Team:UCL/Expert-Guidance-Human-Practices

Expert Advice:

Bench-to-Bedside - Getting Expert Advice on the Treatment Translational Process

As mentioned on our summary page we integrated stakeholder feedback in four major aspects of our project: product design, industry relevance, safety, and ethics through expert guidance and direct interaction with clinicians and people affected by breast cancer. Here we will summarize our interactions with some of the experts we received guidance from, and detail how we integrated this into our project design and implementation.

Early on in our project, we collaborated with academics, such as Prof Steve Brocchini, and clinicians, such as Dr Yin Wu, to identify clinical targets for our drug delivery vehicle, and to assess the feasibility of treating patients with such a drug delivery platform.The feedback that we received from these experts allowed us to further develop our project, targeting HER2+ breast cancer specifically. It was here that we were made aware of patient preferences, and the factors contributing to patients’ quality of life, such as type of administration (intravenous/subcutaneous), duration of treatment, dosages and cost.

After speaking with clinicians, we wanted to contact breast cancer patients. We acknowledged that patient preferences must be incorporated early on the development of treatments, to ensure that the quality of life of patients is maintained, without impeding their recovery. As we were developing a targeted treatment, we wanted to ensure that side effects of conventional therapies were prevented, and this would also contribute to patient comfort and quality of life. Therefore, to understand other aspects of treatments that breast cancer patients may find uncomfortable, we sought the opinions of breast cancer patients, by contacting breast cancer research charities, Shine Cancer Support and Breast Cancer Now. These interactions are detailed on our Human practices page.

Industry

To evaluate the value of MESH in the pharmaceutical industry, we contacted industry specialists, Dr Michael O’Neill at AbbVie pharmaceuticals, Dr Christopher van der Walle, at AstraZeneca, which is renowned global,research-based biopharmaceutical company and Dr Nihal Sinha at F-Prime Capital, a global venture capital firm. We incorporated the feedback that we received from these experts at each step in the development of our project, and considered their advice on future development of our project.

Safety

Safety is at the core of our project, as any treatment that we develop must be bio-safe and non-toxic in order to be attractive to clinicians, patients, and pharmaceutical industries alike.To ensure this, we sought feedback from experts in drug design as well as industry experts to understand the guidelines on biosafety in drug development and how they could be implemented in the design of MESH.

Expert Advice

Academic

Dr Steve Brocchini: UCL School of Pharmacy

Dr. Brocchini has worked in the UCL School of Pharmacy for over 20 years. He was extremely helpful in highlighting problematic areas we were aware of, such as delivery method and endosomal escape, but also areas we had not even considered due to our lack of pharmaceutical background, including scalability, polyvalency, and de-risking strategies. We also discussed the interesting differences in perspective of open-source and non open-source pharmaceutical development, particularly relevant considering iGEM’s open-source ideals. He also made us aware of a couple of interesting recent perspectives published by Dr Christine Allen from the University of Toronto, and Dr. Kinam Park from Purdue University about the state of nanomedicine, prompting us to remain grounded and realistic about the outcomes of our project and our objectives.

“We need to rely on data, i.e., relevant and accurate data. It is time to accept that what we wish is not the same as what we can actually achieve… Scientists do what they can do without exaggeration and hype.” - Dr. Kinam Park -

“Advances are made by adapting and improving what works, and learning from those that do not work. The key to this seemingly obvious process is the strength, confidence, and willingness to accept failure.” - Dr Christine Allen -

Dr Andrew Care: Department of Molecular Sciences, Macquarie University.

Dr. Care is an early career research fellow working at Macquarie University in Sydney. We came across his work by a serendipitous tweet discovery (shown on the right). Intrigued we looking into his work, only to find a yet unpublished project using encapsulins to target breast cancer! Now very excited we got in contact with him and arranged a video call (taking into consideration the near 12 hour time change). He helped us make the very important decision of our cargo molecule of choice, photosensitizers!

Professor Oscar Della Pasqua: UCL School of Pharmacy

Professor Della Pasqua teaches the MSc/MRes course in Clinical Drug development at UCL. We contacted him seeking some advice on early drug design and development. He stressed the importance of testing the effectiveness of our encapsulin-based drug delivery platform in the tumour microenvironment, and advised us to consider the potential immunogenicity of the encapsulins, as they are bacteria-derived proteins. Drawing on his industry experience, he advised us to develop a method of manufacturing our drug delivery vehicles that prevents contamination, therefore ensuring the sterility of the treatment so that it can be administered safely to patients. He also advised us to follow the pharmaceutical stability guidelines outlined by the International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) to ensure the product quality of our drug delivery platform and to tailor our drug for large-scale production.

Dr Priscilia Lagoutte:

Dr Priscilia Lagoutte was one of the authors of one of the first papers that we read about encapsulins. Therefore, we contacted her to seek her expert advice on one of the early designs of our drug delivery platform. She told us to ensure that our encapsulins assembled properly, and that the DARPins didn’t lose conformation upon attachment to the encapsulin. To implement this, we modelled the interaction between encapsulins monomers and DARPins by varying the length of the linker to investigate the optimum length of linker required to give the desired configuration of the DARPins relative to the encapsulin.

Dr Ahad Rahim: UCL School of Pharmacy

We contacted Dr Ahad Rahim after being introduced to him by Prof Steve Brochinni. He is an Associate Professor at the UCL School of Pharmacy, working on gene therapy and advanced therapeutic medicinal products (ATMPs), as such, we approached him seeking guidance on early drug design. As much of his work involved engineering viral capsids, he was able to advise us on the immunogenic aspects of our drug delivery platform. He advised us to consider producing MESH in human cell lines or in eukaryotic cells, which would quell some of the concerns related to immunogenicity. This may make our drug delivery platform more attractive to pharmaceutical industries, one of our major stakeholders. He suggested that we should predict the manufacturing problems that we would encounter if we were to consider producing our drug delivery platform on a larger scale, before approaching pharmaceutical industry specialists. He also advised us to be mindful of the immune responses triggered against MESH after repeat doses, as he had seen a similar effect in viral capsid-based gene therapies. This secondary immune response would have an impact on the efficacy of our drug delivery platform, however, by speaking with Dr Andrew Care, we learnt that we could potentially harness the inflammatory response triggered against MESH to target the immune system to the site of the tumours - this may aid in patient recovery. An interesting aspect of our conversation with Dr Rahim was the consideration of Intellectual Property rights - it was here that we became aware of the fact that pharmaceutical industries would be interested to know whether or not any parts of our drug delivery platform have already been patented by others. Luckily, as our innovation is novel in its design, we wouldn’t necessarily need to worry about this. However, as DARPins have previously been used in targeted therapies, we may need to be mindful of any patents associated with the DARPin that we use in MESH. Overall, we received very insightful comments from Dr Rahim, and were keen to incorporate them into our product design.

Professor Paula Lorgelly: Health Economics at University College London

Prof Lorgelly measures outcomes of new drugs and uses this data to map out the economic evaluation of new drugs, to determine whether they have a high chance of being integrated into existing healthcare systems, such as the NHS (National Health Service) in the UK. She gave us an in-depth perspective into the implications of health economics on our project and was highly instrumental in introducing us to patient preferences. Pharmaceutical industries, clinicians and academics use data collected from patient preferences to determine patient needs and concerns, in order to develop more patient-driven treatments. This inspired us to approach our product design from the view of patients. As we were targeting breast cancer with MESH, we contacted breast cancer research charities, including Shine Cancer Support and Breast Cancer Now, in order to make our project more stakeholder-driven. This was a key element of human practices, and we were able to integrate the opinions of breast cancer patients to some degree into further development of our project.

Dr George Foot: Sixfold Bioscience.

Sixfold Bioscience is a young UK company started by three entrepreneurs, one of which, Anna Perdrix Rossell, was listed on Forbe’s 30 under 30. Sixfold Bioscience is using RNA for targeted drug delivery to treat cancer. We were interested in the company due to the parallels between their work and ours, and had the opportunity to chat with one of the co-founders, George Foot, via video call. We talked about our respective motivation, what is driving us to strive to help treat cancer. We also got some technical advice on endosomal escape strategies, although George was not able to share too much due to patenting issues.

Clinical

Dr Yin Wu: Academic Clinical Fellow at Fitzwilliam College, University College London

Dr Yin Wu was the first clinician that we contacted in order to get specific stakeholder feedback on our project. As he had considerable knowledge about a wide range of cancers, he was able to advise us on the development of cancers and how best to target them with novel therapeutic solutions. He told us that currently HER2+ breast cancer that has not metastasized is treatable:

  1. If it is local, then it is excised and treated with adjuvant chemotherapy to remove traces of cancer cells
  2. If the cancer has metastasized, then the line of action involves directly targeting using Pertuzumab® and Herceptin®, along with chemotherapy.

Although he did he appreciate the proposed double selectivity of our platform to reduce off-target toxicity, which is made possible by the use of photosensitizers, he deemed it less effective, as it involves more steps than conventional therapies. He did warn us of the potential limitations of our drug delivery vehicle, which included determining the immunogenicity of our platform. He recommended expressing our platform in CFPS (cell-free protein synthesis) or mammalian-based systems. He was extremely instrumental in advising us on the appropriate ways of approaching cancer patient needs and preferences.

Industry

Dr Nihal Sinha M.D.

Nihal is a Principal at F-Prime Capital, which is a US venture capital fund. He focuses on investment opportunities in novel biotechnologies and medical devices, healthcare information technology (IT) and services that are headquartered in Europe. Nihal studied medicine at the University of Cambridge, completed his foundation training as a medical doctor at UCL hospitals and was appointed Academic Clinical Fellow in medicine at Oxford University, during which time he conducted research in cognitive neuroscience. Nihal has also worked as a management consultant at BCG providing strategic and operational advice to business and clinical institutions in the UK. As potential investors were also key stakeholders of our technology, we wished to learn about the ways in which we could alter the design of our project to attract investors. Nihal was very excited about the modularity of our platform, as it would allow us to target different types of cancers in the future. However, he also made us aware that potential investors tend to invest in very few projects even though they may come across many potential ideas: Of the 100 deals the investors see, just 20% would be interesting and of those 15% wouldn’t be feasible. Therefore, 5% of such projects may show great potential, however, often only 1/100 actually get transacted. This gave us a reality check! We now realised the huge competition across the field of therapeutics, and in order to further understand how to overcome this competition, we approach some pharmaceutical industry experts.

Dr Michael O’Neill: Senior Director of Biology Drug Discovery and Senior Research Fellow at AbbVie (Biopharmaceutical company)

We approached Dr Michael O’Neill, as he had had more than 30 years of experience in the pharmaceutical industry. He was well-versed with the established protocols that are used to determine the incorporation of novel treatments into the existing pipelines of therapeutics in the industry. Thus, he advised us on the ways in which we could modify the design of MESH to suit the requirements of pharmaceutical industries. Most importantly, he told us to be wary of the potential immunogenicity of our drug delivery platform - conducting specific experiments testing the immunogenicity of our platform would greatly aid in the acceptance of MESH into the industry. He also advised us to examine the efficacy and potency of our platform by investigating its behaviour in the tumour microenvironment. Conducting aggregation studies to investigate the behavior of the encapsulins once drug delivery has been successful, as well as considering the long term impact of the drug. As HER2+ receptor tends to undergo mutations, this would render MESH ineffective after repeated treatments. To quell fears about immunogenicity and purity, he advised using CFPS to produce MESH, as well as investigating the potential of expression in mammalian cell systems. Lastly, he made us aware of the competition in the field of therapeutics. A lot of nanoparticles and targeted drug therapeutics have been developed that can target breast cancer. Hence, we need to be able to portray the stability of our platform in the tumour microenvironment, and would need to study the stability of encapsulins by themselves as well as in conjunction with cancer cells. Our conversation with Michael made us aware of the numerous considerations that we would need to investigate to mould our project with respect to the preferences of pharmaceutical industries.

Dr Christopher van der Walle: Director, Fellow at AstraZeneca

We contacted Dr Christopher van der Walle, he gave us insight for the requirements needed for MESH to be translated into a treatment. We would need to consider several factors including immunogenicity, bioassays examining DARPin affinity, potential for large-scale bioprocessing, toxicology reports, costs of production. He also informed us to be wary of assumption that out technology could pass solid tumours and to be careful in communication and explanation of a new cancer therapy, as these types of technology usually have massive interest which could mislead people if they do not fully understand the hurdles to reach the final treatment stage.