SCIENCE OF nfP2X7
THE nfP2X7 ONCOLOGY TARGET
nfP2X7 is a cancer-specific form of the P2X7 ion channel that is located on the surface of some normal cells. P2X7 is a ligand gated ion channel, consisting of three identical protein subunits. In response to high concentrations of extracellular ATP, P2X7 forms a channel driving a range of diverse physiological functions including proliferation and immune cell functions. In response to prolonged ATP stimulation, at concentrations present routinely in the tumour micro-environment, P2X7 can form a membrane pore that is associated with induction of cell death. Published data also strongly links P2X7 to cancer cell survival and metastatic potential.
Dr Barden, a Biosceptre founder, has demonstrated that a different form of P2X7 is expressed by cancer cells. This form of P2X7 is unable to open the large pore that drives cell death. Hence, the expression of nfP2X7 enables cancer cells to survive in the tumour micro-environment where high and sustained levels of ATP would otherwise kill cells expressing fully functional P2X7. This conformationally distinct receptor identified by Biosceptre is termed nfP2X7 (non-functional P2X7).
Biosceptre has shown that nfP2X7 retains critical signalling capabilities that support cancer cell survival. Due to its modified conformation, nfP2X7 possesses novel epitopes that are available for antibody binding, and importantly, are not detected at the surface of functional P2X7. Targeting cancer cells via these nfP2X7 epitopes offers great specificity and is the basis of our technology.
Biosceptre has shown that nfP2X7 is widely expressed on over 20 types of cancer which together account for approximately 95% of cancers diagnosed by location and has developed therapeutics and diagnostics that target nfP2X7 selectively.
CAR-T CELL THERAPY
Biosceptre is developing a nfP2X7 targeted CAR-T for the treatment of haematological malignancies and solid tumour cancers.
CAR-T therapy works by collecting a small portion of the patient’s T-cells from the patient’s own blood (immune cells that help protect from infection and disease), re-engineering these in a specialised lab to produce chimeric antigen receptors (CARs) on the surface of the cells. After this reengineering, the T-cells are known as chimeric antigen receptor (CAR) T-cells. These CAR-T cells are then expanded and reinjected into the patient where they multiply and seek to identify and attack cancer cells throughout the body. CAR-T cell therapies have been shown to achieve durable clinical responses for some patients suffering from cancers refractory to standard therapies.
MONOCLONAL ANTIBODY THERAPY
Targeted monoclonal antibody therapy is a form of immunotherapy that uses monoclonal antibodies (mAb) to bind specifically to certain proteins on target cells, with the objective of modulating the patient’s immune system to attack and kill the cancer cells.
Over 30 antibody therapeutics in the form of mAbs alone or mAbs conjugated with a cytotoxic agent have been approved by the FDA for various oncology indications. However existing cancer therapies, including systemic antibodies, often demonstrate relatively poor efficacy and have a modest impact on quality of life. Recent developments with immunotherapies such as checkpoint inhibitors have been very encouraging, but side effects, as well as lack of response and relapse continue to be significant problems, and the unmet need for therapies that can make a meaningful difference remains high.
Biosceptre is developing a human monoclonal antibody targeting nfP2X7 for use in both solid and haematological tumours. In early preclinical data the ability to reduce tumour growth and inhibit metastasis has been shown. Formal toxicology studies have demonstrated an excellent safety profile supporting the approval of a phase 1 clinical trial in Australia, which we plan to pursue following further optimisation of the product.
PUBLISHED PAPERS & PRESENTATIONS
- ATP in the tumour microenvironment drives expression of nfP2X7, a key mediator of cancer cell survival
SM Gilbert, CJ Oliphant, S. Hassan, AL Peille, P. Bronsert, S. Falzoni, F. Di Virgilio, S. McNulty, R. Lara
A phase I clinical trial demonstrates that nfP2X7-targeted antibodies provide a novel, safe and tolerable topical therapy for basal cell carcinoma
S.M. Gilbert, A. Gidley Baird, S. Glazer, J.A. Barden, A. Glazer , L.C. Teh, J. King
Markers for the development of early prostate cancer
Slater MD, Lauer C, Gidley-Baird A, Barden JA; J Pathol 2003- 199, 368-377
Increased Expression of apoptotic markers in melanoma
Slater M, Scolyer RA, Gidley-Baird A, Thompson JF, Barden JA; Melanoma Research 2003, 13-137 – 145
Genetic Polymorphisms of the Human P2X7 Receptor and Relationship to Function
Wiley JS, Gu BJ, Zhang W, Worthington RA, Dao-Ung P, Shemon AN, Sluyter R, Liang S, Barden JA
- Early prostate cancer detected using expression of non-functional cytolytic P2X7 receptors
Slater M, Danieletto S, Gidley-Baird A, Teh LC, Barden JA; Histopathology 2004, 44, 206-215
- Differentiation between cancerous and normal hyperplastic lobules in breast lesions
Slater M, Danieletto S, Pooley M, Teh LC, Gidley-Baird A, Barden JA; Breast Cancer Research & Treatment 83- 1-10, 2004
- Differentiating keratoacanthoma from squamous cell carcinoma by the use of apoptotic and cell adhesion markers
Slater M, Barden JA; Histopathology 2005, 47, 170-178
- Detection of preneoplasia in histologically normal prostate biopsies
Slater MD, Delprado WJ, Murphy CR, Barden JA; Prostate Cancer Prostatic Dis. 2001, 4(2) 92-96
An Ile-568 to Asn Polymorphism Prevents Normal Trafficking and Function to the Human P2X7 Receptor
Wiley JS, Dao-Ung LP, Li C, Semon AN, Gu BJ, Smart ML, Fuller SJ, Barden JA, Petrou S, Sluyter R
- Non-Functional P2X7: A Novel and Ubiquitous Target in Human Cancer
Julian A. Barden, Aysen Yuksel, John Pedersen, Suzanne Danieletto, Warick Delprado; J Clin Cell Immunol 2014, 5:4
- Therapeutic Targeting of the Cancer-Specific Cell Surface Biomarker nfP2X7
Julian A Barden, Angus Gidley-Baird1, Liew Cheng Teh, G-Halli Rajasekariah, John Pedersen, Neil I Christensen, Derek Spielman, David M Ashley; J Clin Cell Immunol 2016, 7:3