Necrotic foci are common anatomic and histologic features of human solid tumors, and these necrotic areas of solid tumors are generally anaerobic or hypoxic as compared with the normal tissues. The decreased vascular perfusion of these tumors makes delivery of chemotherapeutic agents challenging. In addition, the treatment of solid tumors by systemic administration of chemotherapeutic agents has some disadvantages: 1) it is necessary to administer large doses of such agents to the whole body in order to achieve adequate exposure at the tumor site and 2) large systemic doses are associated with significant adverse events.
Anaeropharma has been developing to overcome such circumstances by modifying non-pathogenic anaerobic bacteria, which naturally localizes and proliferates in an anaerobic environment, to express pharmacologically active proteins, enzymes that will generate the anti-tumor drug locally in the tumor environment and other pharmacologically active molecules. In this way, APS is developing genetically engineered anaerobic bacteria of the genus Bifidobacterium as a new DDS.
- Leading Anti-cancer Drug Candidate; APS001F
The company’s leading anti-cancer drug candidate, APS001F is recombinant anaerobic bacteria Bifidobacterium modified to express the cytosine deaminase (CD) gene, which results in overexpression of the CD enzyme. Bifidobacteria are a major component of normal human intestinal flora; they can be detected in a wide variety of mammalian species. When APS001F is administered intravenously to tumor-bearing mice, the bacteria localize and grow specifically in the tumors, but not in normal tissues. When flucytosine (5-FC, a fluorinated analog of cytosine that is licensed for use as an anti-fungal agent) is administered in the presence of APS001F, the CD enzyme converts the cytosine residue of 5-FC to uracil, producing Fluorouracil (5-FU), an established cancer chemotherapeutic agent. 5-FC is less inherently toxic than 5-FU. Thus, by selective targeting tumor tissues, APS001F facilitates the local conversion of 5-FC to 5-FU in the tumor environment, resulting in tumor-specific exposure to 5-FU while minimizing exposure of normal tissues. It is anticipated that higher intra-tumoral 5-FU concentrations will be achieved with APS001F than with systemic administration of 5-FU because APS001F-mediated 5-FU delivery to the tumor will not be limited by systemic toxicity. In experiments using tumor-bearing mice and rats, it has been demonstrated that APS001F rapidly disappeared from normal tissues while at the same time colonizing tumor tissue and proliferating at the site. Following administration of 5-FC, high concentrations of 5-FU were detected in tumor tissue (more than 10,000 ng/g tumor tissue), while very low levels of 5-FU were detected in the normal tissues, approximately a 1000-fold difference. This is a significant improvement over the tumor vs. normal tissue ratios observed for other agents designed to improve intra-tumoral 5-FU concentration relative to normal tissues.
The Phase I trial of APS001F started in 2012 in US. This is the first-in-human dose escalation study designed to explore APS001F in patient with advanced and/or metastatic solid tumors whose disease is no longer considered responsive to available treatments. The trial is to evaluate safety, tolerability and efficacy of the study agent.