Oncojans™ are a new class of immunotherapeutic drug-loaded particles that target and gain entry to the tumour vasculature and cancer cells. They do this by taking advantage of the CD95L surface ligand that is selectively and heavily expressed in tumour vasculature and cancer cells but not healthy tissue. CD95L promotes tumour immune evasion, cancer cell proliferation and metastasis. It is an essential gene for cancer survival and promotes cancer stem cells. High levels of CD95L expression in patient tumours are associated with increased malignancy and poor prognosis. Once inside CD95L+ve tumour cells, Oncojans™ slowly release therapeutic drugs at the point of need whilst sparing healthy tissue. The oncojan™ platform is compatible with a range of drug classes from small molecule therapeutics to larger biologicals.
BMT101 is BioMoti’s showcase lead Oncojan™ based ovarian cancer candidate that has shown very promising potential in early preclinical studies; low toxicity and very high efficacy. BMT101 is very likely to be active in a greater number of CD95L+ve tumour types and BioMoti is seeking to develop further API-Oncojan™ candidates in collaboration with established drug developers.
Tissue level | CD95R inhibits CD95L, targets and sustains drugs at tumours
Cell level | CD95R inhibits CD95L, targets and sustains drugs at tumours
Growing literature on the role of CD95R/CD95L system in tumour biology
The CD95 receptor (Fas, APO-1) was first discovered by Peter Krammer and his team at the German Cancer Research Centre in Heidelberg, Germany [Trauth BC, Klas C, Peters AM, Matzku S, Möller P, Falk W, Debatin KM, Krammer PH. Monoclonal antibody-mediated tumor regression by induction of apoptosis. Science 1989;245:301-5]. It was subsequently cloned by Shigekazu Nagata and his team at the Osaka Bioscience Institute in Japan [Watanabe-Fukunaga R, Brannan CI, Itoh N, Yonehara S, Copeland NG, Jenkins NA, Nagata S. The cDNA structure, expression, and chromosomal assignment of the mouse Fas antigen. J Immunol 1992;148:1274–1279] who also went on to describe and clone its natural ligand CD95L (FasL, APO-1L) [Suda T, Takahashi T, Golstein P, Nagata S. Molecular cloning and expression of the Fas ligand, a novel member of the tumor necrosis factor family. Cell 1993;75:1169-78].
The CD95R ‘death’ receptor has classically been described for its role in apoptosis following ligation to its ligand CD95L [Nagata S. Apoptosis by death factor. Cell 1997;88:355-65]. This is an important mechanism of tissue maintenance and cellular homeostasis. However, CD95L has now been shown to be commonly and selectively overexpressed on cancer cells and tumour vasculature where it is tumourigenic, promotes metastasis and immune evasion. It has been shown to be an essential gene for tumour survival and to have a role in the promotion and protection of cancer stem cells.
World-class scientists continue to advance our knowledge of CD95R/CD95L tumour biology and it is already very clear that targeting this system represents a new and exciting prospect to develop new treatments for cancer. Here is a selection of studies from key groups around the world working on various topics with important implications in CD95R/CD95L tumour biology:
Cancer stem cell
CD95L reverse signalling