PROTEUS still has a long way to becoming a usable treatment against some of the world’s deadliest cancers. Our team likes to think of our Implementation page as explaining the path from the present to our intended, ideal future. The cancer therapeutic approval process is an arduous journey, even for some of the most well-endowed prospective ventures in the industry (Sharma et al., 2022). Thus, our team has laid out a plan of action – with several potential branches – to maximize the likelihood of achieving our vision. We have broken the process down into several more digestible pieces, which are summarized in the figure below:
Implementation Timeline: Our 5 stages to taking our venture from its current stage to our desired end goal.
This timeline serves as the basis for the subsequent subsections of our Implementation page. Below, we expand on our logic model in greater detail to provide insight on the necessary actions to achieve success. Given ongoing progression to establishing PROTEUS as a clinically approved, effective cancer therapeutic, we break down each stage of the timeline in its own subsection. The more immediate the stage, the more straightforward; later stages require more conditionals and alternative development strategies given the uncertainty as well as the dependence on the path established in previous stages.
Overview of Current Stage of Development
In order to commercialize, our team would seek to incorporate as well as establish partnerships with major manufacturing corporations to develop a functional scale-up. The main benefits of incorporating include:
- Limiting personal liability due to the company becoming a separate legal entity
- Greater access to capital through venture capitals and angel investors
- Corporate tax rates on any revenues
- Establishing an official strategy for company equity/shares
Incorporation requires filing with Corporations Canada, which involves the preparation and submission of Articles of Incorporation and the Registered Office and Directors form, as well as a $200 federal incorporation fee plus provincial registration fees. Our team has prepared the required documents and plans to officially incorporate upon rudimentary in vivo validation. The Basic Incorporation option in Canada allows for a maximum of 10 directors as well as a maximum of two share classes (voting and non-voting). Our team would elect 5 members from our founding team and 5 members of our graduate advisory board (most likely our two principal investigators and three PhD students that had a central role in supporting the development of the project) to maintain a balance of interest. We would select two share classes, Class A (voting), and Class B (non-voting), to provide the company the ability to grant equity without forfeiting control over its organizational structure.
After incorporation, the company would have reason to focus on expanding technological assets and filing additional patents in order to bolster IP and pursue scale-up to become a profitable venture. The modularity of our proof of concept (POC) system would provide opportunities for the team to expand its IP portfolio by investigating other applications, such as in lung, colorectal, and brain cancers, and targeting other forms of cell death. After establishing an in vivo POC with pancreatic cancer, this would be one method of expanding new technology assets in the pre-seed to seed stages of the company.
Due to our affiliation and funding from McGill University, the company would need to minimally develop our POC patent in parallel with the university. Internally, McGill has its own process for pursuing patenting and takes a royalty on all revenues generated from licensing. Luckily, this comes with the benefit of interest-free financial coverage of the legal expenses associated with maintaining the patent up until the date of the license (at which point there is a payback period to the university for patent expenses incurred). Further patent applications for future investigations would be solely regulated by McGill iGEM, so long as future research and development as well as recurring patent fees can be independently covered by revenues, low-interest debts, and other investment instruments.
Our team has worked extensively with the McGill University Office of Innovation and Partnerships to prepare a Manuscript and Report of Invention demonstrating the novelty, utility and non-obviousness of our invention. Due to our support from McGill University, patent filing must be conducted through McGill’s internal Technology Transfer Office; our team is currently working with McGill’s Technology Transfer Manager, Chris Corkery, to establish a patent for PROTEUS. In addition to coverage of legal expenses associated with the upkeep of the patent, McGill also provides support and guidance on spinning off and scale-up (McGill Innovation and Partnerships, 2022; McGill Innovation and Partnerships, n.d.). As per McGill’s Spinoff Handbook, McGill splits the revenues obtained from the license to the spinoff 60 to 40. That is, 60% of McGill’s revenues from licensing the patent go to the inventors and contributors named on the Report of Invention, and 40% goes to the university (McGill Innovation and Partnerships, 2022). Determining who is eligible to be considered an inventor or contributor was a difficult task for the team given the collaborative, open-source nature of iGEM, as well as our team’s commitment to focusing on the group’s success rather than individual recognition. This is expanded on in the Business Plan.
McGill University’s standard technology transfer process from their Guide for Faculty Inventors. After ideating and developing a proof of concept, one can submit a report of invention (ROI) to McGill’s technology transfer office. Afterwards, the office assesses the feasibility and patentability of the idea before initiating IP protection. Afterwards, the creator(s) can either find a license recipient to exit, or they can spin off to commercialize the project.
One consideration of spinning off is that, as per McGill’s Policy on Inventions and Software, upon being granted license to spin off, the company would be expected to repay all patent costs incurred by the university (McGill University, 2017). The timeline for this payback is negotiable on a license-by-license basis (McGill Innovation and Partnerships, n.d.; McGill Innovation and Partnerships, 2022), though it does represent a substantial liability in the first few years of the company that could have a severe impact on our balance sheet and cash flows. Planning the payback effectively would be of utmost importance for the early financial stability of the company, as well as the appearance of our financial statements. After finalizing the licensing arrangements, the spinoff would also become liable for the entirety of its own patent expenses. Other licensing terms include a small annual royalty and equity in the spinoff (again both negotiable, though generally on the order of 5% or less) (McGill Innovation and Partnerships, 2022). Fortunately, after the spinoff incorporates, it is the sole beneficiary of the exclusive license created by patenting the invention through McGill, less McGill’s minor equity claim and royalties.
Another consideration of filing with McGill University is the built-in measures to protect our IP assets against infringement, misappropriation, and unauthorized use of the technology by competitors and third parties. Given McGill’s initial protection and complete payment for the legal expenses of upkeeping a patent, our team benefits from the inherent protection against misuse of the invention by others. While our team will do our due diligence to search for misuses or infringements, there will be a dedicated effort by McGill to ensure protection of the invention until the McGill iGEM team licenses the technology or abandons the patent.
All plans for future IP development rely on a foundation of security with regards to the intellectual assets developed by the team; to remain as the beneficiaries of our idea, it is necessary that the technologies we develop are not disclosed in their entirety. Regardless, partial and rarely even complete disclosures are sometimes essential in commercializing a venture. Thus, our team has developed and refined non-disclosure agreements as well as standard internal policies and strategies for minimizing external exposure to our intellectual assets. This has allowed our team to have a uniform approach to all disclosures, limiting the liability of sharing information on our project; we have taken all necessary precautions to see the fruits of our labour. A more in-depth discussion of our team’s IP strategy and IP roadmap are provided in the Intellectual Property Strategy section of the Business Plan.
While we have developed a standard approach to disclosures, one unavoidable breach of our idea will be during the iGEM Grand Jamboree. Given that we cannot avoid public disclosure at the Jamboree, our team plans to take advantage of the grace periods provided in many countries. Many provide a 12-month grace, while others a 6-month. We have taken note of the countries with the shortest graces (Germany, the UK, France, China, all of which have 6 month graces) as well as those with slightly longer graces (the US, Canada, Japan, Brazil, the Philippines, etc.). When we file in these jurisdictions, we will always prioritize our beachhead markets (Canada, the US, and Europe primarily). Countries that do not provide a grace would become inaccessible for patent protection following the Grand Jamboree; thus patent coverage in these countries must be assumed infeasible. A country-by-country overview of patent laws (especially related to grace periods) is provided by the WIPO (WIPO, 2023).
Given the relevant existing patents and patent applications issued by other groups, McGill iGEM must be meticulous in deciding what to consider in our eventual patent application; in particular, given the extensive patent claims for Craspase and Craspase-related applications (especially in RNA sensing), we will likely focus our IP towards our novel gasdermin-Csx30 fusion proteins, and their use in tandem with the Craspase CRISPR-Cas system. We will not specifically frame our patent application around pancreatic cancer given the inherent modularity for the system to target and effectively subdue any cancer with highly homogeneous driver mutations. In initial submissions for patent applications, broader claims are often ideal to maximize the potential protection granted by the regulatory agency. If the regulatory body believes the claims are too broad, the venture always has the opportunity to narrow the focus. Thus, we aim to base our patent on the use of Craspase to cleave fusion proteins that go on to induce pyroptosis in the host cell (assuming in vivo usage). More generally, we would like to patent fusion proteins that integrate Csx30 into a flexible, intrinsically disordered linker region between two native proteins or native protein domains (where the domains are from different proteins or the same original protein). For instance, similar to the technology in Strecker et. al, our patent would cover integrating Csx30 between a membrane anchor protein and a Cre recombinase for the goal of spurring Cre recombinase to perform a downstream excision of a LoxP site elsewhere in the cell (Strecker et al., 2022).
Canada is one country that luckily provides a 12-month grace post-public disclosure. The US is the same case (these facts played largely into our interest in focusing on Canada and the US for the early stages of the venture). The specific process for filing a patent in Canada is outlined in the infographic timeline provided below:
The standard IP roadmap in Canada, provided by the Canadian Intellectual Property Office (CIPO) (Innovation, Science and Economic Development Canada, 2020).
The timeline demonstrates the key deliverables that must be generated within the year following public disclosure at the Grand Jamboree. The initial patent application must include many details, such as the inventors, a detailed description of the technology (an abstract and technical drawings to support the technology), and several legal formalities (a petition for the patent, a claim to invention, statement of entitlement, etc.). Following approval of the application and certification of compliance by the CIPO, most inventors need to ensure payment of maintenance fees. Luckily, in our case, our team is affiliated with McGill University, providing some initial coverage of patent fees.
Within four years of our initial filing, we must also undergo an examination by an officer of the CIPO. If successful, our patent is granted, and we have 20 years of protection on PROTEUS. If the examining officer makes suggestions for reconstruction of the patent application (which in most cases they do), we have four months to make the necessary changes before submitting for re-evaluation. If after reconsideration, the officer still deems the technology unfit for patent protection, then we will be officially unsuccessful; otherwise, we should be able to assume that PROTEUS would be patentable as early as late 2025, or approximately 2 years following the 2023 Grand Jamboree (for lack of certainty, we can estimate it as November 2025).
The US follows a very similar route to patenting as in Canada. Uniquely, the US has three types of patents: utility, design, and plant. Utility patents are for anyone who invents “a new and useful” invention (USPTO, n.d.). Design patents are for the invention of an “ornamental design for an article of manufacture” (USPTO, n.d.). Finally, there are plant patents for “anyone inventing or discovering and asexually reproducing any distinct and new variety of plant” (USPTO, n.d.). Evidently, the best fit for PROTEUS is the utility patent. We must decide whether to submit a provisional or nonprovisional patent as well in the US. The provisional only provides 12 months of protection before being abandoned. Therefore, our team must file a nonprovisional regardless; it is only a matter of whether we will directly file a nonprovisional, or first a provisional to buy time. Given the time restraints for covering our IP following exposure at the Grand Jamboree, our team will likely file a provisional in the US first. This exempts us from examination until we file for a nonprovisional (USPTO, n.d.). Realistically, we can expect a provisional patent by January 2024, not long after the competition. The buffer of a few months is to account for the time required to assemble a provisional on our end, as well as the turnaround time for the United States Patent and Trademark Office (USPTO) to settle the provisional.
Immediately after finalizing a provisional, our team would begin working on a nonprovisional. This patent application is more rigorous, requiring the following:
- A specification (description and claims)
- Technical drawings
- An oath or declaration to inventorship
- Filing, search, and examination fees
Following submission of the nonprovisional, there is an examination by an officer of the USPTO, similar to the process in Canada with the CIPO. The USPTO describes the examination as follows:
“The examination consists of a study for compliance with legal requirements, along with a search through U.S. patents, publications of patent applications, foreign patent documents, and available literature. This is to see if the claimed invention is new, useful, and non-obvious, and if the application meets patent statute requirements and rules of practice. If the examiner gives a favorable decision, a patent is granted.”
More information on the specific process of inspection is provided by the USPTO in their online services (USPTO, n.d.). After examination, the examiner will either issue an approval, or demand changes be made to the claims, description, or legal documentation. The examiner searches for prior art and will be scrupulous in ensuring we formally state relevant past works and patents, and that we thoroughly differentiate our technologies from prior art in order to be patentable. Based on the standard timeline in the US, we estimate that we could expect nonprovisional protection by mid-to-late 2025, though likely just before Canadian protection is issued (we estimate September 2025).
While the most immediately pressing consideration for our team is protecting our intellectual property, we are also focused on further validating our system to provide more reliable, robust, and replicable evidence of the efficacy of the system in vitro. At every step of a cancer therapeutic’s development, it is essential to provide extensive evidence to demonstrate the claims of the therapy, as well as the safety profile. In the in vitro stage, the primary consideration for safety is avoiding significant off-target effects; we hope that our system will prove to have more manageable off-target effects than current treatment modalities on the market, providing a competitive advantage given the increased patient survival and health outcomes. In order to provide breadth in demonstrating the safety of PROTEUS, we plan to test our system in several models. Following POC in S. cerevisiae, we plan to expand to mammalian cell lines containing KRAS mutations such as the one we chose to target in our POC, such as HKP1 mouse lung cancer cells, MiaPaca 2 and Capan-1 human pancreatic cancer cell lines. In choosing KRAS-mutant cell lines to test Proteus first in, we would like to definitively prove that the Proteus system can be used to target KRAS-mutant cancers such as those that dominate in PDAC. However, during our iHP consulting with Dr. Logan Walsh, we discussed future steps for testing Proteus in an in vitro setting. Specifically, given the inherent modularity of the system, we will also tailor in vitro validation to cancers besides PDAC which similarly have oncogene addiction towards a few key oncogenes. Some cancers fitting this description would include KRAS-driven lung and colon adenocarcinomas (Singh & Settleman, 2009), BCR-ABL1-driven chronic myeloid leukemia, KIT-driven gastrointestinal stromal cancer, BRAF-addicted melanoma, and several others (Pagliarini, Shao, & Sellers, 2015). The advantage of this approach is that it lets us to test out Proteus in a wide variety of cells that all vary genetically and phenotypically, and allows us to discover if there are any specific weaknesses to our system in particular cell types. The table below provides several cancers, the oncogene to which they are addicted, and secondary mutations that provide the cancer additional resistance, which we could pursue in vitro testing in:
Developing effective models for each of these cancers would rely on selecting chassis which emulate the phenotype of human cancer cells of that cancer. We discussed with several experts in the field, including Director of the Rosalind and Morris Goodman Cancer Centre (RMGCC) Professor Morag Park, Professor Logan Walsh of the RMGCC, and Dr. George Zogopoulos of the Research Institute of the McGill University Health Centre (RI-MUHC). They offered insight into recommended models for in vitro mammalian validation of the system for a variety of oncogene-addicted cancers. In addition, the Cancer Cell Line Encyclopedia allows researchers to search for cancer cell lines which express certain oncogenes of interest. We will use this resource, as well as the recommendations of the many experts with which we have established relations, to finalize the cancer cell lines we choose to use to model and validate our system in mammalian cells.
In the initial stages, we will focus on pancreatic cancer cell lines – primarily MIA Paca-2 and Capan-1, as mentioned previously. Dr. Zogopoulos has access to these lineages and has offered to provide samples for our mammalian validation. However, for the most accurate models, we aim to use pancreatic cancer cell lineages with the KRAS G12V mutation to match our proposed flagship target. Lines with this mutation include Capan-1, Capan-2, and CFPAC-1 (Deer et al., 2010). In order to establish breadth in our mammalian validation, we would aim to test our system in several of the aforementioned cell lines, as well as some additional lineages from the table below:
Lineages with the KRAS G12V mutation are bolded and will be key to in vitro validation of the efficacy for treatment of KRAS G12V PDAC. Notably, only three common pancreatic cancer cell lines express the KRAS G12V mutant (most express G12D). We will employ a variety of lineages, using wild type, G12D, G12V, and G12C mutants, varying the gRNA in order to target whichever KRAS variant is expressed. The goal at this stage is to determine the efficacy of PROTEUS against PDAC manifestations in general, as well as test the modularity of the system for downstream validation against other cancers.
Based on the results of these experiments, we plan to explore cell lines from non-PDAC cancers, such as the aforementioned oncogene-addicted cancers. However, we must first establish the efficacy against pancreatic cancer lineages in order to make any attempt at non-PDAC cancers. These downstream experiments will elucidate the true modularity of the system as a potential treatment against a wide variety of cancers.
The delivery method for this therapeutic will be extremely important. Following several conversations with experts from different fields, we came to the conclusion that the systems that are most likely to be effective for us are gutless adenoviruses (GLAds) and Red Blood Cell Extracellular Vesicles (RBCEVs).
There are several important considerations in determining an ideal delivery method. Additionally, these will all have to be tested, and validated in a preclinical model to determine the most efficient one. Although our therapy is not technically a gene therapy, it still requires the delivery of DNA to target cells. Thus, we extensively considered FDA approved delivery methods and those currently undergoing clinical trials to help determine the most ideal delivery method.
Important considerations in our therapeutic delivery system are the following: safety, ability to be used more than once, efficacy, tissue tropism (which tissue it targets, i.e. if there is accumulation in the liver for LNPs for example, or if it is possible to have a systemic effect), and the overall advantages and disadvantages of each method. We performed extensive literature review and expert consultation of each of these systems, and our findings are summarised in the table below.
Based on our findings from literature review, the gutless adenovirus (GLAd) seemed to satisfy a lot of our system’s needs. It is also important to note that this method was suggested to us during four of our expert consultations. We concluded that it has a large enough payload to hold our system, as we require only over 10 kB of purely ORFs and this viral method has a large payload of up to 40 kB. This viral method has a high transduction efficiency, while maintaining low toxicity, minimal off-target effects, and low immunogenicity (Lee et al., 2019). As well, its broad tissue tropism allows us to maintain the modularity of our therapeutic since we can successfully deliver our system to different tissues. This viral method can easily be administered to patients via intravenous injections.
It is important to also note that we are still considering the use of Red Blood Cell Extracellular Vesicles (RBCEVs) as a potential delivery method since it also appears to satisfy our system’s needs, but further consideration is needed.
Many therapeutics are proven to be efficacious in the petri dish, but the biggest challenge lies in optimizing them for efficacy in an in vivo context. Following validation of the PROTEUS system in mammalian cells, the next step would be testing PROTEUS in a mouse model of cancer.To successfully test PROTEUS in vivo, there are two major considerations:
Therapeutic safety: ensuring that PROTEUS itself does not cause any major adverse health effects. The two main concerns are
1) the off-target effects of the Craspase system itself, causing it to activate inside and kill healthy cells, and
2) the potential body-wide immunogenicity of causing pyroptosis of a large tumorous mass and systemic spreading of released inflammatory cytokines.
Therapeutic efficacy: successfully eliminating the tumor is the primary efficacy objective of the PROTEUS system. Furthermore, it will be important to ensure that there is no recurrence of tumors post-treatment. Finally, since we hope that the PROTEUS system induces a durable immune response against the tumor, validating that the immune system learns to recognize tumor-specific antigens and can fight off future occurrences of that tumor post-PROTEUS treatment would also be an important consideration.
The workflow for testing both of these considerations would first consist of determining the safety of the viral vector carrying the therapeutic, by equipping it with a non-targeting RNA and a GFP gene. We would determine the distribution of the viral particles across the mouse body, to determine any areas of viral accumulation - for example, accumulation in the liver is expected.Next up, we would test Proteus in a mouse model of cancer. Typically, cancer mouse models are performed in immunocompromised mice that receive implants of tumors from human patients, known as patient-derived xenografts (PDXs). These mice typically lack an adaptive immune system as well as parts of the innate immune system, to prevent rejection of the xenograft in the mouse and inability to study the tumor. The benefit of PDX mouse models is that since the tumors are derived from human patients, they more accurately represent the molecular and phenotypic heterogeneity and evolution of real tumors. In the case of most chemotherapeutics, these immunocompromised mouse models are fine, because the immune system is not significantly involved in the anti-tumor mode of action of these drugs. In our case however, we are interested in both the immunological memory conferred from inflammatory pyroptosis in the tumor due to Proteus, as well as any inflammatory side effects that may arise from large-scale pyroptosis, a fully immunocompetent mouse model would be necessary.Therefore, we would consider using a syngeneic mouse model where the implanted tumor consists of KRAS-mutant cells from a mouse from the same genetic background. An example of this would be implanting HKP-1 cells into C57BL/6 mice, since the HKP-1 cells that were engineered to express mutant human KRAS G12D were derived from the common C57BL/6 mouse model.
Following subcutaneous tumor implantation in the flank of a mouse, the Proteus system packaged in the delivery vector of choice (i.e. RBCEVs or GLAds, also co-carrying an encoded fluorescent protein for downstream imaging) would be delivered either locally to the tumor via an injection or systemically via an intraperitoneal injection. Penetration of the virus into the tumor core for either and/or both local & systemic delivery approaches will be measured by fluorescent imaging of the tumor after surgical resection. The extent of delivery vector penetration will help us determine an optimal dosage (i.e. does the dosage need to be increased for higher tumor penetration?), delivery method, and treatment regimen for Proteus.
During the course of treatment, tumor size will be monitored non-invasively using MRI over the time-course of treatment to measure the kinetics of cancer killing and tumor regression in vivo. Kaplan meier survival curves will be created to track the survival rates of mice with and without Proteus treatment. We would compare the Proteus system against state-of-the-art tumor therapeutics, such as recent chemotherapeutics as well as immunotherapies such as immune checkpoint blockade (ICD), to compare their efficacy in combating tumor growth. This would be absolutely crucial at the clinical stage point, where FDA approval is dependent on the therapeutic being an improvement upon the state of the art. Furthermore, as mentioned above, we would be very interested in measuring the synergy between Proteus and an anti-tumor response, due to the pro-inflammatory “hot tumor” environment that Proteus would ignite. There are several methods of testing this:
- Administer two tumors to the mouse at the same time; one containing the mutant oncogene and one without. Once the tumors have both grown and one systemically administers Proteus targeting the oncogene, the mutant oncogene-containing tumor should shrink. If there is anti-tumor immunity that emerges where adaptive immune cells such as T cells and B cells learn to recognize tumor-specific antigens, the other flanking tumor that does not contain the mutant oncogene (and thus should not be targeted by Proteus directly) should shrink as well. Single-cell profiling of immune cells in and around the tumor as well as in the bloodstream for states such as activation (CD44), proliferation (Ki67), and effector function (GzmB) will reveal whether an anti-tumor response is mounted
- Another complementary approach is to engineer the implanted tumor cells to express a unique tumor-specific protein such as bovine serum albumin (BSA) or a fluorescent protein. This will allow subsequent profiling of immune cells to see if they have acquired these tumor specific antigens after therapy - and thus directly measure the emergence of anti-tumor immunity. For example, after treatment of a GFP-expressing tumor with Proteus in a mouse model, we can isolate antigen presenting cells such as dendritic cells from the blood and probe whether they are also fluorescent via flow cytometry - due to the uptake of the tumor cell-expressed fluorescent protein. If there is an increase in green fluorescent dendritic cells, this means that dendritic cells were recruited to the tumor area due to the pyroptotic inflammatory environment, and took up and presented tumor-specific antigens on their surface.
To evaluate the safety profile of a Proteus treatment, we would measure markers of toxicity in mice, such as: body weight over the course of treatment, posture and behavioral traits such as motor activity and cognitive function, liver function and post-mortem tissue stiffness. In addition, to measure the level of inflammation caused by our Proteus system in our mouse model, we would take blood samples over the course of treatment and use commercial multiplex cytokine assay kits to monitor the levels of crucial cytokines that are prognostic markers for local and systemic inflammation. This would not only be done for blood samples during treatment but also done post-mortem/post-sacrifice of the mouse’s tumor, to explore the immune reaction inside the tumor, not only systemically. Examples of cytokines that we would probe through multiplex assays include TNFα, IL-1β, IL-6, IFN-γ. Different cytokines will also give us insights into the response of different immune cells, because each immune cell subtype secretes its own profile of unique cytokines. For example, higher IFN-γ levels would indicate activated T-cells and Natural Killer (NK) cells, indicative of an immune response either against the tumor itself (advantageous), or characteristic of systemic inflammation (a dangerous side effect) - depending on the location of these cytokines.
Ultimately, our mouse model preclinical trials give us the opportunity to test various crucially important treatment factors - such as therapy dosage, number of treatment administrations and timing between administrations, and benefits of systemic versus local treatment, all of which should be thoroughly tested to ensure an optimal treatment outcome for clinical trials. Furthermore, we would be interested in testing the combination of Proteus along with immune checkpoint blockade, and exploring whether it presents any therapeutic advantage over individual treatment with either therapy.
While mice studies are the gold standard for proving both efficacy and safety of cancer therapeutics prior to proceeding to phase I clinical trials, we learned through a number of our iHP consultations, such as those with Dr. George Zogopoulos, Dr. Morag Park, Dr. Logan Walsh and Dr. Cameron Black that organoids are increasingly used to test preclinical efficacy of a therapeutic, as well as its safety and off-target effects. As an alternative to costly and time consuming mouse trials, our team could employ organoids to screen for toxicity issues relating to Proteus, as well as optimize drug treatment regimes before going into mouse models. We foresee the preclinical trials that we would run as a strategic balance between high-throughput screening in organoids to optimize therapeutic parameters mentioned above, followed by mouse trials for observing more complex traits such as anti-tumor immunity and potential systemic off-target effects.
We had several great conversations to better understand the regulatory scene, and try to design our project with the end goal in mind. These conversations range from experts in Oncology like Cameron Black (hyperlink to iHP), Annette Hay, and patients through Kay Kays.
All these conversations revealed great insights that became important for the future implementation of our project.
We would have to initially write a clinical trial protocol, strictly defining inclusion, and exclusion criteria upon which patients would be recruited. Our initial proof of concept focuses on pancreatic cancer, but in principle this system could be adapted to various kinds of cancers, so depending on the preclinical data, we may choose to target different types of cancers. An important piece of information that we received is that many oncology companies tend to try to do clinical trials in the United States, since typically Health Canada will follow what the FDA is approving (given it is a governmental organization with much more capacity). We would likely operate clinical trials in the United States, and try to pursue FDA approval, but this would also depend on the partnerships that we would be able to strike, and the interest of other companies. Similarly a company based out of Montreal, Inversago, having just completed a phase 2 clinical trial was acquired by Novo Nordisk. This clinical trial was performed in the United States, and governed by the FDA.
As our therapeutic develops, so will our dry lab pipeline. Initially, we would target patients who have had their tumors sequenced for specific driver mutations that we could then target. Following this we would have to do a phase 1 clinical trial, which would focus mainly on safety, and where the method of delivery will be extremely important.
We will be delivering our therapeutic through intravenous injection, as that is very common, but it is also possible, that it would be favorable to attempt a local delivery following surgical resection (all this would depend on the specificity of the clinical trial application which would in turn depend extensively on the preclinical results).
Following a successful Phase 1 we would likely pursue a Phase 2 (2a for dosing safety, and 2b for efficacy at the specific doses) clinical trial. As we have seen before, it is common that at this point there are potentially interested suitors, or other organizations that might be interested in co-leading this clinical trial with us to help bring it to market. More information on our strategy with respect to this can be found in the business plan. In short we would require validation through all clinical trials, and subsequent FDA approval. After this, we would be able to begin targeting patients, and getting this therapeutic to the people that need it.
In an ideal world, a patient could walk into a hospital, have their tumor sequenced to determine the driver mutations, and then rapidly have gRNA’s to target the mutations synthesized, and sent to the hospital, so that the therapeutic can be administered. This would require massive organizational structure, Good Manufacturing Practice (GMP) facilities and partnerships if it is outsourced (as it is likely to be at least initially), managing insurance costs and ensuring that patients know they would be eligible for this sort of treatment depending on the results of their sequenced tumor.
As mentioned in explicit detail in our Business Plan found in the entrepreneurship section, we will be focusing on validating this system in clinical trials.
From extensive consultations, we have learnt that it is essential that the design of these is very rigorous, otherwise we may have difficulty even recruiting patients for a trial, and no matter the supposed efficacy of our system, we may never be able to test it. In parallel we will also have to have financial support at this point, since clinical trials are extremely expensive, with the figure of 1 billion dollars being quoted often as the total cost of actually getting a drug to market.
We will have to decide which type of cancer will be easiest to target, and this will be heavily informed from the efficacy of our pre-clinical work, and the lack of effective therapies for patients - such as for pancreatic cancer.
Market Entry and Scale-Up
Skill Gap Analysis table broken down by category of skill, then ranked in terms of immediate relevance, as well as our current team’s level of expertise. The most essential skills to develop based on the analysis are highlighted in grey, while the less pressing skills are left as white. Evidently, our focus in early-stage team development and recruitment will be on rounding out our technical skills, as well as working on regulatory considerations and business development.
Our value chain graphic for PROTEUS displays all business activities required throughout the development of the therapeutic, including operations and secondary activities.
In addition to the value chain, we have also created a supply chain to demonstrate the required steps between manufacturing and administering the therapeutic. This diagram will help our team define the key partners with which we need to build relations, such as therapeutic wholesalers, freight and shipping, health insurance providers, and hospitals and physician’s offices.
Supply Chain Graphic: General protocol from manufacturing to delivery of PROTEUS with cash flows and flow of the therapeutic.
At a high level, drug and therapeutic manufacturers produce and distribute medications to various intermediaries, including wholesalers and pharmacies. In Canada, the government negotiates drug prices, while in the US, various entities, including Pharmacy Benefit Managers (PBMs) and insurers, negotiate these prices (U.S. GAO, 2007). Both countries have insurance systems—Canada's predominantly public and the US's a mix of private and public—that determine coverage and reimbursement rates for medications. The insurance providers then dictate the out-of-pocket costs or co-payments required from patients, which can vary based on the specifics of each individual's insurance plan. Patients, subsequently, obtain their medications from pharmacies or hospitals, paying the amount designated by their respective insurance coverage.
Given that McGill iGEM aims to target a niche market, we would likely partner with a cancer therapeutic wholesaler to better reach our target market. We would ideally partner with a top ten oncological pharmaceutical company based in North America, such as Johnson & Johnson (J&J), Celgene, Pfizer, or Bristol-Myers Squibb (BMS).
Given that gene therapies tend to be expensive and new on the therapeutic stage, it is unlikely that federal, or state/provincial health insurance plans will cover PROTEUS in the near future. The much more likely scenario is that individuals pay out of pocket, or rely on their health insurance provider, at least in the early stages.
Our business plan document expands on the above topics in much greater detail. Please explore our business plan for more insight into our plan of action for establishing PROTEUS’ value chain and supply chain.
The traditional initial treatment for PDAC is combination therapy using paclitaxel and gemcitabine. If the disease progresses after gemcitabine-based therapies, fluorouracil and irinotecan liposome injection combination therapies are often subsequently used. Unfortunately, these treatment modalities are potently cytotoxic and indiscriminately target all dividing cells (both cancerous and healthy). For example, severe or life-threatening neutropenia (neutrophil deficiency) occurred in 20% of patients receiving irinotecan/5-FU/leucovorin (LV) combination therapy, one of the most common combination therapies following gemcitabine-based treatment (DailyMed, 2023). Furthermore, with current pancreatic cancer long-term survival rates still sitting at a low 12%, these treatments are not incredibly fruitful, providing a large gap in the market for safe, effective therapies.
The pancreatic cancer drug treatment field is constantly changing, though highly effective drugs have yet to be brought to market. Regardless, some of the key recent developments in the industry are reported below:
> In January 2022, the FDA gave orphan drug status to multitargeted T-cell therapy. This therapy has shown the potential to elicit sustained responses in individuals with advanced or metastatic pancreatic cancer when combined with chemotherapy as a first-line therapeutic option (Grand View Research, n.d.)
> In September 2021, Roche partnered with NovoCure to develop Tumor Treating Fields, electric fields that disrupt cancer cell division, in combination with atezolizumab for patients with metastatic PDAC (Novocure, 2021; Fortune Business Insights, 2021)
> In July 2021, Novartis received orphan drug status for NIS793, a novel antibody specific for Transforming Growth Factor Beta (TGFβ), a cytokine that has an important role in metastatic PDAC and other solid tumors (Novartis, 2021)
> In June 2020, Ipsen pharma received fast-track designation by the FDA for the use of irinotecan in combination with 5-FU/LV and oxaliplatin, known altogether as NALIRIFOX, for the treatment of patients suffering from locally advanced and metastatic PDAC (Fortune Business Insights, 2021)
>
In December 2019, AstraZeneca and Merck received FDA approval for Lynparza (olaparib) for its use in the U.S. for the maintenance treatment of patients suffering from pancreatic cancer (Fortune Business Insights, 2021)
Pancreatic cancer treatment expenses are already high; chemoradiation often costs upwards of $10 000 USD per month, depending on the stage (I through IV) and phase (initial, continuing, or terminal) that the patient is in (Tramontano, 2019). Stage indicates the extent of tumour development (lower stages correspond to less metastasis and infiltration into surrounding tissue), while phase describes the patient’s general health progression (with ‘initial’ being the most healthy and ‘terminal’ being terminally ill). Given that pancreatic cancer treatments are already expensive, even though they tend to be ineffective, PROTEUS would not suffer in consumption due to high cost; in fact, its much increased predicted efficacy would likely outweigh the potential detriment of its foreseeable high price tag.
Revenue Generation
The strategic landscape for biotech companies in the biopharma sector is complex. Among the most crucial decisions is the choice of business model, which in turn influences who the company partners with and how it scales. The primary business models exist: technology partnering, asset-creation/out-licensing, and product development and commercialization; however, many firms operate as some combination of these three.
In the technology partnering model, biotech firms license their scientific platforms to more established biopharma companies. This approach has the advantage of providing immediate revenue streams, thereby alleviating some of the financial pressures that young companies often face. Importantly, this model also minimizes risk, as the responsibility for developing and commercializing pharmaceutical products lies primarily with the partnering biopharma company. Entering a technology partnership can have ripple effects beyond immediate financial relief; it serves to validate the biotech’s platform in the eyes of the wider biopharma and investor communities. Companies that engage in early partnerships with well-known biopharma corporations see a significant boost in their credibility. This credibility is not just symbolic; it enhances the young company's bargaining power in future negotiations, be they for subsequent partnerships or funding rounds.
On the other side of the spectrum is the asset creation and out-licensing model. Here, biotechs use their proprietary technology to develop their pharmaceutical assets. This approach is resource-intensive upfront, requiring both time and financial investment. However, the payoff can be considerable. Once these assets reach a scientific proof-of-concept, they can be licensed to larger biopharma companies for further development and commercialization. This not only generates revenue through upfront fees and milestone payments but also significantly de-risks the later, often more expensive, stages of asset development. Partnerships in this model often revolve around complementing capabilities, as the biotech company can focus on early-stage development while the biopharma partner can use its greater resources and expertise for late-stage commercialization.
A third model, and by far the most ambitious, is one of complete in-house product development and commercialization. This model is a complete in-house project in which the young firm inherits all the risks but also all of the rewards of successful development. Companies adopting this model intend to take pharmaceutical assets from conceptual stages right through to market. The financial risk here is much higher, as is the burden of development and regulatory compliance. But, if successful, the returns are unparalleled, as the company retains full ownership of the product. Naturally, this model requires the most significant influx of capital, either from investors or from a steady revenue stream generated from previous deals, other sources or a combination.
As companies grow and evolve, many find themselves adopting a hybrid approach that combines elements of the above models. For our purposes, we will likely pursue a hybrid technology partnering and in-house product development model. Technology partnering offers a more rapid, less risky path to revenue, while in-house product development and commercialization offers the highest returns and the most control, but requires the most resources and carries the greatest risk. Thus, blending the two likely provides the most optimal approach to maximizing revenues.
With regard to planning an exit strategy, executives in early-stage biotech companies are faced with many potential options. Successful early-stage biotechs are either acquired or go public via IPO, whereas failed commercial startups will generally go bankrupt. M&As and IPOs have alternated as the preferred exit route over the past several decades. Post-interest rate hikes in 2022, the more common route has definitely moved away from public markets and towards acquisitions.
Financial metrics obviously matter significantly when contemplating an exit. This includes not just revenue streams, profit/loss, and growth margins, but also venture capital funding and other forms of financial backing. However, a company's valuation at the time of exit is not solely influenced by its balance sheet. Whether a company has a single promising asset or a diversified portfolio can affect its attractiveness to potential acquirers or investors. The richness and maturity of the R&D portfolio also weigh heavily and are almost always the exclusive factor driving an early-stage biotech company’s valuation.
Beyond these factors, the importance of strategic partnerships cannot be overstated. Collaborations with academic institutions can lend credibility and depth to R&D efforts, while partnerships with other biotech and pharma companies can provide the necessary capital and resources to bring a product to market more rapidly. These alliances often serve as a de facto validation of a company’s potential, making it more appealing to potential acquirers.
Data indicates that the upfront deal values tend to rise significantly between Phase II and Phase III. However, the total deal value remains relatively consistent across these phases. Essentially, this means that if a company is willing to take on the additional risk of advancing its asset to a later clinical stage, it might command a higher upfront payment upon exit without significantly altering the total deal value. This underscores the importance of ensuring our tolerance for risk in shaping our exit strategy.
The ability to exit is also crucial to securing venture capital funding; VCs have a variety of investing styles, but many will prefer to maximize their internal rate of return (IRR), which favours shorter time horizons. Thus, depending on the specifics of VC funding, if an investor has control of the company board, it may not be up to the management whether or not an exit, in this case an acquisition, will occur.
In summary, navigating a successful exit in the volatile and high-stakes world of biotech requires a multi-faceted approach. Our executives will have to balance financial metrics, R&D maturity, market potential, and strategic partnerships, all while carefully timing their exit to maximize both upfront and total deal values. It is a delicate act, necessitating a nuanced understanding of both the scientific and commercial landscapes, as well as a willingness to manage risk strategically.
In many markets, the price of drugs is regulated by the government on behalf of the citizens. The exception to this is the United States, where prices are almost entirely unregulated. This gives firms much more price-setting potential and is a main contributor to the US being the world’s largest drug market. The US pharmaceutical industry sees substantial revenue growth, partially due to the lack of regulation around drug pricing. Companies can raise the prices of their drugs beyond inflation rates, even if the demand is not high. Most of a pharmaceutical company's revenue comes from repeatedly increasing the prices of existing drugs rather than new drug sales, which has led in part to US medical inflation rapidly outpacing the rest of the consumer price index. In this report, we focus on drug pricing in the United States because that is where a young biotech company has the most freedom to set prices and the jurisdiction where the firm will more than likely capture most of its revenue.It is important to note that recent legislation—most notably the Inflation Reduction Act of 2022— aims to negotiate the prices of high-cost prescription drugs for Medicare beneficiaries. Starting in 2026, the act will target 10 high-cost drugs and expand to 20 by 2029. Companies refusing to negotiate could face a 95% tax penalty. The act also caps Medicare beneficiaries' out-of-pocket drug costs at $2,000 starting in 2025 and monthly insulin costs at $35.
Once PROTEUS is a commercial therapeutic, the following factors will need to be considered when setting its price.
- The uniqueness of the therapeutic: If a firm is developing a therapeutic or drug for a condition that has limited treatment options, the company may be able to set a higher price when the drug eventually goes to market.
- Competition: Understanding the landscape of existing treatments will be crucial. If the market is saturated, the young biotech may need to price its drug competitively. If the drug offers additional benefits over existing ones, it might justify a higher price. Pancreatic cancer has many drugs indicated for its treatment, however, patient outcomes remain suboptimal.
- Effectiveness: The more effective the drug or therapeutic, the higher the potential price. If the biotech's therapeutic can prevent expensive surgeries or other medical treatments, or if it can significantly extend or improve quality of life, these factors could justify a higher price point. If PROTEUS can offer superb patient outcomes, then a higher price for the therapeutic is justified.
- Research and Development Costs: R&D is often the most expensive part of therapeutic development, especially for a young biotech without revenue from other IP. These costs will need to be recouped through the therapeutic’s pricing. Investors and stakeholders will be keenly interested in how these costs balance against projected revenue. The goal is to minimize the cost of research and development to be able to maximize return on investment.
- Regulatory Environment: Being aware of regulations and regulatory hurdles like the Inflation Reduction Act of 2022 can help a young biotech plan for potential negotiations with Medicare or other governmental bodies in the future. Additionally, a significant sum will be spent during the R&D phase on compliance with the FDA, which needs to be faceted into the pharmaceutical’s price.
- Revenue Goals: Like any business, the ultimate aim would be to maximize revenue. Understanding the dynamics of pricing — too high could limit prescriptions, too low could undervalue the drug — will be key to financial viability.
- Customer Out-of-Pocket Costs: Depending on the patient population, consideration of what customers can afford may also be a factor, especially in light of potential caps on out-of-pocket expenses for certain categories of drugs and therapeutics.
- Generic Competition: Once the patent on the therapeutic expires, generic versions could become much cheaper. Revenue models must take into account this eventual drop in pricing power.
Understanding these elements could be key for any young biotech company, aiding in attracting investors by providing a detailed roadmap of how they intend to price their drug or therapeutic for maximum profitability and market penetration.
Pricing a therapeutic incorrectly can have a significant impact on its market success. Pharmaceutical companies raise prices primarily to maximize revenue, and the lack of competition for patented therapeutics allows them to do so freely. Generic drugs are cheaper because they do not incur the original R&D costs. Insurance companies and pharmacies determine the final amount a customer pays for a therapy, though the US government is not involved in setting the initial prices.
Note on Business Plan
Many elements of this section are inspired by excerpts from our Business Plan document. If you are interested in a more meticulous analysis of our commercialization strategy, please consult the Business Plan.
During product development and creation of an eventual proof of business, McGill iGEM aims to provide the highest quality of care available in the pancreatic cancer therapeutics space. Taking the proper precautions is essential for customer safety and satisfaction. PROTEUS has significant promise as a therapeutic, but comes with inherent risks given its ability to kill host cells based on recognition of a certain transcriptomic sequence.
For each patient that is eligible for using PROTEUS as a treatment option, we will act according to the following systematic approach to treatment:
- Patient cells are extracted, both healthy and oncogenic cells
- Cells are lysed, and DNA is extracted. Whole exome sequencing (WES) is performed to create a read for each lysed cell.
- Running the reads through our next-generation sequencing (NGS) pipeline, we can determine the best oncogenic target transcripts.
- We use our gRNA program to produce the most efficient gRNAs with minimal off-target effects based on the patient’s WES results.
- We test the gRNAs in vitro on patient-derived cells to determine the effects on both healthy and cancerous cells.
- We provide a minimal dosage to the patient using our viral vector delivery system and monitor the effects in vivo.
- We provide the suggested dosage, specifically targeting the tumour. The patient is monitored hourly for several days after the dosage to ensure comfort and no complications. Monitoring of general tumour shrinkage and patient health is recommended for several months following the first dose. Secondary or tertiary doses may be required.
The figure below provides an overview of the workflow:
Overall workflow for PROTEUS, from patient biopsy to final full-dose delivery. This is an idealized workflow that does not consider failure; in the case of poor quality or deleterious results, the workflow is restarted to ensure safe, effective treatment for each and every patient.
At each step of the workflow, several testing procedures are enforced to ensure the quality and reliability of the product as well as the safety for each and every patient. In the cell extraction step, we will recommend endoscopic ultrasound-guided fine needle core biopsy (EUS-FNB), which has been shown to be an effective method for diagnosing pancreatic malignant lesions; EUS-FNB provides well preserved tissue for histologic grading and subsequent molecular biological analysis (Yang et al., 2016). Most importantly, EUS-FNA is widely accepted as safe and effective; it is considered a minimally invasive biopsic protocol with an exiguous complication rate of approximately 1-2% (Yang et al., 2016; Adler et al., 2005; Kedia, Gaidhane, & Kahaleh, 2013). For DNA extraction and WES, there are minimal direct safety concerns for the patient; however, it is exceedingly important to ensure that WES is performed on a large sample size of both cancerous cells and healthy cells to effectively differentiate their phenotypes with statistical confidence. Both subsets will then be compared with a reference genome to perform variant calling. After developing a list of the most common variant alleles in the cancer cells (and absent in healthy cells) through the NGS pipeline, a medical practitioner can select which cancer genes should be targeted for the PROTEUS treatment. Instead of simply selecting the most common mutations, we recommend the support of medical professionals to ensure a balance of safety and efficiency in determining the optimal target mRNA(s). Specifically, the recommendations of both a clinical geneticist and a clinical immunologist would be optimal. These physicians may provide insight in the mRNA selection process to prevent over-inflammation, inefficient targeting of cancer, or off-target effects. Based on the mRNA target selected, there could potentially be high variance in the effects observed in the patient; hence, we consider the advice of credible medical professionals essential at this stage of the workflow.
After target selection, we run the target transcript sequences through our gRNA program. This program acts as an in silico model, outputting gRNAs with the most efficient binding properties to the target. It searches the output of the patient’s WES and compares the host genome to the most efficient gRNAs. The system has a built-in safety metric; if the gRNA exceeds a certain level of off-target activity based on its efficiency, the gRNA will be rejected, and the system will scan the next most efficient gRNA for its safety. This system has exceedingly conservative requirements to ensure the safety of the patient; any gRNAs with relatively high efficiency binding to other sites throughout the patient’s transcriptome are immediately discarded. One parameter we use to filter gRNAs is the extent of complementarity between the gRNA and potential secondary targets; any gRNAs with less than three mismatches with another region in the patient’s transcriptome are conventionally rejected. Even if the gRNA has minimal complementarity with off-target loci, it is nonetheless thoroughly scrutinized in terms of hybridization minimum free energy, RNA secondary structures, GC content, and other factors. gRNAs that pass these filters move on to in vitro testing in patient-derived cells. We transform patient cells – both healthy and cancerous – with the system and create growth curves by measuring cell viabilities at short increments over several days. By comparing cancer and healthy cell viabilities, we are able to more accurately determine how the gRNAs will behave in vivo on a patient-by-patient basis.
If at any point in the in silico to in vitro to in vivo workflow we find potential risks for the patient, we immediately return to in silico modelling to ensure patient safety. We go above and beyond taking minimal precautions, focusing on patient outcomes first and foremost. After finding acceptable results in vitro, we provide a minimal dose using our AAV delivery system both to assess the patient’s tolerance to the AAV, as well as to see the effects on tumour viability and any unforeseen consequences for healthy tissue. Depending on the extent of pyroptosis in healthy tissue, we will decide from the minimal dose whether the suggested dose will be safe and comfortable for the patient. These parameters will be determined based on results from human trials elucidating the ideal regimen to administer based on the patient’s specific circumstances and needs.
The final step of the workflow is administering the full dosage. At this point, the proper safety precautions have been taken to minimize harm to the patient all while delivering an effective, genetic level therapeutic against the patient’s cancer. We recommend maintaining constant monitoring of the patient in the first few days after delivering the treatment, followed by routine care and monitoring for the months following. Based on the patient’s disease progression following the primary dose, as well as monitoring of their immune response and potential health complications, a secondary or tertiary dose may be recommended to expedite patient recovery or increase the strength of the treatment for especially aggressive cancer cases.
This workflow will provide efficient, consistent results for patients eligible for treatment using PROTEUS. To ensure the highest quality products, we aim to seek review through ISO 9001:2015 Quality Management Systems and adhere to the guidelines provided by the Government of Canada for Good Manufacturing Practices (GMP) (ISO, 2015; Government of Canada, 2023). Naturally, the cancer therapeutic space is already tightly monitored for safety and quality; regardless, our team aims to enforce frequent quality inspections and maintain exhaustive documentation on a patient-by-patient case. Post-seed funding, our team aims to have a separate division for quality control. This is further discussed in Section 3 of the report. This division would ensure we meet the criteria to be certified under Quality Systems ISO 13485 by a third party auditing organisation akin to recognized registrars of the Canadian Medical Devices Conformity Assessment System (CMDCAS) (Government of Canada, 2019).
One potential bottleneck that arises in the workflow is the time constraint of providing care on a patient-by-patient basis. Naturally, given each patient will have unique genetic drivers behind their cancers, it becomes difficult to create a standardized, generalizable approach to cancer treatment. One option is to create a ‘library’ of sorts, where the most frequent driver mutations are kept on file; we could create standard gRNAs for these mutations and have them readily available in the case that they are requested by a physician’s office for a patient. This would save time for our most common orders, and would provide more consistency and assurance that the system will yield its regular results.
As mentioned, we plan to keep record of each treatment to ensure proper documentation in the case of regulatory scrutiny as well as for patient safety and medical histories. This will also allow us to develop our library of the most common orders by tallying the frequency of each mutation targeted. Our record-keeping practices through our Administration and Accounting division will have policies in place to maintain the privacy and dignity of all patients who choose PROTEUS. We plan to have a policy of no third-party disclosure of patient data.
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