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Harmless Clostridium bacteria as a highly targeted, continuous delivery system for immunomodulatory anti-cancer drugs

Periodic Reporting for period 1 - CMI2T IA (Harmless Clostridium bacteria as a highly targeted, continuous delivery system for immunomodulatory anti-cancer drugs)

Reporting period: 2017-09-01 to 2018-08-31

The goal of the project, CMI2T IA, is to determine the feasibility and lead the development of a new line of R&D in DualTPharma BV (DTP). This comprises the application of non-pathogenic Clostridium bacteria as a novel tumour delivery vehicle for anti-cancer drugs. This will leverage DTP’s growth by expanding DTP’s drug pipeline with a very novel and promising cancer drug delivery candidate.

Next to this the project opened up new career opportunities for the IA (Dr. Aleksandra Kubiak), by obtaining transferable skills in both the business and technical field.

Antibody therapy directed against several negative immunologic regulators (checkpoints) is demonstrating significant success and is likely to become a major treatment component for patients with a variety of malignancies. One of the best studied and most promising immune regulators for the treatment of cancer are antibodies inhibiting PD-1 (programme death 1 receptor; functions as an immune checkpoint). As shown in previous studies, antibody blockade of PD-1 results in highly effective anti-tumour immunity. Our solution is to use engineered non-pathogenic clostridia as a customised living vaccine expressing anti-PD-1.

These engineered bacteria have two further attractive properties: (1) their localisation in the tumour can be imaged with a PET scan and (2) they can be safely removed when treatment is completed (by using antibiotics). These specific characteristics of Clostridium make it a novel and highly attractive solution for tumour targeting and recent studies have already demonstrated the feasibility of our approach.
The feasibility of the clostridium tumour anti-drug delivery vehicle was researched from a technical, business and economical perspective. Based on the IA’s microbiology expertise, first, technical feasibility was researched based on our existing knowledge, which includes integration technology, cloning expertise in Clostridium, and feasibility of expressing antibodies. The IA determined what technical requirements were needed to realise a clostridial drug delivery system for clinical use, and what the associated timeline and costs were.
Then the IA determined the feasibility from an economic and strategic perspective. An IP strategy was formulated, based on an assessment of (1) freedom to operate and (2) possibility of protection of DTP’s own (developed) IP. Based on the investment needs (from the above) and envisioned pricing and marketing strategies DTP will now develop a business model.

We conducted scientific experiments in order to construct Clostridium strain harbouring immunotherapeutic of choice as well as in vitro validate the strain to confirm the activity of the expressed produc. Initially, we have proposed to focus on testing anti-PDL1 as a target molecule (novel group of checkpoint inhibitors developed for the treatment of cancer). Nevertheless, the initial stages of the experiment design revealed that cytokine IL-2 will be more suited target molecule to use for the exemplification of our proposed bacterial-based therapy. All scientific investigations were carried out in close collaboration with Nottingham University (UoN) to maximise the chances of completing all proposed activities.
DTP is a high-tech SME located in the Netherlands that is dedicated to the development of smart drugs to treat cancer. Our pipeline includes unique candidates for cancer treatment, including hypoxia-activated prodrugs. The\ integration of bacterial genetics in our business enables us to broaden our scope and to develop novel solutions
for the treatment of cancer, resulting in a frontrunner position in the oncology field. In addition, the development of this system will have a major impact on DTP’s business. DTP has selected non-small cell lung cancer (NSCLC) as first focal indication with respect to the large unmet need, market size, industrial interest, and access to patient
cohorts. In 2010, there were 547,000 new cases of lung cancer in the seven major markets. Of these patients, 331,996 are non-small cell lung cancer (NSCLC) cases in stage III-IV. 57,400 patients account for stage III-IV small cell lung cancer (SCLC). Addressing a share of this market as small as 1-5% with our Clostridium-based treatment
would result in multi-million Euro revenues and royalty payments for lung cancer treatment alone. In addition, areas of necrosis, where the bacteria localise, occur in most solid cancers and hence this treatment could be scaled relatively quickly to a much larger market. This is also illustrated by the high market sales of marketed
immune checkpoint inhibitors with sales numbers exceeding $1200 million 2014 (Ipilimumab).

This project will make DTP an expert in the field of microbiology and bacterial genetics with a unique focus on Clostridium in relation to oncology. The new expertise in this field will allow DTP to kick-start development of our customised living vaccine, including through the planned feasibility study, and further down the road successfully
bring this product initially onto the NSCLC (and later onto a broader oncology) market. As this tumour delivery vehicle will increase the efficacy of immunotherapies, the potential for success of the therapies that DTP is developing will further increase. DTP foresees to market a combination platform where expression of anti-PD-1 is
integrated in the delivery vehicle to yield high efficacy. In addition, the development of Clostridium as a delivery vehicle for drugs also opens doors to other applications with commercial potential, e.g. in diagnostic imaging. Combined, these factors offer DTP a strong competitive edge and excellent growth potential for the future.
Schematic overview of Clostridium Mediated Individualised Immunotherapy