Cancer – a global challenge
Cancer is one of the most common causes of death, being responsible for about 20% of deaths in the western world. Globally, about 14 million people are diagnosed with cancer every year, and over 8 million of them die of the disease . New treatment methods are needed and of those coming to the fore in the field of immunotherapy, Cantargia’s candidate CAN04 has great potential. With its unique double mechanism of action, it has the potential to become a more effective variant, either as a single drug or in combination with other treatments.
Despite significant progress in the treatment and diagnosis of cancer diseases, there continues to be a great need for new therapeutic methods. Initially, Cantargia is focusing its clinical development on non-small cell lung cancer (NSCLC) and pancreatic cancer. Cantargia has chosen to focus on these two forms of cancer because interleukin-1 has been found to be active in development of the tumours and because Cantargia’s own research has found a high expression of IL1RAP on tumours from these cancer types. There are also good prerequisites for using the product candidate CAN04 as an immune-oncological platform for several types of cancer, including leukaemia [2,3]. There is also considerable interest in evaluating CAN04 in combination with other therapies in which the mechanisms of action complement each other .
Lung cancer is the type of cancer that generates the most deaths, making it the fifth most common cause of death after cardiovascular diseases, stroke, COPD and respiratory tract infections. In 2018, about 2 million new cases of lung cancer were confirmed worldwide, with over 1.7 million deaths as a result of lung cancer. Approximately 80-85 per cent of all lung cancer cases are non-small cell lung cancer.
Lung cancer is a cancer type that is difficult to treat, with a substantial medical need and large numbers of patients. The disease is treated primarily by means of surgery in combination with radiotherapy, chemotherapy or immunotherapy, primarily antibodies to PD-1 and PD-L1, which stimulate the immune system. However, survival after 5 years is still lower than 20%.
A clinical phase III study that was published in The Lancet showed that the risk of lung cancer is reduced by 67% when patients with cardiovascular diseases are treated with an antibody that blocks interleukin-1β . The study also showed a reduction in inflammatory biomarkers that could be very positive in combating tumours. A generally reduced risk of death from cancer diseases and a reduced risk of autoimmune diseases was also observed. In other studies, interleukin-1 has also been shown to play an important role in the spread of lung metastases [6,7].
Sales of drugs for non-small cell lung cancer in 2015 were worth USD 6.2 billion in the eight most important markets, and this is expected to rise to USD 26.8 billion in 2025. Sales are driven primarily by an increase in the use of antibody-based immunotherapies. The common feature of these therapies is that they block signals that the tumour uses to hide from the immune system, as a result of which the immune system is able to recognise the tumour and kill it. Another important feature that is driving the market is a global increase in the incidence of lung cancer.
Roughly 456,000 new cases of pancreatic cancer were confirmed in 2018 worldwide. At the same time the disease resulted in about 432,000 deaths in that same year. Globally, it is predicted that the number of people falling ill with the disease will increase by 78 per cent in the period to 2040.
Pancreatic cancer is difficult to treat as it is often discovered late when surgical removal of the tumour is difficult and the cancer has often spread to other organs. Survival after 5 years is approximately 7%.
Pancreatic cancer is treated using a combination of several chemotherapies, but also radiotherapy and surgery where possible, and there is a great need for new therapeutic methods. Pancreatic cancer is one of the cancer diseases in which inflammation plays an important part in the tumour’s development and where interleukin-1 play an essential role in growth of the tumour [8,9].
The global market for the treatment of pancreatic cancer is expected to be worth USD 4.1 billion by 2025. In 2017 the market was worth approximately USD 2 billion. The market is expected to grow at an annual rate of about 8 per cent between 2018 and 2025. Growth in this market is being driven primarily by an increase in the number of cases, which in turn is driven by an ageing population and more cases of diabetes, which are risk factors for the development of this disease.
AML (Acute myeloid leukaemia)
Cantargia and its founders have studied AML [10-13] and have shown that IL1RAP is expressed both on leukaemia stem cells and on the mature cancer cells. AML is the most common form of acute leukaemia in adults. It is characterised by a rapid increase in white blood cells that accumulate in the bone marrow, where they disrupt the production of normal blood cells. The disease progresses rapidly, and without treatment, the patient dies within a few months. The underlying cause of the disease is genetic damage, which has been charted in detail in recent years. In 2019 it is estimated there will be 21,000 new cases in the USA, and about 11,000 deaths . In recent decades, there has not been any significant progress in the treatment of AML. Cytostatics, which are currently the most common form of treatment, are characterised by low effectiveness and serious side effects.
Cantargia’s research into the central role played by IL1RAP in the inflammatory process is applicable to numerous areas of disease. Cantargia has therefore launched the development of a new antibody against IL-1RAP which is to be the subject of a patent application. This new antibody is being designed to treat autoimmune/inflammatory diseases that are largely driven by interleukin-1, and the initial focus will be on Systemic sclerosis and myocarditis.
In 2019, Cantargia conducted a review together with a number of independent US specialists in order to obtain objective data for identifying diseases on which the development activities could be focused. At the outset, the study looked at around 150 different diseases based on aspects such as the biology behind the diseases, the medical need, competition and the complexity of clinical development. Based on this study, we have chosen to start with two diseases: systemic sclerosis and myocarditis. Both are serious diseases for which there are currently no good treatments. In 2020, we will be studying CAN10 in various models of these diseases and will also initiate the development of a production process and conduct the first toxicity study. The goal is to initiate patient studies in early 2022.
About Systemic Sclerosis
Systemic sclerosis is a chronic autoimmune disease that is characterised mainly by inflammation and fibrosis of the skin and subcutaneous tissue as well as blood vessels and internal organs such as the lungs, heart and kidneys15.
Systemic sclerosis is a complex, heterogeneous disease that can occur with a variety of clinical manifestations ranging from less severe to life-threatening. The estimated annual incidence of systemic sclerosis is approximately 4.5 per 100,000 in North America and 1.8 per 100,000 in Europe16,17,18. The main cause of death in patients with systemic sclerosis is interstitial lung disease and the medical need is particularly high in these patients.
Myocarditis is characterised by inflammation of the muscular tissues of the heart (myocardium), which have different origins, including genetic causes and infection mechanisms, that are not well characterised19,20. Regardless of its aetiology, myocarditis is characterised by initial acute inflammation that can progress to subacute and chronic stages, resulting in tissue remodelling, fibrosis, and loss of myocardium architecture and contractile function19,20.
The estimated incidence of myocarditis is about 22 per 100,00021 (1.7 million) and globally the disease accounts for about 0.6 deaths per 100,00022 (46,400) each year. The medical need is great for subgroups of patients with fulminant myocarditis (acute disease) and dilated cardiomyopathy (chronic disease), where mortality is very high in certain immune subtypes. For these patients, heart transplantation is currently the only definitive treatment.
 Acuner Ozbabacan, S.E. et al. (2014) The Structural Pathway of Interleukin 1 (IL-1) Initiated Signaling Reveals Mechanisms of Oncogenic Mutations and SNPs in Inflammation and Cancer. PLoS Comput Biol 10(2): e1003470. doi:10.1371/journal.pcbi.1003470
 Dinarello, C.A. (2010) Why not treat human cancer with interleukin-1 blockade? Cancer Metastasis Rev 29:317-329. Doi 10.1007/s10555-010-9229-0
 Globocan 2012 http://globocan.iarc.fr/
 Ridker, P.M. et al. (2017) Effect of interleukin-1β inhibition with canakinumab on incident lung cancer in patients with atherosclerosis: exploratory results from a randomised, double-blind, placebo-controlled trial. The Lancet 390(10105): 1833-1842; doi 10.1016/S0140-6736(17)32247-X
 Wang et al. (2014) IL-1b-Mediated Repression of microRNA-101 Is Crucial for Inflammation-Promoted Lung Tumourigenesis Cancer Res; 74(17)
 Carmi, Y. et al. (2011) Microenvironment-Derived IL-1 and IL-17 Interact in the Control of Lung Metastasis J Immunol 186:3462-3471; doi: 10.4049/jimmunol.1002901
 Wörmann, S.A. et al. (2014) The immune network in pancreatic cancer development and progression. Oncogene. Jun 5;33(23):2956-67. doi: 10.1038/onc.2013.257.
 Tjomsland V. et al. (2011) Interleukin 1α Sustains the Expression of Inflammatory Factors in Human Pancreatic Cancer Microenvironment by Targeting Cancer-Associated Fibroblasts Neoplasia. 13(8):664-75.
 Järås M, et al. (2010) Isolation and killing of candidate chronic myeloid leukemia stem cells by antibody targeting of IL-1 receptor accessory protein. PNAS 107(37) 16280-16285; doi:10.1073/pnas.1004408107
 Askmyr et al. (2013) Selective killing of candidate AML stem cells by antibody targeting of IL1RAP Blood 121: 3709-3713
 Ågerstam, H. et al. (2015) Antibodies targeting human IL1RAP (IL1R3) show therapeutic effects in xenograft models of acute myeloid leukemia PNAS 112 (34) 10786-10791; doi:10.1073/pnas.1422749112
 Ågerstam H, et al. (2016) IL1RAP antibodies block IL1-induced expansion of candidate CML stem cells and mediate cell killing in xenograft models. Blood (prepublished 12/9-2016); doi: 10.1182/blood-2015-11-679985
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