Technology



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

Tumour oncojans

 

 

Cell level | CD95R inhibits CD95L, targets and sustains drugs at tumours

 

Cell oncojans

 

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:

Immune evasion

  • Green DR, Ferguson TA. The role of Fas ligand in immune privilege. Nat Rev Mol Cell Biol. 2001;2:917-24
  • Ryan AE, Shanahan F, O’Connell J, Houston AM. Addressing the “Fas counterattack” controversy: blocking fas ligand expression suppresses tumor immune evasion of colon cancer in vivo. Cancer Res 2005;65:9817-23
  • Ryan AE, Shanahan F, O’Connell J, Houston AM. Fas ligand promotes tumor immune evasion of colon cancer in vivo. Cell Cycle 2006;5:246-9
  • Motz GT, Santoro SP, Wang LP, Garrabrant T, Lastra RR, Hagemann IS, Lal P, Feldman MD, Benencia F, Coukos G. Tumor endothelium FasL establishes a selective immune barrier promoting tolerance in tumors. Nature Medicine 2014;20:607–615

Proliferation

  • Chen L, Park SM, Tumanov AV, Hau A, Sawada K, Feig C, Turner JR, Fu YX, Romero IL, Lengyel E, Peter ME. CD95 promotes tumour growth. Nature 2010;465:492
  • Hadji A, Ceppi P, Murmann AE, Brockway S, Pattanayak A, Bhinder B, Hau A, De Chant S, Parimi V, Kolesza P, Richards J, Chandel N, Djaballah H, Peter ME. Death induced by CD95 or CD95 ligand elimination. Cell Reports 2014;7:208-222

Cancer stem cell

  • Ceppi P, Hadji A, Kohlhapp FJ, Pattanayak A, Hau A, Liu X, Liu H, Murmann AE, Peter ME. CD95 and CD95L promote and protect cancer stem cells. Nat Commun 2014;5:5238

CD95L reverse signalling

Nanomedicine

  • Ateh DD, Leinster VH, Lambert SR, Shah A, Khan A, Walklin HJ, Johnstone JV, Ibrahim NI, Kadam MM, Malik Z, Gironès M, Veldhuis GJ, Warnes G, Marino S, McNeish IA, Martin JE. The intracellular uptake of CD95 modified paclitaxel-loaded poly(lactic-co-glycolic acid) microparticles. Biomaterials 2011;32:8538-47
  • Lu YM, Huang JY, Wang H, Lou XF, Liao MH, Hong LJ, Tao RR, Ahmed MM, Shan CL, Wang XL, Fukunaga K, Du YZ, Han F. Targeted therapy of brain ischaemia using Fas ligand antibody conjugated PEG-lipid nanoparticles. Biomaterials. 2014;35:530-7

Clinical expression

Ovarian cancer:

  • Munakata S, Enomoto T, Tsujimoto M, Otsuki Y, Miwa H, Kanno H, Aozasa K. Expressions of Fas ligand and other apoptosis-related genes and their prognostic significance in epithelial ovarian neoplasms. Br J Cancer 2000;82:1446-52
  • van Haaften-Day C, Russell P, Davies S, King NJ, Tattersall MH. Expression of Fas and FasL in human serous ovarian epithelial tumors. Hum Pathol 2003;34:74-9
  • Abrahams VM, Straszewski SL, Kamsteeg M, Hanczaruk B, Schwartz PE, Rutherford TJ, Mor G. Epithelial ovarian cancer cells secrete functional Fas ligand. Cancer Res 2003;63:5573-81
  • Minas V, Rolaki A, Kalantaridou SN, Sidiropoulos J, Mitrou S, Petsas G, Jeschke U, Paraskevaidis EA, Fountzilas G, Chrousos GP, Pavlidis N, Makrigiannakis A. Intratumoral CRH modulates immuno-escape of ovarian cancer cells through FasL regulation. Br J Cancer 2007;97:637-45
  • Hasby EA. Weapons ovarian epithelial tumors may use in immune escape: an immunohistochemical correlational study. Pathol Oncol Res 2012;18:509-18

Clinical intervention

  • Tuettenberg J, Seiz M, Debatin KM, Hollburg W, von Staden M, Thiemann M, Hareng B, Fricke H, Kunz C. Pharmacokinetics, pharmacodynamics, safety and tolerability of APG101, a CD95-Fc fusion protein, in healthy volunteers and two glioma patients. Int Immunopharmacol 2012;13:93-100
  • Wick W, Fricke H, Junge K, Kobyakov G, Martens T, Heese O, Wiestler B, Schliesser MG, von Deimling A9, Pichler J, Vetlova E, Harting I, Debus J, Hartmann C, Kunz C, Platten M, Bendszus M, Combs SE. A phase II, randomised, study of weekly APG101 + reirradiation versus reirradiation in progressive glioblastoma. Clin Cancer Res 2014; Epub ahead of print