Understanding the role of inflammation in COVID-19 patients: a little is good, too much might kill youDecember 3, 2020
COVID-19 is the medical emergency of the century. Since the pandemic began in December 2019, the new coronavirus, termed SARS-CoV-2 has caused havoc in almost every country, with more than 40 million proven cases of the disease termed COVID-19, including one million deaths.
We still understand little about the biology of COVID-19. Key questions are why is there such a wide spectrum of disease severity, with about 40 to 45% asymptomatic, of the symptomatic 80% mild, needing no medical attention, 15% of cases moderate and 5% severe and potentially fatal. Another is what underlies the most severe cases. What is now understood is that uncontrolled inflammatory responses are associated with the worst patient outcomes.
The role of inflammation role in COVID-19
When the lungs are infected by a virus like influenza or SARS-CoV-2, the body tries to defend itself. It does this by the release of many mediators to combat the infection. There is evidence that interferons are very important early in defense, since patients with defects in interferon production or endogenous antibodies to interferon do badly1 and inhaled interferon has been successful in an early trial. Studies from Mount Sinai hospital in NY, the epicenter of the first wave, and others2, report that high levels of cytokines including IL-6 and TNF correlated with bad outcomes. High levels of TNF and IL-6 induce inflammation that can result in respiratory and multi organ failure2 leading to death. Such uncontrolled hyperinflammation is sometimes called a “cytokine storm”. It occurs in many severe illnesses and in recent years has been reported to be a common side effect of chemotherapy and even cancer treatment with CAR-T cells. But inflammation mediated by TNF3 and other cytokines is not limited to autoimmunity and viral infections, it is also an important factor that drives the growth of solid tumors and is a cause of severe weight loss in cancer patients.4
This hyperinflammatory reaction in COVID-19 cases is characterized by much higher-than-usual serum TNF, interleukin IL-6 and IL-8 concentrations, but comparatively low concentrations of IL-1 or IL-2, as in the case of influenza2. Thus, therapies that address respiratory failure in COVID-19 could prove useful for many different diseases.
A major characteristic of deteriorating lung function in COVID-19 patients is capillary leak5, often the result of inflammation driven by several key inflammatory cytokines: TNF, IL-1, IL-6, and vascular endothelial growth factor (VEGF) and reactive oxygen species also contribute. In 30% of severe cases corticosteroids like dexamethasone may reduce inflammation and capillary leak, and lead to a better outcome, as shown in the large RECOVERY trial, conducted by Oxford University.6
Due to the high levels of cytokines resulting in the hyperinflammation in severe disease, some researchers have turned their focus to blocking cytokines for the treatment of COVID-19. The first of these, which centered on blocking IL-6,has regrettably had little beneficial effect so far, as assessed in multiple clinical trials.7
Anti-TNF and where it has worked
A more effective way of treating COVID-19 hyperinflammation could be by blocking TNF. Research led by Sir Marc Feldmann, Enosi co-founder, in the 1990s showed that rheumatoid arthritis patients treated with anti-TNF monoclonal antibodies which blocked TNF, also blocked many other pro-inflammatory cytokines such as IL-1, IL-6, GM-CSF, VEGF and others8. The efficacy of anti-TNF treatment led to it being routinely used for multiple autoimmune inflammatory disorders, including inflammatory bowel disease, psoriasis and ankylosing spondylitis. The many patients treated effectively and safely has resulted in TNF inhibitors being the largest drug class in the world since 2012.
Because TNF is elevated in hospitalized COVID-19 patients, Feldmann and his colleagues9 suggested in April 2020, that anti-TNF therapy might be useful in patients with COVID-19 as it could also reduce the production of other cytokines and minimize the dangerous lung inflammation including capillary leakage. Consequently, anti-TNF might decrease the need for oxygen, ventilation and the mortality rate associated with COVID-19.
The potential of anti-TNF therapies in the treatment of COVID-19 is supported by early empirical clinical data obtained from databases of patients already on various anti-inflammatory drugs including anti-TNF. Patients with inflammatory bowel disease receiving anti-TNF therapy who develop COVID-19, do better than those using alternative agents. In this observational study, anti-TNF treatment is currently inversely associated with mortality from COVID-19 and hospital admissions. Subsequently, it has been reported by the Global rheumatology alliance, led by Prof Phil Robinson10, that in patients with arthritis, those already on anti-TNF treatment do very well, having only 30% the likelihood of hospitalization compared to those not on anti-TNF. Added to this there are small studies which document that hospitalized patients given the IV anti-TNF infliximab do well, but these are too small to be definitive. Hence bigger trials are needed, and they have begun in hospitalized patients in UK (CATALYST, enrolling) and in US (ACCTIV-1). The former is only using IV anti-TNF, the latter is also employing the antiviral Remdesivir). As good clinical trials require many patients, they take a lot of time and so we will only know the outcome by summer 2021.
A problem that requires precision
TNF is an important pro-inflammatory cytokine, it is the only one to have 2 receptors, TNFR1 present on all cells which promotes inflammation, and TNFR2 on some cells which inhibits inflammation and promotes resolution. In order to improve upon existing TNF blockers which block both, selective inhibitors are needed.
Enosi Life Sciences is developing two TNF-blocking therapeutic candidates for different uses. EN1001 is a TNFR1-binding protein inhibiting TNFR1 without compromising TNFR2’s healing capabilities, while EN3001 inhibits TNFR2, useful for blocking regulatory T cells in cancer, or in fibrosis. These second-generation TNF inhibitors, based on understanding of the TNF pathways, are likely to be more effective. EN1001 blocking just TNFR1 will be more effective than blocking TNF, as it spares regulatory T cell function1112. There is evidence that insufficient T regulatory cell function is involved in COVID-1913.
Key point: since inflammation is associated with severe COVID-19, an anti-inflammatory therapy proven to be safe and effective and readily available, such as anti-TNF, deserves consideration.
As delays in clinical trials have reminded us, developing a COVID-19 vaccine is not an overnight process and even the most promising candidates are many months away from being available and distributed at the scale required. Treatments for severely ill patients with COVID-19 are urgently needed and since we now know the connection between the virus and inflammation, widely used anti-TNF therapeutics are appropriate for addressing COVID-19. Since clinical trials have started, we will know next year whether the current generation of anti-TNFs is effective at combating severe symptoms of COVID-19.
But even when there are vaccines, it will be many years, if ever before severe illness due to COVID-19 is just a memory. Hence based on its more specific anti-inflammatory effect, drugs blocking just TNFR1 should be better. Enosi is working hard to be able to test that possibility.
About the authors
Sir Marc Feldmann is Co-founder and Board Member of Enosi Life Sciences. He is a preeminent immunologist, and an Emeritus Professor at the University of Oxford. With Sir Ravinder Maini, he identified TNF as a target. They led the successful trials of the first anti-TNF antibody called Infliximab (or Remicade), and prompted J&J’s $4.9B USD acquisition of Centocor. Total Remicade sales so far amount to more than $50B USD globally. Professor Sir Marc Feldmann is a Fellow of the Royal Society of Australian Academy and a Foreign Member of the US National Academy of Sciences; he was knighted in 2010 and received the Australian equivalent. He has received many accolades including the Lasker~DeBakey Clinical Medical Research Award., the Crafoord Prize, the Canada Gairdner Award, the Paul Janssen Award, and the Ernst Schering Award.
Dr. H. Michael Shepard is a serial entrepreneur and also serves as CEO, CSO, Co-founder and Board Member of Enosi Life Sciences. Dr. Shepard led the research at Genentech that resulted in Herceptin/trastuzumab, an antibody therapy now used for HER2-positive breast and gastric cancers. About 3 million women have been treated with Herceptin, many of them very successfully. Dr. Shepard has been recognized by his peers and by the Harvard Medical School Warren Alpert Prize (2006) and by the Lasker~DeBakey Clinical Medical Research Award (2019).
Dr Fiona McCann is associate scientific director of CannBioRx Life Sciences and advisor for Enosi Life Sciences. She has previously held the position of group leader at Kennedy Institute of Rheumatology, University of Oxford, leading translational discovery programs for autoinflammatory and fibrotic diseases. She identified a key immunoregulatory role for TNFR2 signaling in resolution of arthritis, implicating selective TNFR1 targeting as an improved therapy in chronic inflammatory disease.
1 Hadjadj J, Yatim N, Barnabei L, et al. Impaired type I interferon activity and inflammatory responses in severe COVID-19 patients. Science 2020; 369(6504): 718-24.
2 Del Valle DM, Kim-Schulze S, Huang HH, et al. An inflammatory cytokine signature predicts COVID-19 severity and survival. Nat Med 2020.
3 Brennan FM, Maini RN, Feldmann M. TNF alpha–a pivotal role in rheumatoid arthritis? Br J Rheumatol 1992; 31(5): 293-8.
4 Beutler B;Greenwald D;Hulmes JD;Chang M;Pan YC;Mathison J;Ulevitch R;Cerami A; “Identity of Tumour Necrosis Factor and the Macrophage-Secreted Factor Cachectin.” Nature, U.S. National Library of Medicine, 1985, pubmed.ncbi.nlm.nih.gov/2993897/.
5 Wu MA, Fossali T, Pandolfi L, et al. COVID-19: the key role of pulmonary capillary leakage. An observational cohort study. medRxiv 2020.
6 Group RC, Horby P, Lim WS, et al. Dexamethasone in Hospitalized Patients with Covid-19 – Preliminary Report. N Engl J Med 2020.
7 Mullard A. Anti-IL-6Rs falter in COVID-19. Nat Rev Drug Discov 2020; 19(9): 577.
8 Brennan FM, Chantry D, Jackson A, Maini R, Feldmann M. Inhibitory effect of TNF alpha antibodies on synovial cell interleukin-1 production in rheumatoid arthritis. Lancet 1989; 2(8657): 244-7.
9 Feldmann M, Maini RN, Woody JN, et al. Trials of anti-tumour necrosis factor therapy for COVID-19 are urgently needed. Lancet 2020; 395(10234): 1407-9.
10 Gianfrancesco M, Hyrich KL, Al-Adely S, et al. Characteristics associated with hospitalisation for COVID-19 in people with rheumatic disease: data from the COVID-19 Global Rheumatology Alliance physician-reported registry. Ann Rheum Dis 2020; 79(7): 859-66.
11 McCann FE, Perocheau DP, Ruspi G, et al. Selective tumor necrosis factor receptor I blockade is anti-inflammatory and reveals immunoregulatory role of tumor necrosis factor receptor II in collagen-induced arthritis. Arthritis Rheumatol 2014; 66(10): 2728-38.
12 Tseng WY, Huang YS, Clanchy F, et al. TNF receptor 2 signaling prevents DNA methylation at the Foxp3 promoter and prevents pathogenic conversion of regulatory T cells. Proc Natl Acad Sci U S A 2019; 116(43): 21666-72.
13 Meckiff BJ, Ramírez-Suástegui C, Fajardo V, et al. Imbalance of regulatory and cytotoxic SARS-CoV-2-reactive CD4+ T cells in COVID-19. Cell 2020.