Final Report Summary - SUPPRESSTEM (Testing and validation of bispecific antibody combinations targeting treatment-resistant cancer stem cells using organoid-based screening tools: a new drug discovery paradigm)
Executive Summary:
In 2013 the European Union funded the suppresSTEM consortium with a €6 million funding package from the 7th Framework Program of the European Union (FP7-HEALTH-2013-INNOVATION-2, Proposal No: 601876). The suppresSTEM consortium is coordinated by Merus NV. (The Netherlands) and includes as participants the Institute for Research in Biomedicine (Spain), the Welcome Trust Sanger Institute (United Kingdom), the Hubrecht Institute (The Netherlands) and OcellO B.V. (The Netherlands). The suppresSTEM consortium was formed to develop therapeutics that addresses important resistance mechanisms exploited by colorectal cancer cells to overcome conventional cancer treatments. To increase the likelihood of clinically translating these goals, screening and selection of drug candidates was performed directly on relevant human patient material (both tumour and normal) using organoid technology and novel imaging readouts. Using this screening technology permitted far greater accuracy in predicting which treatment/drug would be beneficial to which patient and reduces the need to use experimental animal models. As a result, the suppresSTEM consortium delivered a novel bispecific antibody-based therapeutic that modulates developmental, growth and survival pathways specific to cancer stem cells with minimal toxicity on healthy tissue. In addition, the consortium delivered a novel ex-vivo screening technique available for the drug development community which is expected to be applicable not only in colorectal cancer but for other types of cancer as well.
The goal of suppresSTEM was twofold; the generation of a novel antibody-based therapeutics for the treatment of metastatic colorectal cancer (CRC) and the collection of genetically annotated patient-derived CRC organoids for drug screening using novel tools developed in the project. Both objectives were achieved. The efforts within suppresSTEM lead to the identification of the bispecific antibody MCLA-158, which binds to cancer stem cells and is being developed as a treatment for colorectal cancer and other solid tumours. MCLA-158 has been shown to significantly inhibit tumour growth both in vitro and in vivo in organoid based assays. A patent application was filed covering the lead drug candidate. The suppresSTEM consortium also demonstrated the value of applying high content imaging to the complex patient-derived organoid tissue providing a rich new tool for drug discovery that will help reduce the high clinical failure rate in cancer drug research and also reduce dependency on the use of small animal models in drug discovery.
Using this screening technology may permit far greater accuracy in predicting which treatment/drug will be beneficial to which patient, in other words it could be used to select the patients with the greatest chance of response to treatment using already available gene typing diagnostics. This would result in significant extension of quality of life for colorectal cancer patients, but also would also avoid unnecessary treatment of patients that will not respond. In addition both the organoid technique and the drug are expected to be applicable for other types of cancer as well.
www.suppresstem.eu
Project Context and Objectives:
In 2013 the European Union funded the suppresSTEM consortium with a €6 million funding package from the 7th Framework Program of the European Union (FP7-HEALTH-2013-INNOVATION-2, Proposal No: 601876). The suppresSTEM consortium is coordinated by Merus NV. (The Netherlands) and includes as participants the Institute for Research in Biomedicine (Spain), the Welcome Trust Sanger Institute (United Kingdom), the Hubrecht Institute (The Netherlands) and OcellO B.V. (The Netherlands). The consortium was formed with a dual aim to develop new antibody treatments against colorectal cancer and to establish and validate a novel drug-discovery paradigm with broad application in the development of cancer therapeutics.
Colorectal cancer
Colorectal cancer is the third most prevalent malignancy in men and second most common in women. It is the 4th most common cause of cancer mortality worldwide. The 5 year survival rate of metastatic cancer ranges between 30-50%. With the aging of the population, the incidence of colorectal cancer and other carcinomas is expected to increase. The drugs developed as part of the program are designed to reduce the mortality associated with colorectal cancer (and potentially other cancers) and extend people’s lives.
While some new treatments have been advanced in colorectal cancer, many have failed clinical testing; metastatic colorectal cancer is still largely incurable. Traditionally most cancer drug discovery has focused on agents that block essential functions and kill dividing cells. However, in cases of advanced cancer, no matter how aggressively applied, even to the point where patients suffer life-threatening side-effects from the treatment, chemotherapy rarely results in a complete cure. In most cases, the tumours in the patients stop growing or temporarily shrink (referred to as remission) only to start proliferating again, sometimes more rapidly (referred to as relapse), and become increasingly more difficult to treat. More recently, the focus of cancer drug development has moved away from broadly cytotoxic chemotherapy to targeted cytostatic therapies with less toxicity. Treatment of advanced cancer with targeted therapy that specifically inhibits signalling pathway components has been validated clinically in leukaemia. In a majority of carcinomas however, targeted approaches are still proving ineffective. In colorectal cancer >80% of patients overexpress the receptor tyrosine kinase EGFR but treatment with EGFR blocking therapies results in response rates of ~ 10% and, as with chemotherapy, these responses are not durable. While in some patients the poor response rate can be linked to activating mutations downstream of the blocking agent, scientists now believe that a special type of self-renewing cancer cell may explain the limited activity of cancer drugs in many situations. Cancer stem cells are tumour cells that share characteristics with normal stem cells, most importantly the ability to give rise to all cell types within a given cancer. They form a very small subpopulation of the tumour. Recent evidence suggests that while conventional chemotherapy kills differentiated and differentiating cells that form the bulk of tumours, the self-renewing cancer stem cell is less effectively targeted. In tissues of the gastrointestinal tract such as the stomach, colon and rectum where there is a high rate of cell turn over, cancer stem cells are thought to arise from adult stem cells that have accumulated one or more mutations that initiate cancer development. The cancer stem cells proliferate and differentiate like normal stem cells but their progeny contain mutations that cause them to behave differently from normal differentiated cells. In particular, they are unresponsive to normal growth control signals.
Bispecific drug development
Antibody-based therapy for cancer has become an established strategy for treating patients with different kinds of tumors. Antibody-based therapy uses specially engineered human antibodies to bind specifically and tightly to molecular targets present on the surface of tumors. Using modern techniques it is possible to obtain a human antibody specific to almost any extracellular - or cell surface target. These therapeutic antibodies are in many ways indistinguishable from the natural antibodies the body makes to fight viral and bacterial infections. This is one of the reasons they are an exceptionally well tolerated class of drugs with very few toxic side effects. A bispecific antibody differs from conventional therapeutic monospecific antibodies because it has two different antigen binding sites and consequently binds to two different antigens or epitopes. Many different types or formats of bispecific antibodies have been experimentally generate. Biclonics® is the proprietary bispecific antibody format of Merus. Through their ability to bind to two different epitopes on a single or on multiple target antigens, bispecific antibodies can often exert more potent biological activities than conventional therapeutic antibodies. They have the ability to bind target cells more specifically and therefore are useful for drug conjugate technologies. They can also be applied to redirect immune effector cells such as T cells or NK cells for potent target cell killing.
The first objective of the suppresSTEM consortium was to develop a therapeutic that specifically targets cancer stem cells in colorectal cancer (CRC-SC’s) and shuts down important growth and differentiation pathways in these cells. Specific targeting was achieved by using bispecific antibodies containing one binding arm specific for a stem cell target and the other binding arm specifically blocking a growth factor receptor pathway. The rationale behind this combination was that in this way the stem cells can either be directly killed or will be sensitized to chemotherapy. By removing the proliferating source of the tumour it was expected that response rates with these treatments were significantly better than with existing treatments
Organoid technology
Despite an increase in understanding the causes of colorectal cancer, disease modelling systems available to researchers were limited until recently. The development of robust 3D culturing systems as designed by the Hubrecht Institute revolutionised the world of colorectal research. The Hubrecht Institute showed that stem cells from human primary tissues and cancers can be used to establish long-term cultures (‘organoids’) that resemble in many ways the original tissue. Organoids are stem cell-derived human epithelial ‘mini-organs’ from tissues of patients with various diseases including cancer and cystic fibrosis. In cell culture, organoids stably maintain the genotype/phenotype of the patient’s diseased tissue, thereby representing an in vitro platform for preclinical drug discovery and validation and a tool for precision medicine. Importantly, organoids proved to be both genetically and phenotypically stable during prolonged periods of cell culture and are amenable to all standard experimental manipulations.
In this project we generated an organoid “biobank” of paired colorectal cancer tumours and surrounding normal tissue. This panel of paired cancerous and normal organoids was used in screening the stem cell targeting bispecific antibodies for specific inhibitory activity and to select the lead candidate. To measure the growth inhibitory effect on the organoids novel imaging readouts were applied that simultaneously compare multiple phenotypic changes allowing for a better differentiation of drug effects.
Part of the promise of the suppresSTEM program was based on the expectation that combination of these two technological developments will dramatically increase the predictive power of drug screening. I.e. instead of measuring activity of drug candidates on artificial cell lines that only capture a fraction of tumour heterogeneity, screening can be performed on panels of relevant human patient material and instead of measuring only one aspect of the drug activity multiparametric analysis in high throughput settings will be possible. It was anticipated that, once realised, these technologies will increase the speed and effectiveness of cancer drug discovery, reduce the reliance on animal use for drug screening (in line with EU directives) and increase the success rate of drugs moving through clinical development – directly benefiting patients, the pharmaceutical industry and healthcare providers.
Objective
The goal of suppresSTEM was twofold; the generation of a novel antibody based therapeutics for the treatment of metastatic colorectal cancer (CRC) and the collection of genetically annotated patient-derived CRC organoids for drug screening using novel tools developed in the project
Project Results:
Work flow
In order to reach the twofold goal of suppresSTEM, the project was divided into discrete interconnected work packages under the leadership of different consortium members. The activities carried out in the work packages were designed to meet the objectives and were structured in two overlapping project streams. The first stream aimed on delivering a first in class therapeutic targeting CRC-SC’s ready for pre-clinical safety testing and the second project stream aimed on delivering a superior validated drug discovery technology platform (Figure 1).
Figure 1 | Interrelationship between work packages, the project objectives and project output
WP1 Generation of bispecific antibody panels
The first objective of the suppresSTEM consortium was to develop a therapeutic that specifically targets cancer stem cells in colorectal cancer and shuts down important growth and differentiation pathways in these cells. Specific targeting was achieved by generating and using bispecific antibodies containing one binding arm specific for a stem cell target and the other binding arm specifically blocking a growth factor receptor pathway. In WP1, panels of common light chain (cLC) antibodies were generated and characterized against at least four CRC-SC specific targets (LGR5, LGR4 ZNRF3, and RNF43). These were combined with potent antagonistic cLC antibodies against EGFR and HER3 in the Biclonics® bispecific antibody format. In the first phase the suppresSTEM consortium has generated over 500 different bispecific antibodies that collectively address six different cancer stem cell targets in different combinations. With this panel of bispecific antibodies, milestone one (MS1) was achieved in a timely manner.
WP2 Generation and testing of organoid screening panel and high content imaging assay
In this part of suppresSTEM, the consortium generated an organoid “biobank” of paired colorectal cancer tumours and surrounding normal tissue. This panel of organoids was used in screening the stem cell targeting bispecific antibodies for specific inhibitory activity and to select the lead candidate. To measure the inhibitory effect on the organoids novel imaging readouts were applied that simultaneously compare multiple phenotypic changes allowing for a better differentiation of drug effects.
Establishment of the biobank required (1) the generation, storage (master cell banks as well as working cell banks) and documentation of long term colon organoid cultures (>50 matched pairs of primary tumour and healthy colon and >20 metastatic tumours) derived from colon cancer patients (Hubrecht Institute) and (2) to determine the DNA mutations in the (metastatic) cancer organoids (primary, metastatic versus normal organoids) via high resolution exome sequencing. The exome sequencing data generated by the Sanger Institute will be published in their public database Cosmic. We have successfully generated, stored, documented and sequenced colon organoid cultures of 67 primary and 11 metastatic tumours. Subsequently, the somatic mutations in colorectal organoids were identified and interpreted. Mutational burden and profile of driver genes were highly similar to those identified in primary colorectal cancers. The generated and genetically characterized organoids derived from the tumoroid samples of several patients formed a solid basis to develop a high throughput morphology based assay for colon cancer organoids and for screening with a set of bispecific antibodies.
The high throughput-screening assay based on patient derived colon cancer organoids was successfully developed and validated using high content imaging as readout. The aim was to develop an imaging-based organoid screening assay in 384-wells plates, capable of distinguishing the morphological differences between colorectal cancer-derived tumoroids with different mutational backgrounds (and normal colon organoids), and to establish a screening window for measuring the effect of therapeutic agents. An organoid screening assay has been established that successfully and reproducibly identifies the morphological differences between organoids of different origin, organoid-specific growth factor responses and responses to pathway-specific drugs and antibodies.
WP3 Identification and characterization of the lead bispecific
The third phase of the project involves using the novel assay system to screen the bispecific antibody panel for drug candidates. The functional activity of the stem cell targeting bispecific antibodies was successfully tested in the organoid based screening assay. Approximately 140 bispecific antibodies were shown to have significant activity on at least one organoid. A panel of 53 lead candidates was selected from these assays that were further functionally characterized and biophysically/biochemically analysed. Based on the outcome of these studies a panel of bispecific antibodies with the best activities were produced at a larger scale and characterized analytically. Functional benchmarking was carried out in xenograft models. Three bispecifics were found to meet the deliverable criteria for lead candidates and MCLA-158 was found to be functionally the most potent bispecific and biophysically/ biochemically suitable for process development and manufacturing. MCLA-158 demonstrates superior activity to EGFR targeting reference antibodies in both in vitro and in vivo tumour organoid based assays. These preclinical data suggest MCLA-158 could benefit patients with metastatic CRC and warrant clinical evaluation. MCLA-158 will be developed as an ADCC-enhanced Biclonics® for the treatment of solid tumours and in particular colorectal cancer. MCLA-158 binds to cancer (stem) cells expressing leucine-rich repeat-containing G protein-coupled receptor 5 and epidermal growth factor receptors (EGFR). MCLA-158 has two different mechanisms of action. The first blocks growth and survival pathways in cancer (stem) cells. The second involves the recruitment and enhancement of immune effector cells to directly kill cancer (stem) cells that persist in solid tumours and cause relapse and metastasis. Through the identification of a lead drug product candidate, milestone 4, predefined as a major go/no-go decision point, was successfully achieved.
WP4 Lead product definition and manufacture
MCLA-158 was found to be functionally the most potent bispecific and biophysically/ biochemically suitable product candidate for process development and manufacturing. Following the milestone 4 go decision, the activities in WP4 commenced: a master cell bank for manufacturing was created and a toxicology batch of the bispecific antibody was produced to begin non-clinical safety studies. Additionally, to facilitate the clinical evaluation of MCLA-158 in cancer patients a clinical development plan was generated.
WP5 Validation and market definition of drug screening
In order to achieve commercialization of the organoid screenings assay several steps were performed.
First, a business plan was drafted for the organoid screenings assay. This includes a description of the services to be commercialized, an evaluation of the business case, analysis of the market and an analysis of the competition. Further attention was paid to the short and long-term financing required for commercialization and timelines to profitability.
Second, standard operating procedures were developed for both the organoid culturing as well as the high-content screenings assay; The Hubrecht Institute developed robust procedures for the culture and banking of organoid cultures. Freezing, thawing and culturing conditions were optimised, qualified and validated. Standard operating procedures were drafted and approved to ensure consistent performance and, in the case of licencing, that customers are able to utilize the technology successfully. A know-how document was assembled that provides potential licensees with all information necessary to use the organoid technology.
Additionally, the developed organoid screening assay was further validated. The dedicated organoid assay was successfully validated to measure the responses induced by treating organoids with compounds and antibodies in 384-wells plates in a high throughput format. The organoid screening assay performed very well in both primary and validation screens.
Based on the guidance resulting from the business plan and the completion of the standard operating procedures and assay validation the launch of the commercial use of the organoid assay was performed on the 23rd December 2016 with the execution of the licensing agreement between OcellO, the Hubrecht Institute and the HUB and with a full commercial launch marked by the issue of a press release on the 30th of January 2017.
Summary
In conclusion, in the suppresSTEM project we achieved all major milestones; Generation of a large bispecific antibody panel, development of an organoid screening assay and selection of a lead drug product for manufacture and clinical testing. The next steps after suppresSTEM will be twofold; Commercialization of the patient derived organoid assay and further development of the lead drug for clinical testing in 2018.
Potential Impact:
Impact for patients
Colorectal cancer (CRC) is the third most prevalent malignancy in men and second most common in women. It is the 4th most common cause of cancer mortality worldwide. The 5 year survival rate of metastatic cancer ranges between 30-50%. With the aging of the population, the incidence of CRC and other carcinomas is expected to increase. The drug developed as part of the program has the potential to reduce mortality associated with CRC (and potentially other cancers) and extend people’s lives. The main targeted therapies for CRC inhibit EGFR and antibodies are superior to small molecules in this indication. However, although 80% of cancers over-express the EGF receptor only 10% of patients respond to EGFR inhibitory treatment. In patients that do respond to treatment progression free survival (PFS) is only 4-5 months. The generated clinical candidate MCLA-158 was screened on a large panel of genetically phenotyped patient material (Organoids). In the future this information could potentially be used to select patients with the greatest chance to respond to treatment using already available gene typing diagnostics. This would result in significant extension of quality of life years for CRC patients. MCLA-158 would also be expected to have significant activity in other solid cancers.
Drugs for haematological cancers have been twice as successful in reaching the market as those for solid tumours. One contributory factor may be that during drug discovery, haematological tumour cells can be easily sampled by drawing blood or bone marrow and used to screen for active compounds. Drug development for solid tumours does not have that benefit. The use of patient organoids both in drug screening and potentially as a diagnostic tool enables drugs to be selected based on activity against patient tumours before the expensive and time consuming process of drug development begins. Preclinical screening will eliminate poor performing drugs faster and may facilitate identification of drugs potentially missed by conventional screening methods. Since the estimated cost of bringing a single new drug to the market is approximately US$ 1.9 billion (Mestre-Ferrandiz, J., Sussex, J. and Towse, A. (2012) Office of Health Economics) more relevant information from preclinical drug discovery that is translated into a higher success rate during clinical development of drug candidates for the treatment of solid tumours would have substantial financial and societal consequences. A first step has been taken by the Hubrecht foundation for organoids; as announced on the 4th of January 2017 in the Netherlands, the Hubrecht Organoid Technology (HUB), and the health insurance companies CZ, Zilveren kruis, and Menzis announced that they will start a €3 million validation trial for use of HUB Organoid Technology to test if it can be used to determine the response of Cystic Fibrosis (CF) patients to new drug therapies. This is a major breakthrough for the organoid technology and this project will demonstrate whether the HUB Organoid Technology can be used as predictive test for the treatment.
Scientific Impact
In this project a set of state of the art tools (human bispecific antibodies & combinations thereof, patient derived organoid cultures, exome sequencing and 3D imaging) were exploited in an integrated scientific approach. CRC SC’s (and the tumours they propagate) have not previously been successfully targeted therapeutically. Demonstration of external targeting of the Wnt pathway in CRC SC’s resulting in colorectal cancer tumour inhibition will have profound fundamental scientific repercussions and inspire numerous drug discovery projects in different cancers. The same holds for the application of organoids in drug screening and patient stratification. For the first time, a fully characterized patient 'biobank' is not only available for drug screening, but also for fundamental cancer research including novel target identification and validation. The details of the biobank will be made available through a scientific publication aimed in 2017 in a high impact journal. Dissemination of project results to target audiences (through scientific publication) will avoid duplication of the research funded in this project by other centres in the EU and internationally. Virtually all cancer drug development involves animal experimentation. In 2010, 51,288 animals were used in cancer research in the Netherlands. Extrapolated to the EU this potentially reaches the millions. Use of the organoid approach will reduce the dependency on the xenograft studies in line with the EU 3 R’s policy.
Impact for consortium partners
The lead product, backups and variants of the Fab’s and bispecific antibodies are covered by strong intellectual property rights (IPR) including newly filed method and product claims as well as previously filed Merus’ background IPR. The Hubrecht organoid patent family may be extended by enabling studies as part of the testing and validation of the drug candidates in this program protecting a new drug development paradigm. For the Hubrecht Institute and particularly OcellO this project provided validation of their technology platforms: OcellO in collaboration with the HUB will bring validated best-in-class drug screening services for CRC to the market. This project will provide the foundation for a broader range of organoid drug screening assays for other cancers, including breast, prostate and pancreas.
Impact for the research Institutes IRB and Sanger includes extension of their expertise by collaborating in this project. They were able to generate publications and train personnel in specialized techniques related to the project activities. Relationships were forged between the coordinators that could lead to follow up collaborations and further scientific breakthroughs in the near future. As a result of suppresSTEM a follow up collaboration was already publically announced on January 5th 2017; Merus and the IRB announced entry into a research collaboration to jointly develop novel agents that target the tumour microenvironment.
Merus
Merus generated a valuable clinical candidate (MCLA-158) that, based on its net present value, will increase the overall value and competitiveness of the company. This has strengthened its ability to pursue capitalization strategies, such as venture capital-based financing as well as the initial public offering in Spring 2016 on the NASDAQ. Merus will increase its head count by 5 FTE based on the direct results of this project. By the end of 2017, Merus expects to file an IND for a planned Phase 1/2 clinical trial of MCLA-158 in patients with colorectal cancer.
IRB Barcelona
IRB obtained important biological insights on the behaviour of colorectal cancer stem cells that help the Batlle lab advance in this area. Several promising lines of research have arisen from observation made during this collaboration that are currently being pursued. In addition, as a result of suppresSTEM a follow up collaboration was already publically announced on January 5th 2017; Merus and the IRB announced entry into a research collaboration to jointly develop novel agents that target the tumour microenvironment.
OcellO
The suppresSTEM project has enabled OcellO to make an important addition to its service offering – namely the extensive panel of colorectal cancer organoid assays. Furthermore, the project provided OcellO the opportunity to extend the performance of its 3D screening platform, increasing its capacity, throughput and the quality of the results that are generated. This has had a positive effect on the entire breadth of OcellO’s service offering beyond the organoid assays. With the launch of the collaboration between OcellO and HUB, formalised by the execution of a service agreement to offer HUB organoid technology over the coming ten years, we anticipate that this alone will have a strong impact on revenues over this period. The investment in technology development and the strong prospect of increased sales enabled OcellO to secure a first round capital investment to enable relocation to larger premises and investment in infrastructure. As a direct result of development and exploitation of the results of suppresSTEM, 4 additional FTE's will be in service at OcellO following the project.
Hubrecht Institute
The organoid technology developed by the Hubrecht Institute in the group of Hans Clevers, based on his breakthrough finding in adult stem cell biology, has become increasingly recognized as paradigm shifting technology in modelling of human disease. The Hubrecht Organoid Technology allows for the generation of cell culture models of human and animal epithelial tissues. Organoids can be efficiently grown in the lab from a variety of organs of all patients and of healthy and diseased tissues such as from cancer. Organoids are used for a variety of applications such as drug development but also predictive personalized treatments. In 2014, the Hubrecht Institute established a non-profit company Hubrecht Organoid Technology (HUB) which aim is to implement and commercialize the technology both for pre-clinical drug development as well as for clinical purposes. The Hubrecht Institute and HUB are members of new consortia and initiates revolving around the organoid technology such as suppresSTEM, CancerGenomiCs, and the international initiative HCMI (Human Cancer Models Initiative). Furthermore, through collaborations, services, and licenses the HUB is working with and for many pharmaceutical companies as well as biotech companies on the organoid technology including Galapagos, Johnson and Johnson, Boehringer Ingelheim, Astra Zeneca, Pfizer and Bayer. Together with these companies HUB uses the organoid biobank of various diseases and organs to discover novel drug targets as well as for drug development. Furthermore, HUB and the Hubrecht Institute collaborate with companies and Institutes to further develop the organoid technology into even more advanced models, for other indications and to develop therapeutics such as cell therapy. Because of the success of the organoids in predicting clinical outcome in preliminary experiments, the HUB has also started its first clinical trials where the organoid technology is used to determine treatment outcome of patients hereby increasing the efficiency of clinical trials, identifying new patient groups that benefit from specific therapies, and to prevent treating patients that will have no clinical benefit from the treatment. Taken together the organoid technology has been introduced very quickly into the different domains of life science and pharmacological research and applications. The HUB is rapidly increasing in size and aims to maintain and expand its role as the reference centre for organoid technology.
Dissemination activities
During the ‘live phase’ of the suppresSTEM project, dissemination activities were carried out more frequently among the internal scientific audience which consisted of suppresSTEM consortium participants, consortium institutions and the EC Research and Innovation directorate. These communications were in most cases treated as confidential. As the subsidized portion of the project has been completed the frequency of contact will diminish. As results in the project accumulated and IPR had been secured, abstracts to scientific conferences were submitted for posters or oral presentations. In this way the broader scientific community was informed about the activities in the suppresSTEM project. In addition, scientific and clinical development advice was sought from key opinion leaders and used to shape the research activities to ensure relevance for stakeholders. In addition to conference presentations, targeted stakeholders in the pharmaceutical industry that might have a role in the later development and commercialization of suppresSTEM results were kept up to date of progress in the project via confidential presentations in one to one meetings often coinciding with scientific or trade conferences. Finally, to engage the broadest audience a dedicated website was set up, maintained and updated with relevant project news (e.g. upcoming abstracts, presentations). Significant events were also highlighted in press releases from the various consortium members. The activities above will continue via the various consortium members after the completion of the project. A manuscript is in preparation and slides have been prepared to share as part of standard talks that are given by the high profile academic members of the consortium. Dissemination was, and will continued to be, aligned to project goals and the requirements of the consortium members via the regular project meetings although these will become ad hoc at the completion of the project. A database containing the project results (e.g. organoid characteristics, mutations, morphology, drug sensitivity) will be available for consortium members and when not in conflict with IPR protection to other relevant stakeholders. During the project feedback from meetings and other avenues was reported back to the consortium to evaluate the effectiveness of dissemination – this is expected to continue after the completion of the project.
Exploitation of results
The suppresSTEM project will only be judged a success if, after the project is completed, the outcomes are exploited to maximise their commercial and societal value. The two main outcomes anticipated in the suppresSTEM project 1) the delivery of a first in class stem cell targeting bispecific antibody therapeutic ready to begin non-clinical clinical safety testing based on a detailed clinical development plan and 2) a best-in-class patient-derived screening platform at the commercialization stage, were realised.
Colorectal cancer therapeutic
At the end of the suppresSTEM project Merus will pursue the clinical development of the CRC therapeutic bispecific antibody product code named MCLA-158. As outlined in the business plan of the grant agreement Merus will invest further capital to prepare MCLA-158 for clinical testing and then perform the first in human testing to generated clinical proof of concept. Merus has successfully performed development activities for two previous bispecific antibody programs now in various stages of clinical development. The consortium prepared a draft clinical development plan that aims to position MCLA-158 initially for use of treatment for metastatic CRC. Merus has secured and set aside the capital to perform these activities. Although this entails risk for Merus it will ensure that the product will reach the next important development phase in the shortest possible time. It also means that the product will be given the best chance to return value to the consortium and to stakeholders in the suppresSTEM project. As outlined in the grant agreement, once clinical proof of concept is reached Merus will have the choice to license out or co-develop MCLA-158 with pharmaceutical companies for upfront licencing fees, milestones and royalties and retain regional or global commercialization rights.
The end goal is to introduce a new differentiated therapeutic for metastatic colorectal cancer to the clinic. This will serve cancer patients globally where there is a high unmet need. It will promote the development of Merus an innovative drug development company that can use the capital flowing from the commercialization of the product to increase its resources to discover and develop new therapeutics.
Organoid screening services
At the end of the period a business plan for the exploitation of organoid screening services was completed. The goal is to offer a technology platform that is ideally suited to the identification of novel drugs, including antibodies, to treat colon cancer and other indications. The combined technologies are of great interest to the drug discovery industry and are expected to have a major competitive advantage over existing commercial screening services based on cell lines. OcellO and the HUB will cooperate to bring high throughput 3D screening assays using colorectal cancer organoids to the market.
Key to successfully exploiting this outcome from the project is active and effective dissemination. Organoid assays that are developed and validated in the project will be actively marketed alongside OcellO’s existing assays through its website (www.OcellO.nl) industrial conferences and direct contact via email-based networks, beginning with OcellO’s current customers. The Hubrecht Institute, through the HUB foundation, will make the organoid technology available for commercial (drug screening) and academic (research) partners. A databank containing information such as genetic profile, patient information and drug treatment regimen will be linked to the organoid samples to provide a tool for better insight in the efficacy of cancer therapies and the development of drug resistance. In addition, the Hubrecht Institute will support the screening services offered via OcellO for colorectal cancer. While OcellO will focus on providing in-house screening services, the longer term plan will be to offer a licensing package, which will include the organoid screening assay and assay-specific 3D image analysis software tools. This will allow larger (international) pharmaceutical companies with the necessary screening infrastructure to conduct screening on their own premises with their own compound libraries that they would otherwise be unlikely to release for outsourcing. Prior to a formal launch of the organoid screening assays, OcellO will conduct pilot studies with customers with the first pairs of developed assays to test performance and obtain customer feedback. The experience with these will guide the development of additional assays, necessary quality control measures and evaluate material and manpower requirements for consideration in a pricing strategy.
Project public website
www.suppresSTEM.eu
List of Websites:
www.suppresSTEM.eu
In 2013 the European Union funded the suppresSTEM consortium with a €6 million funding package from the 7th Framework Program of the European Union (FP7-HEALTH-2013-INNOVATION-2, Proposal No: 601876). The suppresSTEM consortium is coordinated by Merus NV. (The Netherlands) and includes as participants the Institute for Research in Biomedicine (Spain), the Welcome Trust Sanger Institute (United Kingdom), the Hubrecht Institute (The Netherlands) and OcellO B.V. (The Netherlands). The suppresSTEM consortium was formed to develop therapeutics that addresses important resistance mechanisms exploited by colorectal cancer cells to overcome conventional cancer treatments. To increase the likelihood of clinically translating these goals, screening and selection of drug candidates was performed directly on relevant human patient material (both tumour and normal) using organoid technology and novel imaging readouts. Using this screening technology permitted far greater accuracy in predicting which treatment/drug would be beneficial to which patient and reduces the need to use experimental animal models. As a result, the suppresSTEM consortium delivered a novel bispecific antibody-based therapeutic that modulates developmental, growth and survival pathways specific to cancer stem cells with minimal toxicity on healthy tissue. In addition, the consortium delivered a novel ex-vivo screening technique available for the drug development community which is expected to be applicable not only in colorectal cancer but for other types of cancer as well.
The goal of suppresSTEM was twofold; the generation of a novel antibody-based therapeutics for the treatment of metastatic colorectal cancer (CRC) and the collection of genetically annotated patient-derived CRC organoids for drug screening using novel tools developed in the project. Both objectives were achieved. The efforts within suppresSTEM lead to the identification of the bispecific antibody MCLA-158, which binds to cancer stem cells and is being developed as a treatment for colorectal cancer and other solid tumours. MCLA-158 has been shown to significantly inhibit tumour growth both in vitro and in vivo in organoid based assays. A patent application was filed covering the lead drug candidate. The suppresSTEM consortium also demonstrated the value of applying high content imaging to the complex patient-derived organoid tissue providing a rich new tool for drug discovery that will help reduce the high clinical failure rate in cancer drug research and also reduce dependency on the use of small animal models in drug discovery.
Using this screening technology may permit far greater accuracy in predicting which treatment/drug will be beneficial to which patient, in other words it could be used to select the patients with the greatest chance of response to treatment using already available gene typing diagnostics. This would result in significant extension of quality of life for colorectal cancer patients, but also would also avoid unnecessary treatment of patients that will not respond. In addition both the organoid technique and the drug are expected to be applicable for other types of cancer as well.
www.suppresstem.eu
Project Context and Objectives:
In 2013 the European Union funded the suppresSTEM consortium with a €6 million funding package from the 7th Framework Program of the European Union (FP7-HEALTH-2013-INNOVATION-2, Proposal No: 601876). The suppresSTEM consortium is coordinated by Merus NV. (The Netherlands) and includes as participants the Institute for Research in Biomedicine (Spain), the Welcome Trust Sanger Institute (United Kingdom), the Hubrecht Institute (The Netherlands) and OcellO B.V. (The Netherlands). The consortium was formed with a dual aim to develop new antibody treatments against colorectal cancer and to establish and validate a novel drug-discovery paradigm with broad application in the development of cancer therapeutics.
Colorectal cancer
Colorectal cancer is the third most prevalent malignancy in men and second most common in women. It is the 4th most common cause of cancer mortality worldwide. The 5 year survival rate of metastatic cancer ranges between 30-50%. With the aging of the population, the incidence of colorectal cancer and other carcinomas is expected to increase. The drugs developed as part of the program are designed to reduce the mortality associated with colorectal cancer (and potentially other cancers) and extend people’s lives.
While some new treatments have been advanced in colorectal cancer, many have failed clinical testing; metastatic colorectal cancer is still largely incurable. Traditionally most cancer drug discovery has focused on agents that block essential functions and kill dividing cells. However, in cases of advanced cancer, no matter how aggressively applied, even to the point where patients suffer life-threatening side-effects from the treatment, chemotherapy rarely results in a complete cure. In most cases, the tumours in the patients stop growing or temporarily shrink (referred to as remission) only to start proliferating again, sometimes more rapidly (referred to as relapse), and become increasingly more difficult to treat. More recently, the focus of cancer drug development has moved away from broadly cytotoxic chemotherapy to targeted cytostatic therapies with less toxicity. Treatment of advanced cancer with targeted therapy that specifically inhibits signalling pathway components has been validated clinically in leukaemia. In a majority of carcinomas however, targeted approaches are still proving ineffective. In colorectal cancer >80% of patients overexpress the receptor tyrosine kinase EGFR but treatment with EGFR blocking therapies results in response rates of ~ 10% and, as with chemotherapy, these responses are not durable. While in some patients the poor response rate can be linked to activating mutations downstream of the blocking agent, scientists now believe that a special type of self-renewing cancer cell may explain the limited activity of cancer drugs in many situations. Cancer stem cells are tumour cells that share characteristics with normal stem cells, most importantly the ability to give rise to all cell types within a given cancer. They form a very small subpopulation of the tumour. Recent evidence suggests that while conventional chemotherapy kills differentiated and differentiating cells that form the bulk of tumours, the self-renewing cancer stem cell is less effectively targeted. In tissues of the gastrointestinal tract such as the stomach, colon and rectum where there is a high rate of cell turn over, cancer stem cells are thought to arise from adult stem cells that have accumulated one or more mutations that initiate cancer development. The cancer stem cells proliferate and differentiate like normal stem cells but their progeny contain mutations that cause them to behave differently from normal differentiated cells. In particular, they are unresponsive to normal growth control signals.
Bispecific drug development
Antibody-based therapy for cancer has become an established strategy for treating patients with different kinds of tumors. Antibody-based therapy uses specially engineered human antibodies to bind specifically and tightly to molecular targets present on the surface of tumors. Using modern techniques it is possible to obtain a human antibody specific to almost any extracellular - or cell surface target. These therapeutic antibodies are in many ways indistinguishable from the natural antibodies the body makes to fight viral and bacterial infections. This is one of the reasons they are an exceptionally well tolerated class of drugs with very few toxic side effects. A bispecific antibody differs from conventional therapeutic monospecific antibodies because it has two different antigen binding sites and consequently binds to two different antigens or epitopes. Many different types or formats of bispecific antibodies have been experimentally generate. Biclonics® is the proprietary bispecific antibody format of Merus. Through their ability to bind to two different epitopes on a single or on multiple target antigens, bispecific antibodies can often exert more potent biological activities than conventional therapeutic antibodies. They have the ability to bind target cells more specifically and therefore are useful for drug conjugate technologies. They can also be applied to redirect immune effector cells such as T cells or NK cells for potent target cell killing.
The first objective of the suppresSTEM consortium was to develop a therapeutic that specifically targets cancer stem cells in colorectal cancer (CRC-SC’s) and shuts down important growth and differentiation pathways in these cells. Specific targeting was achieved by using bispecific antibodies containing one binding arm specific for a stem cell target and the other binding arm specifically blocking a growth factor receptor pathway. The rationale behind this combination was that in this way the stem cells can either be directly killed or will be sensitized to chemotherapy. By removing the proliferating source of the tumour it was expected that response rates with these treatments were significantly better than with existing treatments
Organoid technology
Despite an increase in understanding the causes of colorectal cancer, disease modelling systems available to researchers were limited until recently. The development of robust 3D culturing systems as designed by the Hubrecht Institute revolutionised the world of colorectal research. The Hubrecht Institute showed that stem cells from human primary tissues and cancers can be used to establish long-term cultures (‘organoids’) that resemble in many ways the original tissue. Organoids are stem cell-derived human epithelial ‘mini-organs’ from tissues of patients with various diseases including cancer and cystic fibrosis. In cell culture, organoids stably maintain the genotype/phenotype of the patient’s diseased tissue, thereby representing an in vitro platform for preclinical drug discovery and validation and a tool for precision medicine. Importantly, organoids proved to be both genetically and phenotypically stable during prolonged periods of cell culture and are amenable to all standard experimental manipulations.
In this project we generated an organoid “biobank” of paired colorectal cancer tumours and surrounding normal tissue. This panel of paired cancerous and normal organoids was used in screening the stem cell targeting bispecific antibodies for specific inhibitory activity and to select the lead candidate. To measure the growth inhibitory effect on the organoids novel imaging readouts were applied that simultaneously compare multiple phenotypic changes allowing for a better differentiation of drug effects.
Part of the promise of the suppresSTEM program was based on the expectation that combination of these two technological developments will dramatically increase the predictive power of drug screening. I.e. instead of measuring activity of drug candidates on artificial cell lines that only capture a fraction of tumour heterogeneity, screening can be performed on panels of relevant human patient material and instead of measuring only one aspect of the drug activity multiparametric analysis in high throughput settings will be possible. It was anticipated that, once realised, these technologies will increase the speed and effectiveness of cancer drug discovery, reduce the reliance on animal use for drug screening (in line with EU directives) and increase the success rate of drugs moving through clinical development – directly benefiting patients, the pharmaceutical industry and healthcare providers.
Objective
The goal of suppresSTEM was twofold; the generation of a novel antibody based therapeutics for the treatment of metastatic colorectal cancer (CRC) and the collection of genetically annotated patient-derived CRC organoids for drug screening using novel tools developed in the project
Project Results:
Work flow
In order to reach the twofold goal of suppresSTEM, the project was divided into discrete interconnected work packages under the leadership of different consortium members. The activities carried out in the work packages were designed to meet the objectives and were structured in two overlapping project streams. The first stream aimed on delivering a first in class therapeutic targeting CRC-SC’s ready for pre-clinical safety testing and the second project stream aimed on delivering a superior validated drug discovery technology platform (Figure 1).
Figure 1 | Interrelationship between work packages, the project objectives and project output
WP1 Generation of bispecific antibody panels
The first objective of the suppresSTEM consortium was to develop a therapeutic that specifically targets cancer stem cells in colorectal cancer and shuts down important growth and differentiation pathways in these cells. Specific targeting was achieved by generating and using bispecific antibodies containing one binding arm specific for a stem cell target and the other binding arm specifically blocking a growth factor receptor pathway. In WP1, panels of common light chain (cLC) antibodies were generated and characterized against at least four CRC-SC specific targets (LGR5, LGR4 ZNRF3, and RNF43). These were combined with potent antagonistic cLC antibodies against EGFR and HER3 in the Biclonics® bispecific antibody format. In the first phase the suppresSTEM consortium has generated over 500 different bispecific antibodies that collectively address six different cancer stem cell targets in different combinations. With this panel of bispecific antibodies, milestone one (MS1) was achieved in a timely manner.
WP2 Generation and testing of organoid screening panel and high content imaging assay
In this part of suppresSTEM, the consortium generated an organoid “biobank” of paired colorectal cancer tumours and surrounding normal tissue. This panel of organoids was used in screening the stem cell targeting bispecific antibodies for specific inhibitory activity and to select the lead candidate. To measure the inhibitory effect on the organoids novel imaging readouts were applied that simultaneously compare multiple phenotypic changes allowing for a better differentiation of drug effects.
Establishment of the biobank required (1) the generation, storage (master cell banks as well as working cell banks) and documentation of long term colon organoid cultures (>50 matched pairs of primary tumour and healthy colon and >20 metastatic tumours) derived from colon cancer patients (Hubrecht Institute) and (2) to determine the DNA mutations in the (metastatic) cancer organoids (primary, metastatic versus normal organoids) via high resolution exome sequencing. The exome sequencing data generated by the Sanger Institute will be published in their public database Cosmic. We have successfully generated, stored, documented and sequenced colon organoid cultures of 67 primary and 11 metastatic tumours. Subsequently, the somatic mutations in colorectal organoids were identified and interpreted. Mutational burden and profile of driver genes were highly similar to those identified in primary colorectal cancers. The generated and genetically characterized organoids derived from the tumoroid samples of several patients formed a solid basis to develop a high throughput morphology based assay for colon cancer organoids and for screening with a set of bispecific antibodies.
The high throughput-screening assay based on patient derived colon cancer organoids was successfully developed and validated using high content imaging as readout. The aim was to develop an imaging-based organoid screening assay in 384-wells plates, capable of distinguishing the morphological differences between colorectal cancer-derived tumoroids with different mutational backgrounds (and normal colon organoids), and to establish a screening window for measuring the effect of therapeutic agents. An organoid screening assay has been established that successfully and reproducibly identifies the morphological differences between organoids of different origin, organoid-specific growth factor responses and responses to pathway-specific drugs and antibodies.
WP3 Identification and characterization of the lead bispecific
The third phase of the project involves using the novel assay system to screen the bispecific antibody panel for drug candidates. The functional activity of the stem cell targeting bispecific antibodies was successfully tested in the organoid based screening assay. Approximately 140 bispecific antibodies were shown to have significant activity on at least one organoid. A panel of 53 lead candidates was selected from these assays that were further functionally characterized and biophysically/biochemically analysed. Based on the outcome of these studies a panel of bispecific antibodies with the best activities were produced at a larger scale and characterized analytically. Functional benchmarking was carried out in xenograft models. Three bispecifics were found to meet the deliverable criteria for lead candidates and MCLA-158 was found to be functionally the most potent bispecific and biophysically/ biochemically suitable for process development and manufacturing. MCLA-158 demonstrates superior activity to EGFR targeting reference antibodies in both in vitro and in vivo tumour organoid based assays. These preclinical data suggest MCLA-158 could benefit patients with metastatic CRC and warrant clinical evaluation. MCLA-158 will be developed as an ADCC-enhanced Biclonics® for the treatment of solid tumours and in particular colorectal cancer. MCLA-158 binds to cancer (stem) cells expressing leucine-rich repeat-containing G protein-coupled receptor 5 and epidermal growth factor receptors (EGFR). MCLA-158 has two different mechanisms of action. The first blocks growth and survival pathways in cancer (stem) cells. The second involves the recruitment and enhancement of immune effector cells to directly kill cancer (stem) cells that persist in solid tumours and cause relapse and metastasis. Through the identification of a lead drug product candidate, milestone 4, predefined as a major go/no-go decision point, was successfully achieved.
WP4 Lead product definition and manufacture
MCLA-158 was found to be functionally the most potent bispecific and biophysically/ biochemically suitable product candidate for process development and manufacturing. Following the milestone 4 go decision, the activities in WP4 commenced: a master cell bank for manufacturing was created and a toxicology batch of the bispecific antibody was produced to begin non-clinical safety studies. Additionally, to facilitate the clinical evaluation of MCLA-158 in cancer patients a clinical development plan was generated.
WP5 Validation and market definition of drug screening
In order to achieve commercialization of the organoid screenings assay several steps were performed.
First, a business plan was drafted for the organoid screenings assay. This includes a description of the services to be commercialized, an evaluation of the business case, analysis of the market and an analysis of the competition. Further attention was paid to the short and long-term financing required for commercialization and timelines to profitability.
Second, standard operating procedures were developed for both the organoid culturing as well as the high-content screenings assay; The Hubrecht Institute developed robust procedures for the culture and banking of organoid cultures. Freezing, thawing and culturing conditions were optimised, qualified and validated. Standard operating procedures were drafted and approved to ensure consistent performance and, in the case of licencing, that customers are able to utilize the technology successfully. A know-how document was assembled that provides potential licensees with all information necessary to use the organoid technology.
Additionally, the developed organoid screening assay was further validated. The dedicated organoid assay was successfully validated to measure the responses induced by treating organoids with compounds and antibodies in 384-wells plates in a high throughput format. The organoid screening assay performed very well in both primary and validation screens.
Based on the guidance resulting from the business plan and the completion of the standard operating procedures and assay validation the launch of the commercial use of the organoid assay was performed on the 23rd December 2016 with the execution of the licensing agreement between OcellO, the Hubrecht Institute and the HUB and with a full commercial launch marked by the issue of a press release on the 30th of January 2017.
Summary
In conclusion, in the suppresSTEM project we achieved all major milestones; Generation of a large bispecific antibody panel, development of an organoid screening assay and selection of a lead drug product for manufacture and clinical testing. The next steps after suppresSTEM will be twofold; Commercialization of the patient derived organoid assay and further development of the lead drug for clinical testing in 2018.
Potential Impact:
Impact for patients
Colorectal cancer (CRC) is the third most prevalent malignancy in men and second most common in women. It is the 4th most common cause of cancer mortality worldwide. The 5 year survival rate of metastatic cancer ranges between 30-50%. With the aging of the population, the incidence of CRC and other carcinomas is expected to increase. The drug developed as part of the program has the potential to reduce mortality associated with CRC (and potentially other cancers) and extend people’s lives. The main targeted therapies for CRC inhibit EGFR and antibodies are superior to small molecules in this indication. However, although 80% of cancers over-express the EGF receptor only 10% of patients respond to EGFR inhibitory treatment. In patients that do respond to treatment progression free survival (PFS) is only 4-5 months. The generated clinical candidate MCLA-158 was screened on a large panel of genetically phenotyped patient material (Organoids). In the future this information could potentially be used to select patients with the greatest chance to respond to treatment using already available gene typing diagnostics. This would result in significant extension of quality of life years for CRC patients. MCLA-158 would also be expected to have significant activity in other solid cancers.
Drugs for haematological cancers have been twice as successful in reaching the market as those for solid tumours. One contributory factor may be that during drug discovery, haematological tumour cells can be easily sampled by drawing blood or bone marrow and used to screen for active compounds. Drug development for solid tumours does not have that benefit. The use of patient organoids both in drug screening and potentially as a diagnostic tool enables drugs to be selected based on activity against patient tumours before the expensive and time consuming process of drug development begins. Preclinical screening will eliminate poor performing drugs faster and may facilitate identification of drugs potentially missed by conventional screening methods. Since the estimated cost of bringing a single new drug to the market is approximately US$ 1.9 billion (Mestre-Ferrandiz, J., Sussex, J. and Towse, A. (2012) Office of Health Economics) more relevant information from preclinical drug discovery that is translated into a higher success rate during clinical development of drug candidates for the treatment of solid tumours would have substantial financial and societal consequences. A first step has been taken by the Hubrecht foundation for organoids; as announced on the 4th of January 2017 in the Netherlands, the Hubrecht Organoid Technology (HUB), and the health insurance companies CZ, Zilveren kruis, and Menzis announced that they will start a €3 million validation trial for use of HUB Organoid Technology to test if it can be used to determine the response of Cystic Fibrosis (CF) patients to new drug therapies. This is a major breakthrough for the organoid technology and this project will demonstrate whether the HUB Organoid Technology can be used as predictive test for the treatment.
Scientific Impact
In this project a set of state of the art tools (human bispecific antibodies & combinations thereof, patient derived organoid cultures, exome sequencing and 3D imaging) were exploited in an integrated scientific approach. CRC SC’s (and the tumours they propagate) have not previously been successfully targeted therapeutically. Demonstration of external targeting of the Wnt pathway in CRC SC’s resulting in colorectal cancer tumour inhibition will have profound fundamental scientific repercussions and inspire numerous drug discovery projects in different cancers. The same holds for the application of organoids in drug screening and patient stratification. For the first time, a fully characterized patient 'biobank' is not only available for drug screening, but also for fundamental cancer research including novel target identification and validation. The details of the biobank will be made available through a scientific publication aimed in 2017 in a high impact journal. Dissemination of project results to target audiences (through scientific publication) will avoid duplication of the research funded in this project by other centres in the EU and internationally. Virtually all cancer drug development involves animal experimentation. In 2010, 51,288 animals were used in cancer research in the Netherlands. Extrapolated to the EU this potentially reaches the millions. Use of the organoid approach will reduce the dependency on the xenograft studies in line with the EU 3 R’s policy.
Impact for consortium partners
The lead product, backups and variants of the Fab’s and bispecific antibodies are covered by strong intellectual property rights (IPR) including newly filed method and product claims as well as previously filed Merus’ background IPR. The Hubrecht organoid patent family may be extended by enabling studies as part of the testing and validation of the drug candidates in this program protecting a new drug development paradigm. For the Hubrecht Institute and particularly OcellO this project provided validation of their technology platforms: OcellO in collaboration with the HUB will bring validated best-in-class drug screening services for CRC to the market. This project will provide the foundation for a broader range of organoid drug screening assays for other cancers, including breast, prostate and pancreas.
Impact for the research Institutes IRB and Sanger includes extension of their expertise by collaborating in this project. They were able to generate publications and train personnel in specialized techniques related to the project activities. Relationships were forged between the coordinators that could lead to follow up collaborations and further scientific breakthroughs in the near future. As a result of suppresSTEM a follow up collaboration was already publically announced on January 5th 2017; Merus and the IRB announced entry into a research collaboration to jointly develop novel agents that target the tumour microenvironment.
Merus
Merus generated a valuable clinical candidate (MCLA-158) that, based on its net present value, will increase the overall value and competitiveness of the company. This has strengthened its ability to pursue capitalization strategies, such as venture capital-based financing as well as the initial public offering in Spring 2016 on the NASDAQ. Merus will increase its head count by 5 FTE based on the direct results of this project. By the end of 2017, Merus expects to file an IND for a planned Phase 1/2 clinical trial of MCLA-158 in patients with colorectal cancer.
IRB Barcelona
IRB obtained important biological insights on the behaviour of colorectal cancer stem cells that help the Batlle lab advance in this area. Several promising lines of research have arisen from observation made during this collaboration that are currently being pursued. In addition, as a result of suppresSTEM a follow up collaboration was already publically announced on January 5th 2017; Merus and the IRB announced entry into a research collaboration to jointly develop novel agents that target the tumour microenvironment.
OcellO
The suppresSTEM project has enabled OcellO to make an important addition to its service offering – namely the extensive panel of colorectal cancer organoid assays. Furthermore, the project provided OcellO the opportunity to extend the performance of its 3D screening platform, increasing its capacity, throughput and the quality of the results that are generated. This has had a positive effect on the entire breadth of OcellO’s service offering beyond the organoid assays. With the launch of the collaboration between OcellO and HUB, formalised by the execution of a service agreement to offer HUB organoid technology over the coming ten years, we anticipate that this alone will have a strong impact on revenues over this period. The investment in technology development and the strong prospect of increased sales enabled OcellO to secure a first round capital investment to enable relocation to larger premises and investment in infrastructure. As a direct result of development and exploitation of the results of suppresSTEM, 4 additional FTE's will be in service at OcellO following the project.
Hubrecht Institute
The organoid technology developed by the Hubrecht Institute in the group of Hans Clevers, based on his breakthrough finding in adult stem cell biology, has become increasingly recognized as paradigm shifting technology in modelling of human disease. The Hubrecht Organoid Technology allows for the generation of cell culture models of human and animal epithelial tissues. Organoids can be efficiently grown in the lab from a variety of organs of all patients and of healthy and diseased tissues such as from cancer. Organoids are used for a variety of applications such as drug development but also predictive personalized treatments. In 2014, the Hubrecht Institute established a non-profit company Hubrecht Organoid Technology (HUB) which aim is to implement and commercialize the technology both for pre-clinical drug development as well as for clinical purposes. The Hubrecht Institute and HUB are members of new consortia and initiates revolving around the organoid technology such as suppresSTEM, CancerGenomiCs, and the international initiative HCMI (Human Cancer Models Initiative). Furthermore, through collaborations, services, and licenses the HUB is working with and for many pharmaceutical companies as well as biotech companies on the organoid technology including Galapagos, Johnson and Johnson, Boehringer Ingelheim, Astra Zeneca, Pfizer and Bayer. Together with these companies HUB uses the organoid biobank of various diseases and organs to discover novel drug targets as well as for drug development. Furthermore, HUB and the Hubrecht Institute collaborate with companies and Institutes to further develop the organoid technology into even more advanced models, for other indications and to develop therapeutics such as cell therapy. Because of the success of the organoids in predicting clinical outcome in preliminary experiments, the HUB has also started its first clinical trials where the organoid technology is used to determine treatment outcome of patients hereby increasing the efficiency of clinical trials, identifying new patient groups that benefit from specific therapies, and to prevent treating patients that will have no clinical benefit from the treatment. Taken together the organoid technology has been introduced very quickly into the different domains of life science and pharmacological research and applications. The HUB is rapidly increasing in size and aims to maintain and expand its role as the reference centre for organoid technology.
Dissemination activities
During the ‘live phase’ of the suppresSTEM project, dissemination activities were carried out more frequently among the internal scientific audience which consisted of suppresSTEM consortium participants, consortium institutions and the EC Research and Innovation directorate. These communications were in most cases treated as confidential. As the subsidized portion of the project has been completed the frequency of contact will diminish. As results in the project accumulated and IPR had been secured, abstracts to scientific conferences were submitted for posters or oral presentations. In this way the broader scientific community was informed about the activities in the suppresSTEM project. In addition, scientific and clinical development advice was sought from key opinion leaders and used to shape the research activities to ensure relevance for stakeholders. In addition to conference presentations, targeted stakeholders in the pharmaceutical industry that might have a role in the later development and commercialization of suppresSTEM results were kept up to date of progress in the project via confidential presentations in one to one meetings often coinciding with scientific or trade conferences. Finally, to engage the broadest audience a dedicated website was set up, maintained and updated with relevant project news (e.g. upcoming abstracts, presentations). Significant events were also highlighted in press releases from the various consortium members. The activities above will continue via the various consortium members after the completion of the project. A manuscript is in preparation and slides have been prepared to share as part of standard talks that are given by the high profile academic members of the consortium. Dissemination was, and will continued to be, aligned to project goals and the requirements of the consortium members via the regular project meetings although these will become ad hoc at the completion of the project. A database containing the project results (e.g. organoid characteristics, mutations, morphology, drug sensitivity) will be available for consortium members and when not in conflict with IPR protection to other relevant stakeholders. During the project feedback from meetings and other avenues was reported back to the consortium to evaluate the effectiveness of dissemination – this is expected to continue after the completion of the project.
Exploitation of results
The suppresSTEM project will only be judged a success if, after the project is completed, the outcomes are exploited to maximise their commercial and societal value. The two main outcomes anticipated in the suppresSTEM project 1) the delivery of a first in class stem cell targeting bispecific antibody therapeutic ready to begin non-clinical clinical safety testing based on a detailed clinical development plan and 2) a best-in-class patient-derived screening platform at the commercialization stage, were realised.
Colorectal cancer therapeutic
At the end of the suppresSTEM project Merus will pursue the clinical development of the CRC therapeutic bispecific antibody product code named MCLA-158. As outlined in the business plan of the grant agreement Merus will invest further capital to prepare MCLA-158 for clinical testing and then perform the first in human testing to generated clinical proof of concept. Merus has successfully performed development activities for two previous bispecific antibody programs now in various stages of clinical development. The consortium prepared a draft clinical development plan that aims to position MCLA-158 initially for use of treatment for metastatic CRC. Merus has secured and set aside the capital to perform these activities. Although this entails risk for Merus it will ensure that the product will reach the next important development phase in the shortest possible time. It also means that the product will be given the best chance to return value to the consortium and to stakeholders in the suppresSTEM project. As outlined in the grant agreement, once clinical proof of concept is reached Merus will have the choice to license out or co-develop MCLA-158 with pharmaceutical companies for upfront licencing fees, milestones and royalties and retain regional or global commercialization rights.
The end goal is to introduce a new differentiated therapeutic for metastatic colorectal cancer to the clinic. This will serve cancer patients globally where there is a high unmet need. It will promote the development of Merus an innovative drug development company that can use the capital flowing from the commercialization of the product to increase its resources to discover and develop new therapeutics.
Organoid screening services
At the end of the period a business plan for the exploitation of organoid screening services was completed. The goal is to offer a technology platform that is ideally suited to the identification of novel drugs, including antibodies, to treat colon cancer and other indications. The combined technologies are of great interest to the drug discovery industry and are expected to have a major competitive advantage over existing commercial screening services based on cell lines. OcellO and the HUB will cooperate to bring high throughput 3D screening assays using colorectal cancer organoids to the market.
Key to successfully exploiting this outcome from the project is active and effective dissemination. Organoid assays that are developed and validated in the project will be actively marketed alongside OcellO’s existing assays through its website (www.OcellO.nl) industrial conferences and direct contact via email-based networks, beginning with OcellO’s current customers. The Hubrecht Institute, through the HUB foundation, will make the organoid technology available for commercial (drug screening) and academic (research) partners. A databank containing information such as genetic profile, patient information and drug treatment regimen will be linked to the organoid samples to provide a tool for better insight in the efficacy of cancer therapies and the development of drug resistance. In addition, the Hubrecht Institute will support the screening services offered via OcellO for colorectal cancer. While OcellO will focus on providing in-house screening services, the longer term plan will be to offer a licensing package, which will include the organoid screening assay and assay-specific 3D image analysis software tools. This will allow larger (international) pharmaceutical companies with the necessary screening infrastructure to conduct screening on their own premises with their own compound libraries that they would otherwise be unlikely to release for outsourcing. Prior to a formal launch of the organoid screening assays, OcellO will conduct pilot studies with customers with the first pairs of developed assays to test performance and obtain customer feedback. The experience with these will guide the development of additional assays, necessary quality control measures and evaluate material and manpower requirements for consideration in a pricing strategy.
Project public website
www.suppresSTEM.eu
List of Websites:
www.suppresSTEM.eu
