Lyramid has invested approximately A$40 million in over 10 years of extensive research studies demonstrating that the blocking of Midkine promotes a positive response from cells when fighting various diseases including severe inflammatory diseases, autoimmune disorders and cancer.
Since its discovery, Midkine and its role in many disease processes has been the subject of over 1,000 scientific publications by an active, integrated network of international researchers (Source: PubMed). From early papers by Professors Muramatsu and Kadomatsu (Nagoya University) characterising the Midkine gene as a highly expressed factor critical for embryonic development, multiple subsequent studies have revealed that Midkine is involved in the pathological mechanisms that operate in many diseased organs examined thus far, including many cancers and severe inflammatory diseases.
A series of papers demonstrated that Midkine contributes to kidney, chronic cardiac, lung and liver diseases; autoimmune disorders; osteoporotic fracture healing; neural injury and neurodegenerative disorders. In oncology, elevated Midkine is a biomarker for all solid and haemotological cancers examined thus far. Blocking Midkine with small molecule inhibitors, antibodies, gene silencing and decoy proteins consistently slows tumour growth, reduces metastasis and importantly overcomes treatment resistance, especially immunotherapy with immune checkpoint inhibitors. Conversely, Midkine plays a beneficial protective and regenerative role in the early stages of acute coronary heart events and stroke, as well as retinal injury. These studies were the subject of a special edition of the British J Pharmacology and the book entitled “Midkine, from pathogenesis to embryogenesis and therapy”, as well as many reviews.
The original murine antibodies acquired from Cell Signals Inc. in 2008 have been further developed against human Midkine in preparation for clinical deployment. This gave rise to corresponding patent applications covering N-domain specific antibodies and the humanised C-domain antibody designated as CAB102. The N-domain Midkine antibodies were shown to be effective in preclinical models of bone fracture healing, autoimmune myocarditis, chronic kidney disease and cancer metastasis. A humanised N-domain antibody (CAB104) has also been developed and shown to bind with high affinity to the Midkine protein. Their ability to inhibit inflammatory processes, especially recruitment and activation of neutrophils, combined with previous studies showing Midkine’s role in repressing T regulatory cells demonstrated the therapeutic potential of targeting Midkine in chronic inflammation and autoimmunity.
An important insight into the way Midkine contributes to the deleterious cross-talk between organs leading to complex syndromes was the hypertension that results from elevated Midkine in lungs of animals secondary to kidney failure (J Clinical Investigation 2009). A consistent feature of Midkine is the promotion of defective inflammatory and immune responses that underpin most chronic diseases. Recent examples of significant publications demonstrating this include evidence of Midkine rewiring tumour immune cells causing resistance to immunotherapy drugs in cancer patients (Nature Medicine, 2020), Midkine’s role in neurone-immune-cancer axis in glioma (Nature Communications 2020), in sleep apnea in melanoma patients (FASEB J 2020), in pulmonary arterial hypertension (Science Reports 2020), in the recruitment and activation of neutrophils in autoimmune heart failure (J Experimental Medicine 2019), and in melanoma metastasis (Nature 2017).