understanding immune pathways

by david lee, m.d. ph.d

special editorial submitted by champion steward partner janssen pharmaceutical companies of johnson & johnson 50 connexions

CChanging the way we consider and classify disease may have a profound impact on how disease is treated. And it’s a change that’s long overdue. For over 250 years, diseases have been categorized by anatomical classification, or the predominant organ system involved, giving us, for example, nephritis for inflammation of the kidney, vasculitis for inflammation of blood vessels, dermatitis for skin inflammation, colitis for lower GI tract inflammation, and so on. This classification led to the assumption that there were distinct drivers based on anatomical location for each ‘disease’, with the result that new treatments were developed on an organ-by-organ basis.2

Prior to anatomical classification, in medieval times, disease classification was based on four “humors” (black bile, phlegm, yellow bile, and blood). The humors were said to be the four main substances that made up the human body. Any disability or sickness only meant that the humors were not balanced appropriately.1,2 The organ-based system radically changed

how medieval physicians and those who followed considered and treated disease, and laid the foundation for many of our specialty approaches in medical treatments for example, “cardiology” for all things heart related, “dermatology” for study of the skin, “hepatology,” for study of the liver, and so on. I believe we are on the verge of a similar revolution today in how we classify disease, one based on our revised understanding of genetic or molecular drivers of disease in the body.

Diseases’ Shared Immune Pathways

New discoveries into our immune system function are leading to profound learnings about drivers of disease. Technology has enabled us to better examine both single cell behavior, as well as information from thousands of cells. Further, advances in genetics have resulted in the identification of more disease-associated genes. Insights indicate that common immune pathways are responsible for seemingly disparate diseases – from multiple sclerosis to cancer to lupus. And clinical research with targeted immune therapies has provided compelling evidence supporting this finding. Today we know that one gene can contribute to multiple diseases, as in the case of anti-tumor necrosis factor (TNF) agents that were initially approved for rheumatoid arthritis, and have shown efficacy in numerous other diseases including those considered dermatologic, or gastrointestinal diseases. This pattern is not unique to anti-TNF agents: immune-targeted drugs typically demonstrate efficacy in multiple diseases, not just in one disease. This is powerful insight. It follows that as we understand how diseases share a common pathway and develop treatments targeting that pathway, we can also advance from a “onedrug/one disease” mindset to a more expanded “one-drug, many diseases” approach. By understanding the common pathogeneses that drive across diseases currently viewed as distinct entities, we can more rapidly and effectively expand the development of medicines into broader populations. In short, categorizing disease by molecular or ‘pathway’ drivers of pathogenesis allows us to cut across current siloing of patients by anatomic predominance of symptoms. This approach could help in the development of treatments for fetal diseases, like hemolytic disease of the fetus and newborn (HDFN), a blood disorder in which maternal antibodies attack fetal or newborn red blood cells (RBCs), and can cause significant morbidity and mortality, especially in settings with limited healthcare resources.3,4

Insights indicate that common immune pathways are responsible for seemingly disparate diseases – from multiple sclerosis to cancer to lupus. And clinical research with targeted immune therapies has provided compelling evidence supporting this finding.

New Insights Into HDFN

HDFN is an immune disease impacting an estimated 3 to 80 in 100,000 patients per year in the U.S., which can lead to anemia, hyperbilirubinemia and jaundice, fetal hydrops, brain damage, and death.4,5 Incidence of severe outcomes of HDFN (hydrops, fetal death) has substantially decreased in the past 50 years due to great strides in identifying blood group antigens and in predicting fetal anemia through noninvasive monitoring, however, questions remain about RBC alloimmunization risk factors, preventative therapies, and treatment strategies.4,6 The immune-mediated hemolysis due to blood group incompatibility between the mother and the fetus is the primary cause of HDFN.7,8 The mother’s immune system develops antibodies, known as immunoglobulin G (IgG), that cross the placenta and attack the RBCs in the baby's blood, causing them to break down.3,4 As with other immune-mediated diseases, it is believed that zeroing in on a specific pathway responsible for IgG activity could hold the key to improved treatments for HDFN. IgG plays a predominant role in the pathogenesis of multiple

autoimmune diseases. Current and future research into the characteristics and functions of pathways regulating IgG are guiding our ability to advance treatments for HDFN and other serious immune conditions that specifically target the mechanisms responsible for damage or tissue disruption caused by these important antibodies.9

Greater Impact Through Immune Pathways Approach

Approximately 31 million people throughout the U.S., Europe and Japan are living with moderate to severe forms of immune-mediated disease, yet only five million are receiving advanced therapy today, and a small fraction of those – about two million – have achieved sustained clinical remission.10 In addition, researchers are identifying the role of the immune system in many disease areas not previously considered immune disease. For example, research and medicines in immune-oncology have exploded in recent years, and similar immunology-based research is ongoing in neurology, cardiovascular disease and many other areas.

Now is the time to pursue opportunities that cut across traditional disease-area boundaries with the next wave of scientific evolution: an immune pathways approach in treating disease. A pathway-centric scientific approach provides the opportunity to develop smarter, more targeted treatment for many diseases, reaching broader patient populations. At Janssen, scientists are pursuing a pathways-based approach to discovering and developing innovative medicines, and opening the aperture of opportunity that pathways-based approaches provide into diseases with high unmet need. Our goal is rebalancing the immune system to achieve long-term remission. To learn more about our work in immunology, visit https://www. janssen.com/immunology.

References: 1. National Institutes of Health: U.S. National Library of Medicine. History of Medicine: The World of Shakespeare’s Humors (2013). Available at: https:// www.nlm.nih.gov/exhibition/ shakespeare/fourhumors.html. Accessed March 2021. 2. National Institutes of Health: U.S. National Library of Medicine. History of Medicine: Emotions and Disease. The Balance of Passions (2012). Available at: https://www.nlm.nih.gov/exhibition/ emotions/balance.html. Accessed March 2021. 3. National Institutes of Health: U.S. National Library of Medicine. Medical Encyclopedia: Hemolytic disease of the newborn (Reviewed September 29, 2019). Available at: https://medlineplus. gov/ency/article/001298.htm. Accessed March 2021. 4. Hall V, Avulakunta Id. Hemolytic Diseases Of The Newborn. [Updated 2020 Dec 15]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2021 Jan-. Available at: https://www.ncbi.nlm.nih.gov/books/ NBK557423/. Accessed March 2021. 5. Ling, L., Yu, D., Gleeson, C. D., & Moise, K. (2021). 968 Estimation of hemolytic disease of the newborn in the United States from 1996-2010. American

Journal of Obstetrics and Gynecology, 224(2), S600–S601. https://doi.org/10.1016/j. ajog.2020.12.993. Accessed March 2021. 6. Hendrickson JE, Delaney M. Hemolytic Disease of the Fetus and Newborn: Modern Practice and Future Investigations. Transfus Med Rev. 2016 Oct;30(4):159-64. doi: 10.1016/j. tmrv.2016.05.008. Epub 2016 May 26. PMID: 27397673. Available at: https:// pubmed.ncbi.nlm.nih.gov/27397673/. Accessed March 2021. 7. Dean L. Blood Groups and Red Cell Antigens [Internet]. Bethesda (MD): National Center for Biotechnology Information (US); 2005. Chapter 4, Hemolytic disease of the newborn. Available at: https://www.ncbi.nlm. nih.gov/books/NBK2266/. Accessed March 2021. 8. Das S. (2019). Hemolytic Disease of the Fetus and Newborn, Blood Groups (A. Tombak, Ed.). IntechOpen, DOI: 10.5772/intechopen.85316. Available at: https://www.intechopen. com/books/blood-groups/hemolyticdisease-of-the-fetus-and-newborn/. Accessed March 2021. 9. Li X, Kimberly RP. Targeting the Fc receptor in autoimmune disease. Expert Opin Ther Targets. 2014;18(3):335-350. doi:10.1517/147282 22.2014.877891. Accessed March 2021. 10. Includes Atopic dermatitis, rheumatoid arthritis, psoriatic arthritis, ankylosing spondylitis, psoriasis, Crohn’s disease, ulcerative colitis, systemic lupus erythematosus, lupus nephritis, Sjogren’s syndrome, myositosis, amyloidosis, hidradenitis suppurativa, graft vs host disease, scleroderma, myasthenia gravis, celiac disease. Sources include Decision Resources, Kantar Health, NIH, Journal of Investigative Dermatology, BMJ, Foster Rosenblatt research, ZS Associates, Truven Claims, Deloitte research, data on file.

As a leading pharmaceutical company in the US, Janssen is named after Dr. Paul Janssen, a leading pharmaceutical researcher, pharmacologist and general practitioner. His company, Janssen Pharmaceutical, joined the Johnson & Johnson family of companies in 1961. The company has grown over the years to serve the changing needs of patients and the healthcare industry, yet is still guided by Dr. Janssen’s values of excellence and innovation.