TR1 Restores Cell Death (Apoptosis) to Cancer Cells
SELLAS’ second lead oncology product candidate, TR1, is designed to eradicate cancer stem cells (CSCs) to prevent tumor recurrence and metastasis. SELLAS’ TR1 therapeutic specifically targets tumor cells with mutations of the p21 gene that have resulted in the loss of apoptotic function. In this approach, TR1 has been designed to deliver the functioning p21 protein into tumor cells by utilizing a patented transporter protein technology. Once inserted, p21 restores the ability for cancer cells to undergo cell death via the p53 pathway. There are no adverse effects on normal cells, which already are regulated by their own p21.
Preclinical in vivo research has shown that restoring the function and activity of p21 within CSCs can suppress tumor development by inducing apoptosis. A Phase 1 study of TR1 is anticipated in 2Q 2016.
TR1 Mechanism of Action
SELLAS’ TR1 product candidate is designed to enable the reactivation of the p53 pathway. P53 is one of the most important tumor suppressors, but it is inactivated in virtually all cancers.
P21, a potent cyclin-dependent kinase inhibitor, is instructed by p53 to suppress tumor creation and growth by stopping proliferation and removing damaged cells.
TR1 Engineering and Development
Targeted cancer therapies currently in development or on the market are unable to reach every single cancer cell, and most do not enter and cross through the Blood-Brain-Barrier (BBB). In developing its TR1 therapeutic approach, SELLAS set out to address this challenge by creating a novel therapy that combines the normal wild type p21 with ANTP (Antennapedia protein). ANTP is a non-toxic substance that mediates transmembrane transport and is able to “carry” p21 across cell membranes, including cells in the BBB, and into the nucleus. Additional characteristics include:
- SELLAS’ TR1 therapeutic serum half-life is relatively short because it rapidly enters surrounding cells.
- Research has shown, that once intracellular, TR1 can travel from cell to cell, establishing an extended intracellular half-life with most relevance for therapeutic activity.
- Effective dose levels have been found to be comparable to other biological drugs such as monoclonals.
Testing in drug-resistant cell lines also has shown activity as a single agent; however, TR1 is currently being developed for combination use with conventional chemotherapy with the goal of showing additional synergy with no added toxicity and without further inconveniencing the patient.