AC BioScience has three drugs in development for fighting cancer.
Frequent failures of chemotherapy treatments in clinical applications are due to their inability to reach the tumor cells, particularly if the vascular network has been impaired.
S.1.p metabolism modulators act as a tumor vascular normalizer. They work by re-instating a functional vascular network, thereby improving the blood flow to – and oxygenation of – tumor tissue, which in turn improves the effectiveness of conventional chemo- and radiotherapy. We therefore expect this neo-adjuvant therapy to significantly improve the efficacy for all types of chemotherapy (except those which include antiangiogenic molecules) and radiotherapy.
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.
Our patented Beta-carboline derivative (ACB1801) is an actin dynamic modulator which induces cellular F-actin network remodeling (tumor reversal); this in turn translates into immuno-competency that allows the immune system to recognize tumor cells and thereby enhances the efficacy of checkpoint-inhibitor immune therapy. Immune checkpoint-inhibitors directly target the immune system of the body and do not harm healthy cells in the process.
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), ACB1801 alone (ACB1801/iso), or a combination of ACB1801 and PD-L1 (ACB1801/PD-1). B16-F10 tumor do not respond to anti-PD-1 alone (Blue curve). ACB1801 significantly decreases the tumor growth (Red curve). However, combining anti-PD-L1 with ACB1801 dramatically improves the therapeutic benefit of anti-PD-L1 (Gray curve).
Our product is a new-generation CAP6 that shows great promise as a highly effective treatment for lung cancer (NSCLC). Lung cancer is one of the most widely prevalent cancers, and one of the most difficult to treat. Eighty-one percent of patients treated for lung cancer die within five years.
The target market for our CAP6 is cancer treatment using chemo- or radiotherapy, or a combination of both. Because of their cationic and amphipathic features, CAP6 (cationic amphipathic peptides) are recognized as novel cancer-targeted therapeutics, with significantly lower cost and fewer side effects. CAP6s represent the molecules of the future as a form of a cancer “biotherapy”, which is well-tolerated and effective.
Our CAP6 has achieved better scores in in vivo trials than the blockbuster lung-cancer drug Erlotinib.
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.
Our molecules are developed as therapeutic products to be used as single or combination treatments, or as part of a neo-adjuvant protocol.
The table below lists the molecules and their applications:
|Disease||Conventional treatment||Clinical status||Molecule/ Formulation||Regulatory status|
|Cancer||Chemotherapy||Treatment||Cationic Amphipathic Peptides||Drug|