Dr Reimar Abraham, Lead Discovery Center GmbH; Dr Johannes Bange, Lead Discovery Center GmbH; Prof. Matthias Ernst, Olivia Newton-John Cancer Research Institute; Dr Tracy Putoczki, Walter & Eliza Hall Institute of Medical Research
Lead Discovery Center
Persistent STAT3 activity leads to promoted survival and proliferation of neoplastic epithelium. It has been shown that aberrant activation of the GP130/STAT3 pathway in cancer cells is mainly triggered by a cytokine-rich tumor microenvironment (TME) rather than accumulation of oncogenic activating mutations in that pathway. Therefore, much attention has been given on the IL-6 cytokine family which is known to induce cancer development. To date, therapeutic antibodies against IL-6 (Siltuximab) and IL-6R (Tocilizumab) have been approved for inflammatory diseases. These antibodies are now tested for anti-cancer applications.
Recently, however, Putoczki et al proved a major role of IL-11 over IL-6 in gastric and colon cancer development. Using a homozygous gp130Y757F/Y757F mutant mouse model, where the negative regulator SOCS3 binding site of GP130 is mutated and therefore GP130 signaling is over-activated, they detected sporadic gastric and – after azoxymethane (AOM) application - colon tumor formation and elevated Il6 and Il11 expression. After genetic inhibition of GP130/STAT3 signaling in gp130Y757F/Y757F mice using Stat3+/-, Il6 or Il11ra1 knockouts, significantly less sporadic tumors are formed in Stat3+/- and Il11ra1-/- mice but not in Il6-/- mice. Ernst & Putoczki hypothesized that the epithelial cell population in the gastrointestinal (GI) tract respond to IL-11 rather than IL-6 and that IL-11 directly stimulates proliferation of neoplastic epithelium in the gastrointestinum.
The overall targeting strategy of IL-11 is the generation of highly affine, neutralizing monoclonal IgG IL-11 antibodies to block IL-11/GP130/STAT3 signaling in tumor cells which leads to the transcription of target genes influencing tumor cell proliferation and survival, and inducing angiogenesis and invasive/metastatic growth. With the support of Prof. M. Ernst and Dr. Tracey Putoczki, LDC will focus on testing IL-11 therapeutic antibody candidates in gastric and colon tumor models. For such preclinical proof-of-concept studies, selected antibodies have to be human/mouse cross-reactive.
Colon (CRC) and Gastric Cancer are among the five third leading causes of cancer deaths in the United States in 2014 and the overall 5-year survival is roughly 65% and 10% respectively. For CRC surgery is still first standard-of-care treatment option. However, there is a desperate unmet medical need for unresectable advanced stages of CRC where chemotherapy and Avastin treatment leads to modest increase in survival times only. In addition, potential combination strategies of anti-IL-11 – in contrast to anti-IL-6 – treatment with cancer immunotherapeutics are not contradictive but rational for improved outcome.
Gastric tumors are often diagnosed in advanced or late stages because symptoms occur late. Novel treatment options besides surgery, radiation or chemotherapy are urgently needed for those stages.
In addition to colon and gastric cancer, a potent anti-IL-11 antibody can be exploited for treating other cancer types where IL-11 levels were shown to correlate with poor prognosis .
IL-11 antibody has been started beginning of 2017. All in vitro assays have been successfully established and a first immunization campaign of rats and mice took place in July 2017. Currently a selection of antibody candidates is under investigation and first promising candidates are being characterized.
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Ernst, M., & Putoczki, T. (2014). Molecular Pathways: IL11 as a Tumor-Promoting Cytokine--Translational Implications for Cancers. Clinical Cancer Research, 20