PCNA-targeted anti-cancer therapy based on NKp44-derived peptides

Introduction:

Proliferating Cell Nuclear Antigen (PCNA) is considered as a hub protein and is a key regulator of DNA replication, repair, cell cycle control and apoptosis. PCNA is over-expressed in many cancer types and PCNA-overexpression is correlated with cancer virulence. Membrane-associated PCNA is a ligand for the NKp44 (NCR2) innate immune receptor. We have identified NKp44-derived linear peptide (pep8), which can specifically interact with PCNA and partly block the NKp44-PCNA interaction. We then tested whether NKp44-derived pep8 fused to cell-penetrating peptides can be employed for targeting the intracellular PCNA for the purpose of anti-cancer therapy. Treatment of tumor cells with NKp44-derived pep8, fused to R11-NLS cell penetrating peptide (R11-NLS-pep8), reduced cell viability and promoted cell death, in a variety of murine and human cancer cell lines. Administration of R11-NLS-pep8 to tumor-bearing mice suppressed tumor growth in the 4T1 breast cancer and the B16 melanoma in vivo models. We therefore identified an NKp44-peptide based agent that can inhibit tumor growth through interfering with the function of intracellular PCNA in the tumor cell. This peptide has double-sward action since by pinpointing NKp44’s binding domain to PCNA, it might be also possible to restore NK’s desirable immunological actions against the cancer cells.

The Technology:

Using a peptide screen approach of the extracellular domain of NKp44, we have identified a peptide derived from NKp44 receptor that demonstrates selective binding to recombinant PCNA. Furthermore, some of these peptides demonstrated highly effective blockade of binding of NKp44 towards PCNA. We further modified the original peptide sequence in order to make it more potent to destroy cancer cells. Thus we created a candidate compound peptide that can both destroy cancer cells by inhibiting PCNA activity and curb cancer cells inhibitory effect on NK cells by interfering with the NK44-PCNA interaction. Proof of concept in breast cancer and melanoma mouse animal models has been shown.

Advantages:

• Peptide blocking tumor-associated PCNA functions in cancer cells over-expressing PCNA can be employed as a drug for variety of solid and leukemic cancers.
• PCNA can be considered as a “hub” protein regulating growth of cancer cells as well as cancer cell response to cellular stress induced by other therapies such as chemotherapies.
• Over-expressed PCNA likely serves as a decoy mechanism that allows cancer cells to evade immune attack by NK cells. By pinpointing NKp44’s binding domain to PCNA, it might be possible to restore NK’s desirable immunological actions against the cancer cells.

Patent Status:

Patent family 1: US Patent No. 9,399,667, European Patent Application No. EP3211002- Pending.

Patent family 2: International patent application No. PCT/IL2017/051352- Pending.

Principal Investigators:

Professor Angel Porgador, NIBN and the Shraga Segal Department of Microbiology Immunology and Genetics, Faculty of Health Sciences, Ben-Gurion University of the Negev, Israel.

For further information, please contact us at: E-mail: nibn@bgu.ac.il , Tel.: +972-8-647-7193