AC BioScience: 2 drugs in development for fighting cancer S.1.p & CAP6

Pipeline

AC BioScience has three drugs in development for fighting cancer.

Sphingosine 1-phosphate lyase inhibitor – ACB2003.4

Our medical objective is to validate and bring to clinical use, a novel approach to improve the treatment of metastatic pancreatic adenocarcinoma using a proangiogenic molecule S1P lyase inhibitor acting as a tumor vascular normalizer.

Our S1P lyase inhibitor ACB2003.4, patented for oncology applications, is a repurposed molecule LX2931/LX3305 originally developed by Lexicon Pharmaceuticals Inc. in the United States for the treatment of rheumatoid arthritis. All pre-clinical and regulatory studies were completed for this molecule in accordance with U.S. regulatory guidelines, and Phase 1 and 2 clinical studies were conducted under an Investigational New Drug application (IND). As part of a collaboration agreement with Lexicon Pharmaceuticals Inc., we have now been granted the rights to use this drug in oncology applications and to make use of all their previous pharmacological, CMC and clinical trial Phase 1 data; favourable comments received from a Scientific Advice submitted to the European Medicines Agency (EMA) for oncology applications now clears the way for a CTA to the regulatory authority in France to commence with a clinical trial Phase 2/3 in mid-2022. Clinical trials will be carried out at the Salpétrière Hospital in Paris.

A successful clinical proof of concept study in metastatic pancreatic adenocarcinoma patients would provide a premise for a similar strategy to be implemented for all poorly vascularized solid tumors, thus, providing a transformative new standard for cancer treatment.

The science behind ACB2003.4

Pancreatic cancer is characterized by excessive dense extracellular matrix deposition associated to vascular collapse and hypoxia with low
drug delivery, explaining at least partly the low efficacy of antiangiogenic drugs in this cancer (Longo et al. 2016, Katsuta et al., 2019).

Frequent failures of chemotherapy treatments in clinical applications are due to their inability to reach the tumor cells, particularly in instances of a vascular disruption of abnormal tumor vessels. Re-instating vascular normalization is therefore one of the key prerequisites for efficient therapy.

The proangiogenic S1P metabolism modulators act as a tumor vascular normalizer. They work by re-building a functional vascular network, thereby improving the blood flow to – and oxygenation of – tumor tissue. Along these lines, and based on clinical observations, the company has developed a new paradigm – in contrast to the prevailing antiangiogenic doctrine – in the form of a neo-adjuvant therapy using a proangiogenic molecule acting as a tumor vascular normalizer and in fine improving drug delivery and treatment efficacy for all type of chemotherapy (except those with antiangiogenic molecules) and radiotherapy. Experimental proof of concept has been demonstrated both in clinical observations and also in a mouse model bearing a pancreatic adenocarcinoma where the combination of gemcitabine and S1P lyase inhibitor displayed a strong antitumor superiority compared to gemcitabine alone.

A functional plasmatic biomarker has been identified, allowing the selection of a subpopulation of eligible patients for such therapy.

Schematic representation of tumor vasculature abnormalities

Beta-carboline derivative (ACB1801)

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.

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), 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).

Cationic amphipathic peptide (CAP6)

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.

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 S1P lyase inhibitors, Beta-carboline derivatives and our CAP6.