Growth factor midkine is emerging as an important disease target, being key to the pathogenesis of diseases of high medical need, including chronic autoimmune and inflammatory disorders, osteoporosis, renal and cardiovascular disease, and cancer. While it does not play an active role in healthy adults, circulating midkine levels are elevated in response to tissue injury or stress, forming part of the body’s response to damage. This response is an important part of the process of repair and recovery from injury, which is normally self-limiting.
Midkine is expressed by lymphocytes and epithelial cells. There is a reservoir of midkine present in the lining of blood vessels.
In chronic conditions, or in response to repeated insult, midkine levels remain elevated and the inflammatory response persists, leading to chronic tissue damage, and progressive disease.
Biological effects of elevated circulating midkine levels include:
- Recruiting inflammatory lymphocytes to tissue
- inducing NETosis of neutrophils that were recruited to inflamed tissue
- Enhancing B cell survival
- Reducing Regulatory T-cells and inducing Th1 and Th17 cells
- Inhibition of apoptosis and autophagy
- Inhibition of bone formation
- Induction of fibrosis
Since midkine was identified as a potential disease target in the late 1980s, an expanding number of research groups worldwide are working on building the understanding of the role of midkine in disease, resulting in a body of over 900 publications.
Lyramid has been involved in much of this research through a collaborative network of leading international clinicians and scientists and has built a strong portfolio of patents around midkine neutralizing antibodies and their use in disease.
Midkine receptors, signaling and related diseases
Midkine interacts with several cell surface proteins (eg PTPRz, ALK, notch and LRPs) that regulate downstream signaling cascades important for response to tissue injury, cell survival, inflammatory processes, organ development and cell differentiation. The ability of midkine to bind such structurally diverse proteins is mediated by the glycosaminoglycan modifications present on cell surface proteins.
Midkine also regulates cell-cell interactions by forming protein complexes with several cell surface proteins. For example, midkine is part of a complex including integrins, ICAM-1 and LRP1 involved in neutrophil arrest on vascular endothelial cells and their penetration into tissues during inflammation.
While midkine contributes to primary disease progression in discrete organs, in more complex disorders involving inter-organ dysfunction such as cardiovascular disease associated with chronic kidney disease, midkine mediates more complex systemic pathophysiology including hypertension and left ventricular hypertrophy that contribute to heart failure. Therefore, targeting midkine has considerable therapeutic potential for several diseases of high unmet need.
Lyramid has identified a series of antibodies that block the activity of midkine and is developing these as novel drugs for treatment of autoimmune disorders, inflammatory diseases, osteoporosis and cancer.