by activating ADAM17," said HSS senior scientist and co-senior study author Carl Blobel, MD, PhD.

"A mechanism to block or inhibit iRhom2 would inhibit two key pathways for renal [kidney] injury in patients with lupus without significant side effects," said HSS rheumatologist and co-senior study author Jane E. Salmon, MD.

According to the article, this approach could be the basis of new treatments for kidney damage in lupus patients.

"From a medical point of view, that's what makes this approach so attractive," said Xiaoping Qing, MD, PhD, the study's first author.

Read the full article at lupusnewstoday.com

Researchers at the Hospital for Special Surgery (HSS) and their colleagues found that inactivating the protein, called iRhom2, prevented kidney injury in mice vulnerable to developing lupus. Particularly promising, according to the researchers, is that the kidneys of mice lacking the iRhom2 gene were shielded by both a reduction in general inflammation and the prevention of irreversible scarring of the organs -- a powerful two-for-one effect.

"A mechanism to block or inhibit iRhom2 would inhibit two key pathways for renal injury in patients with lupus without significant side effects," said Jane Salmon, MD, Collette Kean Research Chair and Senior Research Scientist at the Hospital for Special Surgery, and Professor of Medicine at Weill Cornell Medicine, who led the study in collaboration with Carl Blobel, MD, PhD, the V. F. and W. R. Salomon Chair in Musculoskeletal Research and Director of the Arthritis and Tissue Degeneration Program at HSS and Professor of Medicine at Weill Cornell Medicine.

The researchers reported their findings in the March 5th issue of the Journal of Clinical Investigation.

Systemic lupus erythematosus (SLE) is a chronic autoimmune disorder that affects an estimated 1.5 million people in the United States. The condition frequently leads to severe and potentially lethal damage to a variety of organs including the skin, brain, lungs, heart and kidneys. Women are roughly 10 times more likely than men to develop lupus.

Kidney damage from lupus, called lupus nephritis, affects between 40 percent and 60 percent of adults with SLE. Injury to this organ, which filters waste from the bloodstream and helps regulate blood pressure, involves the gradual accumulation of molecules called immune complexes. These clusters trigger inflammation that can lead to irreversible scarring and eventual failure of the organ. Patients with kidney failure must undergo regular dialysis until a transplant is available.

Over the past 20 years, researchers have identified several proteins that contribute to chronic kidney disease. One of these, a disintegrin and metalloprotease 17 (Adam17), acts like a pair of molecular scissors on the surface of cells. Its job is to clip off, or shed, substances that act as signals to other cells. Among these signaling molecules are a potent driver of inflammation called tumor necrosis factor-alpha (TNF-α), and heparin-binding epidermal growth factor (HB-EGF), a protein that helps maintain the skin and intestinal integrity.

However, in autoimmune diseases such as lupus, HB-EGF is directly linked to irreversible scarring, or fibrosis, of kidney tissue, while having too much TNF-α marshals the immune system to wage perpetual war against the body itself by activating inflammatory cells to attack the organs.

Scientists have tried inhibiting Adam17 in the hopes of reducing or eliminating the excessive shedding of TNF-α that leads to tissue injury in autoimmune illnesses. But Dr. Salmon points out that Adam17 is involved in so many processes – including essential functions such as keeping the skin and gut protected against microbial invaders – that blocking it could prove catastrophic.

In earlier work, Dr. Blobel and colleagues found that iRhom2 and a related gene, iRhom1, control the expression of Adam17. "They separate out the protective and pro-inflammatory functions of the gene. iRhom2 is meant to immediately respond to bacterial invaders by activating Adam17, which tells cells to release defensive substances (TNF-α) and strengthen the integrity of the skin and intestines by releasing HB-EGF," he said. "If you have a breach of the barrier, you want to do two things: You want to rebuild the barrier and you want to activate the immune system."

For the new study, the HSS investigators sought to learn if they could ratchet down Adam17 by manipulating iRhom2. "In patients with lupus nephritis, you see an increase in expression of iRhom2," Dr. Salmon said. "But if you have more iRhom2, you have more Adam17, and therefore more shedding of TNF-α and HB-EGF."

Xiaoping Qing, MD, PhD, an Instructor in Autoimmunity and Inflammation Program studied a strain of mice with a mutation that predisposes them to lupus and kidney injury. Blocking iRhom2 prevented the organ damage. Analysis of the kidney tissue showed greatly reduced inflammation, scarring and other signs of harm.

The researchers also treated the same strain of mice either with a drug that suppresses the activity of TNF-α or a drug that blocks signaling by the receptor for HB-EGF, the EGFR. Treated animals showed significantly less evidence of kidney damage than untreated rodents, indicating that TNF-α and the EGFR play important roles in the disease process of lupus.

Using tissue samples from kidney biopsies, they found that elevated expressions of HB-EGF with the highest levels are associated with irreversible damage. In addition, exploring data from a large national databank revealed that kidney cells from patients with lupus express abnormally high amounts of iRhom2, another indicator of the role of this molecule in the development of lupus nephritis.

The findings are particularly promising, the researchers added, because despite hitting two extremely important molecular pathways at the same time, blocking iRhom2 appears to be quite safe. "From a medical point of view, that’s what makes this approach so attractive," Dr. Qing said. "Nobody can find anything wrong with mice that have no iRhom2, but they seem to be protected from autoimmune diseases."

In future research, the HSS team hopes to test various methods of suppressing iRhom2.