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Ready-to-use 3D Cell Cultures for early de-risking in drug development

Periodic Reporting for period 1 - 3DCC (Ready-to-use 3D Cell Cultures for early de-risking in drug development)

Reporting period: 2016-12-01 to 2017-04-30

"What is the problem being addressed?
The current rate of failure during development for getting new drugs to cancer patients is outrageously high (around 95%). Most of these failures can be attributed to unacceptable toxicity during clinical trials or more often to lack of significant efficacy. Most, if not all, drug screening efforts rely on some form of cell based assays, currently performed using conventional 2D monolayer cultures, that have demonstrated to be poor predictors of the compound response in human clinical trials. However, biology is not flat, tissues, organs, tumors, all grow in 3 dimensions, thus in order to develop truly effective treatments (market’s need), we need testing systems that can recreate the 3D architecture of the real tumor, to better understand the effect of compounds early on and therefore increase the chances of getting them successfully through clinical development to reach the patient.

The question arises as: how do we test compounds in 3D structures in the laboratory? This is where StemTek expertise comes into play. Using biologically relevant 3D tumor models as the 3D tumor spheroid assay, StemTek can rapidly profile the activity of a collection of candidates for anti-cancer cell activity, answering the market’s need of cheaper and faster methods during the drug development initial phases. The realization that most tumors arise from a subset of cancer stem cells has revolutionized cancer biology, with deep implications in therapy. StemTek has a proven record of cutting edge research on cancer stem cell biology. In fact, 3D spheroids performed under StemTek’s technology arise from cell cultures enriched on cancer stem cells, therefore recreating the way tumors grow in the laboratory dish.

Spheroids performed using StemTek technology (patent filed) offer the unique combination of high relevance close to the in vivo situation along with the opportunity for high throughput screening. Drug screening against Cancer Stem Cells based on 3D cell culture systems allows biological relevant, more efficient and reliable drug testing than conventional 2D based monolayer culture systems currently used.

3DCC aims to develop a solution to make cell based assays a commodity: easy to get, easy to buy, easy to use, and disposable, so StemTek eliminates the need for large tissue culture facilities. Previously performing spheroid tumor tissue samples was a research technician’s labour, each lab responsible for sourcing, identifying and testing samples. To simplify this task, StemTek has applied its research experience to develop a 3D spheroid cellular based assay that will save researchers and pharmaceutical industry time and resources on tissue culture.

Why is it important for society?

StemTek proposes the present project in order to take the use of 3D spheroid cultures a step closer to the market, through specific applications. This will have a direct impact in how pharmaceutical industry perform drug development programs, which impacts not only in the global economy, and at the same time will lead StemTek to become the worldwide reference providing solutions to screen for drugs in Oncology, with the necessary production capacity to supply the pharmaceutical industry and the research laboratories.
3DCC solution and its economic benefits for the customers, compared to existing alternatives, are:
• Ready to use functional assay using 3D tumor spheroids. “Ready to use” means less effort (costs) for scheduling tests and much more dynamism for the research lab. One of the contacted potential customer even supported 3DCC publicly stating that ""this product just made my post-doc happy... It is like their dream come true, so tired of preparing spheres. The best is the “easy” part of the protocol.” Our goal is to give customers the freedom to focus on thier biological problems instead of wasting time and effort performing tedious 3D cell culture tasks.
• Save on development costs in identifying lead molecules for drug screening while improving predictability of compound efficacy. All contacted users agreed that 3DCC will be competitive due to its superior performance.
• Frozen – storable. Delivered flash frozen and ready for use or cold storage. Not need of specific scheduling to order/receive the kit, which means “freedom” to operate in the laboratory / testing. We are the first company ever to offer a complete ready to use 3D cell culture solution delivered frozen.
• Companies who desisted some compound developments due to lack of efficacy in 2D will have a new chance to re-analyse their potential. Integrated into laboratory testing and scalable, facilitates drug discovery process and speeds time to clinical trials while reducing false positives. The access curve to the technology is much better for their tests.
• Possibility to evaluate compounds on primary tumor cells, as an improved method for personalized medicine treatments.

What are the objectives?
• To produce tailor made kits (further functionalized) to improve compatibility with drug development programs, leading to a broad range of applications. The project includes the manufacturing of 16 different kits covering the major tumor indications (breast, colorectal, lung, prostate, pancreas, ovarian and brain tumors) ready for market. 160 demonstrator kits are planned to be produced, together with the marketing mix necessary.
• To use all the competitive advantages of CSC enriched 3D spheroid cultures (organotypic morphology, drug response predictability, robustness) in ready to use standard 96 well plate format. All processes will be ready for industrial production, QC set and use case studies developed. Demonstrator kits will be delivered to key decision maker laboratories for real use case development.
• The large-scale production of ready to use kits to be able to enter/supply the pharmaceutical industry to achieve economies of scale, cost reduction via dramatically increasing the production scale of currently 800 kits/year (manually) up to 120.000 kits per year.
• Build 3 panels of PDX derived ex vivo ready to use kits to offer highly predictable models to replace animal use in drug development. Agreements with 3 top 10 players in PDX model generation (Oncodesign, CrownBio and Champions Oncology).
• The integration of CSC testing into the drug development strategy of top 10 Big Pharma companies, in order to obtain dramatically improved compound de-risking and reduced attrition rate via the activity on 3D spheroid cultures, becoming reference mainstream go-to solution (the business development team will grow x3 for UK, Germany & USA).
StemTek’s team led by Angel Martin (three females and three males) has analysed the following issues:
• The state of the art data and set the specific technical scope, assumptions, requirements and objectives of the project, and
• The identification of the technical challenges related to the scale-up of 3DCC production (pilot plan 120 k kits/year production capacity and long-term 1 M kits/year capacity), including the operational requirements (basic engineering design, layout and location).
• Customisation to niches: special requirements of top big pharmas, research groups…
• Made-to-order solution versus cost-efficiency and large productions
StemTek has already filled a patent titled “Methods for producing cancer stem cell spheroids”, and has developed proprietary technology for “producing spheroid cultures enriched with cancer stem cells, to kits and related products containing the cultures, and to uses of the cultures, including in drug screening”. At the moment it is filed in the UK (GB application number: 1609663.8) though during phase 1 this patent will be expanded to the whole Europe, the U.S.A. and Japan.
In addition, the company conducts periodic patent surveillances in order to ensure that no IP conflicts arise. During the last patent search, more than 25 patent and patent applications were found that contained “3D culture cell” in the title while half of them were found to be relevant for drug screening, targeting Cancer stem cells (as this project). Nevertheless, none of them were found to be in conflict (there is no patent or a commercial product about ready-to-use, storable 3D culture cells as 3DCC). The freedom to operate is guaranteed due to the patent search and developed report previous to the first patent filing.

Regarding all regulatory issues during the development process, StemTek will comply with the current legislation at all levels, and will implement the most advanced measures for a safe use of the product. Good Laboratory Practices (GLPs) manufacturing implementation is planned for Phase 2 (following the OECD). Health regulations or ethic related aspects (such as REACH, CLIA certification, etc.), do not apply, as 3DCC is not focused on diagnostics or human use, but on research use.