MMP-9 in Inflammatory Bowel Disease (IBD) and in Metastatic Cancers
Crohn’s Disease (CD) and Ulcerative Colitis (UC) are relapsing/remitting inflammatory diseases of the gut. Although currently prescribed medicines exhibit some efficacy, the quality of life of treated CD and UC patients is poor and surgical intervention is often required to cope with complications.
Despite considerable progress has been made in treatment over the past three decades, patient outcomes for metastatic cancers remain poor underlining the need for further advances.
Calypso Biotech intends to develop a first-in-class drug, which will:
- attenuate intestinal inflammation and will circumscribe the manifestation of complications in IBD.
- control primary tumor growth and metastatic progression.
MMP-9 is a member of the matrix metalloproteinase (MMP) family, which consists of 25 structurally related zinc-dependent endopeptidases.
MMP-9 degrades extracellular matrix (ECM) proteins and processes a number of bioactive molecules. Consequently, MMP-9 plays a major role in inflammation and tissue damage.
MMP-9 is involved in several biological pathways, such as cell migration, angiogenesis, inflammation, tissue remodeling and fibrosis. As a result, MMP-9 is an attractive target for numerous pathologies, from auto-immune and inflammatory diseases to fibrotic diseases and metastatic cancers.
Inflammatory bowel disease (IBD)
Inflammatory bowel disease (IBD) develops due to a combination of genetic predisposition (leading to immunological abnormalities), dysbiosis of the gut microbiota and environmental influence. IBD is characterized by a chronic inflammation of the intestine and consists of two main forms: ulcerative colitis (UC) and Crohn’s disease (CD). The inflammation in CD can affect any part of the gastrointestinal tract, whereas in UC it is restricted to the colon. IBD symptoms include diarrhea, abdominal pain, fever, rectal bleeding and weight loss, as well as complications such as intestinal obstructions, intestinal abscesses and fistulas. Over 1 million people in the USA and 2.5 million in Europe are believed to suffer from IBD.
The medical management of IBD patients is a stepwise approach, starting with non-steroid anti-inflammatory drugs (sulfasalazine) for the induction of remission. The second step is often corticosteroids, which tend to provide rapid relief of symptoms and a significant decrease in inflammation. Immunosuppressors are then used if steroids fail or are required for prolonged maintenance. Anti-TNFα antibodies are currently the most efficacious steroid-sparing drugs for the maintenance of remission. However, in CD only 60% of patients respond to treatment and after one year, only 25% of these patients remain in remission. This highlights the need for alternative treatments for CD patients who are anti-TNFα non-responders.
Blocking MMP-9 in IBD
In the inflamed mucosa of patients with IBD, MMP-9 is the most abundantly expressed protease and its activity correlates with disease severity. MMP-9 triggers disruption of mucosal barriers, recruitment of activated leukocytes and tissue destruction, all of which lead to fibrosis, strictures and/or fistulae.
Calypso Biotech has demonstrated that its CALY-001 anti-MMP-9 development candidate antibody was efficient in a mouse model of IBD (DSS-induced colitis).
Metastatic cancer is a cancer that has spread from the part of the body where it started (the primary site) to other parts of the body.
Virtually all cancers can form metastatic tumors, which are often responsible for death.
Metastatic cancer are currently treated with systemic therapy (chemotherapy, antibody therapy, targeted therapy, hormonal therapy), local therapy (surgery, radiation) or a combination of these treatments. However, the cure rates are low because metastases have often affected several organs and are inoperable.
Main sites of metastases for some common cancer types
Anti-MMP-9 antibody to limit tumor growth and metastasis
MMP-9, secreted by tumor or non-tumor cells, is a unique target in oncology since it mediates almost all steps of cancer metastasis, from primary tumor growth, cancer cell entry into lymph and blood vessels, to migration into other organs. MMP-9 also facilitates angiogenesis, the growth of new vessels which is crucial for the constant supply of oxygen and nutrients to tumors.
Calypso Biotech has demonstrated that its CALY-001 anti-MMP-9 development candidate antibody was efficient in a mouse model of metastatic cancer.
Successive MMP-9-mediated biological events leading to cancer metastasis