Dr Michael Shepard and Sir Marc Feldmann, Enosi Life Sciences, examine the benefits of distinguishing between TNF receptors
Siloed thought processes are potentially costing the pharmaceutical industry billions of dollars per year. One particularly interesting case is that of autoimmune diseases and cancer. These two areas of medicine have a very important link – inflammation – yet researchers in academia and industry continue treating them as distinct, with their own approaches for treatment, and ignoring potential links.
The biggest selling drug class is currently the tumour necrosis factor (TNF) inhibitors, used in autoimmune and inflammatory diseases. However, with appropriate redesign they could be used in autoimmune and inflammatory diseases, and cancer. The first step in this direction has been taken to improve the efficacy and safety of anti-TNF therapy, by making it even more precisely targeted.
There are two distinct TNF receptors on cells: the inflammatory TNFR1 and anti-inflammatory TNFR2. This dichotomy is important; evidence for this is that the dichotomy is found in mice and survived the 50 to 80 million years of evolution between these two species. Potentially more effective anti-inflammatory therapeutics can be generated by targeting TNFR1 (inflammation) and TNFR2 (cancer) selectively.
Inflammation: the tie that binds
The concept of moderation may be most commonly associated with dietary health but it is also very important in the immune system. Inflammation occurs when the body’s immune system reacts against things it believes could do the body harm. However, too much of this ‘good thing’ can have harmful consequences. Research now syndicates that overblown inflammatory responses are closely linked to significant health issues, like autoimmune diseases and cancer. This year, it has been understood that the lung destructive effects of COVID-19 are also the result of an overactive immune response to the virus. It was previously shown that the same is true of other SARS and influenza viruses.
Another instance of an overactive immune response occurs in autoimmune diseases, when a person’s immune system mistakenly attacks healthy cells. This can occur in many parts of the body, and it affects women three times more often than men. Autoimmune diseases come in many different types – with more than 80 variations, as a matter of fact. The associated inflammation causes typical changes, such as heat, swelling, redness and pain. As an autoimmune disease worsens or improves, so too may the accompanying inflammation.
How are these typical changes driven? Inflammatory cells in common autoimmune diseases, such as rheumatoid arthritis, release an overabundance of chemical mediators, which act on the target tissue. One of the earliest, and perhaps the most important, is TNF, the name of which does not reflect the multitude of its effects. Similarly, inflammatory cells in solid tumors also overproduce TNF. These inflammatory responses can contribute to cell proliferation and eventually cancer development.
A group of researchers, led by Sir Marc Feldmann, uncovered the importance of TNF in the development of rheumatoid arthritis. He and his colleague, Sir Ravinder Maini, led the first trials which documented the efficacy of anti-TNF therapy, which led to TNF inhibitors being the world’s biggest drug class since 2012.
Less than half of patients treated with TNF blockers actually respond well to therapy and more than a quarter of patients fail therapy after 12 months. It is clear that existing TNF blockers do a lot of good for patients but even the world’s most successful pharmaceuticals can be improved upon. For instance, there was a time when we thought there could never be anything better for a headache than aspirin.
Researchers have identified two different TNF receptors, each of which triggers its own reaction: TNFR1, which causes inflammation, and the anti-inflammatory TNFR2, which counters the former. This leads to an important possibility: that it would be more effective to just block the pro-inflammatory TNFR1. This has proven to be technically challenging and several companies have abandoned their attempts, but Dr. H. Michael Shepard – who developed the world’s first effective monoclonal antibody inhibitor of a receptor, the drug known as trastuzumab, or Herceptin – is working toward overcoming this challenge.
Recent and upcoming advancements in anti-TNF therapy
Shepard and Feldmann, who founded Enosi Life Sciences, are taking a different approach; they have combined their experience pioneering the development of TNF blocking therapeutics, initially to create a more effective solution for targeting TNFR1 without blocking TNFR2. Feldmann was instrumental in the development of the first anti-TNF used in autoimmunity, Remicade, while Shepard played a major role in the conception and development of Herceptin, another top-10 selling drug. The two believe that by combining their expertise and the networks they have established throughout their scientific careers, they can develop novel multi-specific antibodies that target inflammation, which can improve the treatment of autoimmune diseases and cancer. Shepard and Feldmann believe that the resulting drugs have the potential to offer more complete and longer lasting responses without some of the side effects, like susceptibility to opportunistic infection.
This research is leading to the creation of two TNF-blocking therapeutic candidates for acute or chronic inflammation: EN1001 and EN3001. EN1001 is a TNFR1-binding protein that inhibits the inflammatory TNFR1 without compromising the anti-inflammatory TNFR2’s healing capabilities, while EN3001 inhibits TNFR2.
Further autoimmune disease and cancer therapeutics may block the growth of the cells in the joints that produce TNF. This molecule, EN2001, is an antibody-like protein that ‘mops up’ inflammatory growth factors of the EGF family (called a growth factor trap) thereby limiting the amount of TNF that can be produced.
Huge market opportunities
Because there are so many different autoimmune and chronic inflammatory diseases, there will be many possible uses for EN 1001 blocking TNFR1, such as in inflammatory bowel disease, ankylosing spondylitis and psoriasis
The US National Cancer Institute (NCI) estimated that in the US in 2020, about 1.8 million people would be diagnosed with various forms of cancer and approximately 606,520 people would die of cancer. That is just one developed country – the latest available estimate from the World Health Organization (WHO) suggested that 9.6 million people throughout the world died of cancer in 2018. Perhaps most tellingly of all, these figures are all for single years, so they barely scrape the real scope of the devastation seen across the globe from these priority medical issues.
The sheer scale of cancer around the world is reflected by the global market for oncology drugs, which is projected to surpass $175 billionin just the next five years, nearly double its current value of approximately $97.4 billion. This is driven largely by surges in cancer therapeutics research, growing geriatric populations throughout the world and an ever-increasing number of collaborations between leading pharmaceutical companies and renowned scientists.
According to the US National Institute of Environmental Health Sciences (NIEHS), the 80-plus autoimmune diseases known to scientists affect 24 million people in the US alone, while the National Stem Cell Foundation estimates that nearly 4% of the entire world’s population is affected by autoimmune diseases.
The market for rheumatoid arthritis therapeutics alone – just one of the dozens of known autoimmune diseases – is projected to reach $34 billion over the course of the next five years, increasing its 2017 value by nearly 50%. It is more difficult to quantify the market opportunity for therapeutics for all autoimmune diseases because there are so many of them, so while not every autoimmune disease will have a $34 billion market potential, it is a safe bet that they collectively create a pretty high ceiling.
Pulling on the common thread
It is staggering what blocking a single mediator, TNF, has already done for medicine, patients, and for companies in biotech and pharma. By improving the specificity of the effect of TNF blockade by blocking TNFR1, the effects on inflammation should be greater, as the anti-inflammatory effects of TNFR2 are not blocked. Blocking TNFR2 also offers opportunities to improve cancer treatment, since this will reduce the anti-inflammatory effect of cells carrying TNFR2, the so called ‘regulatory T cells’.
It stands to reason that if researchers are able to develop versions of these historically successful drugs that are more effective and are viable for more patients, they could unlock unprecedented revenue-generating potential. It is clear that whoever finds a way to block the inflammatory TNFR1 while preserving the healing TNFR2 will set this pharmaceutical and medical gold rush in motion.
Dr Michael Shepard is President and CSO of Enosi Life Sciences. He is a global, leading authority on cancer research and therapeutics. He is best known for his invention of “Herceptin”/Trastuzumab, which has remained one of the most profitable platforms for Roche. Dr. Shepard is a highly-experienced and respected leader with many successful ventures in this field—working at Genentech, Canji, and Halozyme. Widely acknowledged as a biomarker pioneer, Dr. Shepard has received the 2019 Albert Lasker Award and the Warren Alpert Prize.
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). 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 accolades including the Albert Lasker Award, the Canada Gairdner Award, the Paul Janssen Award, and the Ernst Schering Award.