The science behind S.1.p
Given the role that it plays in the progression of tumors, angiogenesis has become one of the most attractive targets for developing treatments in the domain of oncology. However, the efficacy of antiangiogenic therapy remains questionable, and there is an accumulation of evidence indicating that inducing hypoxia in tumors favors the invasion processes leading in fine to metastasis. Hypoxia increases the glycolysis and pentose cycle, promotes epithelial to mesenchymal transition, increases metalloprotease activity, increases growth-factor expression and favors the occurrence of a protumoral immune microenvironment. Furthermore, it is clear that the vascular disruption of abnormal tumor vessels impairs the efficient delivery of chemotherapeutic agents, while decreasing tumor radiosensitivity and immunotherapy efficiency.
Along these lines, and based on clinical observations, the company has developed a paradigm-shifting approach – in contrast to the prevailing antiangiogenic doctrine – in the form of a neoadjuvant therapy using a proangiogenic molecule acting as a tumor vasculature normalizer.
A functional plasmatic biomarker has been identified, allowing the selection of a subpopulation of eligible patients for such therapy.
This strategy is under pre-clinical investigation in collaboration with a research team located at the University of Geneva (UNIGE). A Scientific Advice is being sought from the FDA and ANSM on the use of existing safety data for this re-purposed drug.
Schematic representation of tumor vasculature abnormalities
The science behind ACB1801
Cancer cells are known to co-opt the checkpoints – in effect “hacking” the immune system – by sending out false signals indicating that the cells are healthy; this with the result that the T-cells are shut down, thus preventing the immune system from attacking the tumor cells. Checkpoint-inhibitors deactivate the “brakes” and allow the T-cells to get moving again.
Preventing tumors to evade the immune surveillance requires a high expression in cells of TAP and a high level of MHC-1, with an appropriated MHC-1 mediated antigen presentation pathway.
To restore both TAP1 and MHC-1 presentation after loss of tumor phenotype characters, ACB1801 induces genetic and epigenetic modifications. ACB1801, thanks to the restoration of the actin cytoskeleton network in tumor cells, favors the trafficking of antigenic peptides and increases the MHC-1 expression at the tumor cell membrane.
ACB1801 has shown very promising results in the melanoma B16-F10 mouse model, where it displays non cytotoxic, immune-mediated antitumor effect and a strong potentiation of an anti PD-1 antibody (see chart).
T lymphocyte activation through the tumor antigens presentation pathway
TAP : Transport antigen protein | ER : Endoplasmic reticulum
MHC-1 : Major histocompatibility complex class I | TCR: T cell receptor
Antitumor efficiency of ACB1801 on B16 melanoma administred alone or in combination with anti-PD-1
Tumor growth (left) and weight (right) of B16-F10 melanoma in untreated mice (vehicle/iso), and in mice treated with either anti-PD-1 alone (Vehicle/PD-1), ACB-1801 alone (ACB-1801/iso), or a combination of ACB-1801 and PD-L1 (ACB-1801/PD-1). B16-F10 tumor do not respond to anti-PD-1 alone (Blue curve). ACB-1801 significantly decreases the tumor growth (Red curve). However, combining anti-PD-L1 with ACB-1801 dramatically improves the therapeutic benefit of anti-PD-L1 (Gray curve).
The science behind our CAP6
Our CAP6 belongs to a new generation of cancer drugs having few side effects and generally greater efficacy. It displays a dual mechanism of action, specifically targeting tubulin and membranes of tumor cells, with low toxicity for normal cells. CAP6s bind to cancer cells by electrostatic interaction, and this leads to cytotoxicity of cancer cells.
Originally developed for the treatment of non-Hodgkin lymphomas, our CAP6 has since been tested ex vivo for its anti-proliferative properties on 33 tumor cells, and has achieved the best scores in 17 instances. When tested in vivo it showed a significant improvement in terms of reduced lung tumor volume in mice when compared to Erlotinib. Based on the results of a pharmacological test initiated in March 2018, the protocol for the pre-clinical regulatory work has been drawn up, followed by a Phase I/II trial.
CAP 6 acts as a taxol-like molecule specifically on tumor cells
Effect of CAP6 on tubulin network in A 549 tumor cells (upper pictures) or normal human fibroblasts (lower pictures). A549 cells were incubated in the absence or the presence of 15 μM CAP6. Tubulin structures(green) were immunostained with an anti-α-tubulin.
Validation Stages and Timelines
The graphic below shows the stages and timelines for S.1.p, Beta-carboline and our CAP6.
