TAT-S216A is a unique cell-permeable peptide designed from a peptide sequence found in CDC25C, a key phosphatase that regulates G2 to M phase transition, and that abrogates the G2 checkpoint, of the cell cycle.
CBP501 is a version of TAT-S216A optimized for its G2 checkpoint abrogating activity by using a cell cycle phenotype-based screening method, proprietary to CanBas, which is designed to select helper compounds that increase the cytotoxicity of DNA damaging agents in the tumor cells, but not in normal cells.
CBP501 has been found to work by two modes of action:
(1) Calmodulin binding (ED50 ≈ 100nM):
Even with short treatment, this mode of action leads to
(a) increased platinum influx into and cytotoxicity of platinum to tumor cells,
(b) induced immunogenic cell death of tumor cells,
(c) suppression of macrophage activity,
(d) reduced populations of cancer stem cells, and
(e) reduced migration by and epithelial-to-mesenchymal transition (EMT) in tumor cells.
(2) Inhibition of CHK1, C-Tak and MAPKAPK2 (IC50 ≈ 1uM):
This mode of action leads to G2 checkpoint abrogation.
Not only does CBP501 enhance the inhibition of tumor growth by cisplatin, carboplatin, or bleomycin in vivo in a variety of mouse tumor xenograft models without significant adverse effects, but CBP501 also enhances the efficacy of several immune checkpoint inhibitors when these are used in combination with cisplatin or carboplatin.
In the CT-26 syngeneic mice model, use of CBP501 and a platinum agent with anti-PD1, anti-PDL1 or anti-CTLA4, synergistically suppress tumor growth and increases the CD8 T cell count and decreases the M2 macrophage count at tumor sites.
For more scientific information about MOA, please see References.
A Phase 1 clinical study using a combination of CBP501 and cisplatin showed the expected safety profile and promising signs of activity in platinum resistant/refractory ovarian cancer patients.
A Phase 2 clinical study achieved the primary efficacy end point, 4 mo. progression-free survival (PFS) rate, for the treatment of chemo-naive malignant pleural mesothelioma with CBP501 in combination with cisplatin and pemetrexed.
A randomized Phase 2 clinical study on the treatment of chemo-naive non-small non-squamous lung cancer led us to find that CBP501 works best in patient populations exhibiting normal WBC before treatment.
This finding also resulted in a new patent for using of this biomarker as part of a criterion for selecting patients for treatment.
A Phase 1b clinical study with the triple drug combination, CBP501, cisplatin and nivolumab, has been initiated in the United States at the end of 2017 and, although it is early, there are already possibly promising preliminary indications.