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About Peter Hofland
Peter Hofland, Ph.D is the Executive Editor of ADC Review/Journal of Antibody-drug Conjugates, a comprehensive digital platform and peer reviewed publication focusing on news and information about innovative therapies such as Antibody-drug Conjugates (ADCs). Hofland contributes articles on the advances in ADCs - from initial discovery to approved drug. He is also a contributor to Onco'Zine and The Onco'Zine Brief. For more information about Hofland, check his ORCID profile here: orcid.org/0000-0002-8025-0434

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About Sonia Portillo
Sonia Portillo is an associate editor of ADC Review/ Journal of Antibody-Drug Conjugates, an online, peer reviewed publication dedicated to following the developments of ADCs and other targeted therapies. Portillo studies cancer treatment from a pharmacological perspective, specifically in the area of precision and personalized medicine.


YProtech: Specialists in High Value Chemistries, from Early Research and Lead Identification to Optimization

Published on 18th September

Established in 2011 YProtech is a leading Chemistry Services Contract Research Organization specializing in high value chemistry services.

The company offers niche chemistry based services to the pharmaceutical, biotechnology and applied chemistry sectors, including contract research, custom synthesis, targeted library preparation, intellectual property development, chemical process optimization and scale-up and project/supply chain management to support pre-clinical drug discovery from milligrams to kilo scale.

YProtech’s success is based on their unique approach of integrating their services into the client’s organization. The company helps to expand the client’s capabilities and speed up the development of their project pipelines.  This combined with a flexible approach to project design and transparent communication, aids flawless project execution.

Photo 1.0: In 2015 YProtech relocated to the BioHub at Alderley Park in Cheshire, UK, where the company operates a high potency facility that allows them to offer dedicated chemistry services for the non-GMP synthesis and manufacture of cytotoxic compounds on multigram scale to support pre-clinical development for its pharmaceutical and biotech clients. 

Expansion
In May 2015 YProtech relocated to Alderley Park, Cheshire, UK, where the company now operates a high potency facility that allows them to offer dedicated chemistry services for the synthesis and manufacture of cytotoxic compounds on multigram scale to support pre-clinical development for its pharmaceutical and biotech clients.

The facility includes a clean room with isolator for the handling and isolation of cytotoxins, a dedicated high containment chemistry laboratory with multiple fume cupboards for the synthesis of cytotoxins, automated purification capability and access to liquid chromatography–mass spectrometry (LC-MS), and nuclear magnetic resonance (NMR) spectroscopy for compound analysis.

Synthesis of HPAPIs
While the company was initially focused on providing services and products for the broader pharmaceutical and biotechnology sectors, YProtech is now building on the company’s experience in the synthesis of chemical cross linkers. In part, the company’s success is based on their ability to handle and synthesize Highly Potent Active Pharmaceutical Ingredients or HPAPIs such as highly cytotoxic compounds that are used in the treatment of cancer and hematological malignancies.

This unique ability also helps the company manage a catalogue of cytotoxins and chemical linkers for bioconjugation, which can be tailored to individual customer’s needs, i.e. functionalized with linkers of choice and ready for subsequent bioconjugation with antibodies, proteins etc.

Earlier this year we sat down with Stuart Brown, Ph.D, Director of Business Development at YProtech and had the opportunity to get an overview of the company and the type of projects they manage.

Question [Peter Hofland/Sonia Portillo]: Tell me a bit more about the company.

Answer [Stuart Brown]: We provide niche chemistry services to the pharma, biotech and advanced materials sectors.

We focus on early research and development pipelines, from milligram scale to 100-gram scale synthesis. This includes, for example, lead identification and optimization projects for pharmaceutical and biotechnology industries.

With our unique expertise and experience we provide fast, efficient, solutions to our customer’s difficult chemistry challenges.

The speed in which we operate is due in part to clear and succinct communication which makes it possible to flawlessly meet the needs of our customers. Flexibility is another aspect which has helped our success.

Photo 2.0: ” …We focus on early research and development pipelines, from milligram scale to small grams scale synthesis of high potency small molecules.”

Question: Who is your client base?

Answer: Our customer base includes a mix of pharma, biotech and virtual companies who we work with to bridge or minimize the client-customer gap. This ensures that project updates are shared quickly and that customers have all the necessary information available to make the decisions and prioritize activities without delays that could impact project deadlines and research budgets.

Question: You focus on upstream chemistry associated with payloads for antibody-drug conjugates or ADCs…. What are some of the major challenges involved in the work you do?

Answer: Antibody–drug conjugates are a targeted chemotherapeutic that is currently at the cutting edge of oncology medicine. These hybrid molecules consist of a tumor antigen-specific antibody coupled to a chemotherapeutic small molecule.

In the United Kingdom, ado-trastuzumab emtansine (Kadcyla®; Genentech/Roche/Immunogen) was only recently approved for routine use by the National Institute for Health and Care Excellence (NICE). This has opened up new treatment regimens for patients with inoperable HER2-positive breast cancer. [a]

With over 60 antibody-drug conjugates in clinical trials, including 6 in Phase III, there is a lot of work ahead of us, and handling the Highly Potent cytotoxic payloads, can be challenging.

While common payloads such as the auristatins and maytansines are readily available, the more potent toxins such as duocarmycins and pyrollobenzodiazepines or PBDs are not as easily accessible commercially.

These newer, more potent, cytotoxins require an additional level of containment for safe handling, even at small milligram quantities. A number of ADC technology developers simply do not have the expertise or specialized facilities available to carry out the synthetic chemistry work required.

In addition, the toxins on their own may not meet our customers’ requirements as they tend to require toxin-linker payload to be synthesized to a bespoke configuration so that it can be used in subsequent conjugation to an antibody or antibody fragment. Our company offers the high potency chemistry services for these bespoke payloads.

Question: What kind of solutions have you been able to develop?

Answer: We’ve introduced a product offering in both cytotoxins and linkers to demonstrate our expertise in this area. This initial offering is really a precursor to our high potency synthesis services where we work with our clients on their specific needs and develop a bespoke solution for their payload and payload-linker requirements.

Depending on the requirements, we can also scale up their proprietary chemistry and provide them with sufficient compounds for their internal programs, and provide standard toxins or payloads in combination with our customer’s propriety technology for testing purposes, and so on.

Overall, we help our customers to speed up their R&D by supplying them with industry standard materials and assisting them in developing the best in class of products – whether its cytotoxins or linkers or a combination of both.

Question: You’ve recently installed a high potency facility for the synthesis and manufacture of highly potent cytotoxins for applications in cancer treatment. What is included?

Answer: As an extension to our standard chemistry services we have installed a dedicated high potency facility for the synthesis of milligram to gram quantities of highly potent APIs (cytotoxins).

The facility includes:

  • A clean room with an isolator for the safe isolation and dispensing of high potency small molecules or highly cytotoxic compounds. The HP facility isolator has been independently tested and operates at Occupational Exposure Limits or OEL <1ng.m3 as an 8-hour time weighted average (TWA);
  • A connected, fully equipped, wet chemistry laboratory, specifically for carrying out synthetic chemistry and purification with high potency small molecules or highly cytotoxic compounds;
  • A self-contained air handling system for the facility as a whole, with a negative pressure cascade to isolate it from surrounding lab spaces and ensure containment.

Question: How does this help your clients?

Answer: Our clients come to us for contract research services which includes the synthesis of high potency compounds to further their own research and development portfolios.

Typically, the compounds we synthesis are highly cytotoxic with OEL in the low nanomolar region. With our dedicated facility, highly skilled chemists—all of whom are Ph.D level organic chemists- and detailed safety procedures, we can ensure high potent chemistry projects to minimize the risk to the individuals carrying out the work and the surrounding environment.

Question: How do you help your customers in the development of ADCs?

Answer: Our customers are developing the ADCs. We provide them with very specific expertise and capabilities, which in turn speeds up their product development.

Question: What makes antibody-drug conjugates unique… and complex…?

Answer: Through targeted delivery of potent cytotoxins, ADCs exhibit improved therapeutic index and enhanced efficacy relative to traditional chemotherapies and monoclonal antibody therapies.

Today, two of the four currently FDA-approved ADCs, ado-trastuzumab emtamsine and brentuximab vedotin (Adcetris®; Seattle Genetics), are produced by conjugation to surface-exposed lysines, or partial disulfide reduction and conjugation to free cysteines, respectively.[a]

These stochastic modes of conjugation lead to heterogeneous drug products across several possible sites.

But one problem that scientists are dealing with is a limited understanding of the relationships between the site and extent of drug loading and ADC attributes such as efficacy, safety, pharmacokinetics, and immunogenicity.

Question: How do you help your clients increase their understanding?

Answer: While our expertise does not extend to the conjugation of the cytotoxins to the antibodies – we stop at the synthesis of the cytotoxic payload – we provide input into the design of the toxin-linker payloads and potential conjugation strategies based on our customer’s preferences.

In other words, this means that we can help our customers understand the underlying chemistry as well as the pros and cons of each approach and then guide them on the most applicable ways to proceed.

Multiple component agents
Question: What is the most challenging part in the development of a new antibody-drug conjugate?

Answer: Key challenges in the development of antibody-drug conjugates include new toxins, and many existing payloads originated as anticancer drugs that were discontinued in the clinic due to toxicity. But increasingly, we are seeing new toxin structures being developed and designed specifically for applications in ADCs.

There is movement away from the traditional microtubule inhibitors into novel mechanisms of action including DNA alkylators, DNA cross linkers, inhibitors of topoisomerase and RNA polymerase as well as spindle formation inhibitors.

There are now at least 19 different payloads found in the 60+ ADCs in active clinical development. Many of these payloads are found in ADCs that entered the clinic for the first time within the last 2 years.

In addition to cytotoxic payloads and antibodies, linkers also must be considered in the development of ADCs.

Linkers play an active role by holding targeting molecules and payloads together, and leading to the release of the payload once the active site is reached. Linker technology represents another challenge and novel technologies with cleavable and non-cleavable linkers are currently being developed for specific ADCs.

Question: What are you doing to help clients in understanding the importance of linker chemistries?

Answer: Choice of conjugation technology and conjugation site has an impact on the chemistry available for linker activation.

The actual choice of the linker, and whether a cleavable or a non-cleavable linker is desired, depends on the combination of linker and conjugation chemistry and the particular disease target. A number of our customers are experienced and very knowledgeable in these areas, but many also need assistance. We discuss specific disease targets with our customers and how the technology they select will impact the linker strategy. In the end, we reach a consensus on our chemistry approach.

The key here is dialogue and integration rather than providing an arm’s length approach. It is not enough just to synthesize a compound for our customers – the goal is to provide them with successful results and to be able to use the compounds we’ve prepared in their products.

And, finally, while we are not involved in the bioconjugation process itself, we can provide chemistry input on (the best) linker choice for downstream conjugation methodologies with new and existing antibody equivalents including bispecifics, antibody fragments, peptides, and site specific conjugation.  Each of these offer unique challenges.

Question: In recent years, complex biopharmaceutical drugs and biologics have evolved into mainstream therapeutics.

Answer: That’s true. We believe that not any one technology area will succeed on its own, but rather a combination of technologies will ultimately result in more effective, targeted, personalized treatments for an individual’s specific cancer.

Question: The manufacturing of these compounds requires extensive analytical and comprehensive characterization using a variety of techniques, including non-compendial, and sometimes an intricate quality control methodology, to confirm manufacturing consistency and product quality. What are some of the analytical methods you use?

Answer: Our small molecule toxins, linkers and associated payloads are all characterized by 1H Nuclear Magnetic Resonance (NMR) spectroscopy and Liquid Chromatography–Mass Spectrometry (LC-MS).

Because we do not work with the biological components, our analytical challenges are relatively simpler than those associated with the final antibody-drug conjugates.

Question: Following the development of antibody-drug conjugate there are challenges in the manufacturing of these agents. Can you explain?

The complexity of manufacturing an ADC is due in part to the fact that ADCs contain an antibody, a linker and a highly potent small-molecule cytotoxic payload. As a result, manufacturing them is an order of magnitude more difficult than producing any of these components alone.

The handling requirements for each component must be considered on its own and met, despite the fact that some of those requirements can directly contradict one another.

Photo 3.0: Effective containment is imperative to make the highly potent small-molecule cytotoxic payload as well as to have the ability to carry out complex chemical reactions. It’s essential to protect both operators and the environment around a manufacturing suite. YProtech’s Cleanroom with Isolator (Envair) allows for safe reconstitution and dispensing of cytotoxic compounds. while a separate wet chemistry lab is dedicated to cytotoxic chemistry.

Question: Effective containment is a requirement…

Answer: Yes… effective containment is imperative to make the highly potent small-molecule cytotoxic payload as well as to have the ability to carry out complex chemical reactions.

It’s essential to protect both operators and the environment around a manufacturing suite. The simple reason for that is that even tiny amounts of a cytotoxic compound used as part of an ADC are sufficient to have a biological effect. (as low as picomoles for the most active).

Therefore, containment is, and remains, a top priority.

The highly potent cytotoxic payload used in ADCs are typically microtubule disrupting agents that interfere with the cell cycle or DNA-modifying agents that kill cells — whether they are dividing or not. In the development of ADCs, scientists have noted that the many of the HPAPIs – the cytotoxic part of an ADC – cannot be used as therapeutic agents in a simple drug format because their therapeutic index is too low.

They cause too much damage and toxicity as they pass through the body and are likely to exert cell-damaging effects long before they reach cancer cells. In addition, the low dose that exerts a biological effect renders cytotoxic payloads extremely hazardous to operators should exposure occur.

Question: What are you doing to help your customers in this process?

Answer: Our dedicated facility has been designed to safely handle the highly potent small-molecule cytotoxic payloads. Independent OEL testing of our Isolator has confirmed that the facility can safely contain OEL of ≤1ng.m3, as an 8-hour time-weighted average (TWA).

Figure 1.0 Default compound categorization Level 4 to ensure consistency from project to project.

Our clean room with isolator allows us to safely handle solid cytotoxins. In this environment toxins are removed from their primary packaging and dispensed and dissolved prior to being repackaged for safe transfer out of the isolator and into the dedicated wet chemistry lab for further manipulations.

Toxins synthesized in the lab are also transferred in suitable packaging into the isolator for safe weighing/dispensing into their final format or formulation for dispatch to our customers.

We believe that we have an ethical responsibility to our staff, our customers and the surrounding environment to ensure that the highest level of safety is applied.

We use Standard Operating Procedures (SOP), staff training and lab testing, appropriate Personal Protective Equipment (PPE), and consult with independent safety assessors to ensure we meet the level of safety required.

Question: Are there any regulatory requirements involved?

Answer: The U. S. Food and Drug Administration (FDA) deems a drug occupationally potent or hazardous to operators if it is present in the air at a level of 10 μg/m3. That is about a tenth of the amount of dust that the eye can perceive in bright light.

Our services do not operate in a regulated environment, there is no regulatory definition of what makes a drug a highly potent cytotoxin or HPAPI, however, we do have a duty of care, which means that, in our case, ensuring operator safety is essential.

Question: How do you protect your workers/operators?

Answer: We have the specialist facilities mentioned above, all of our chemists operating in these facilities are trained in the use of the specialist equipment, and we enforce the highest level of containment for all projects.

Question: How do you help your clients to protect their workers/operators?

Answer: We discuss with our customers how they plan to use the products we send, e.g. do they have facilities and the capabilities to handle cytotoxins. Some of our customers prefer that we dispatch products to them as a formulated product in frozen solution ready for biocongugation.

Question: What kind of equipment/systems are you using to do this…

Answer: Cleanroom with Isolator, dedicated high potency chemistry lab, isolated air handling system with negative pressure cascade, and automated purification and analysis systems

Question: What are some of the regulatory challenges in developing and manufacturing ADCs?

Answer: Manufacturers and regulators are still learning best practices. That said, regulators have been making progress in creating regulations to ensure that manufacturers of ADCs have comprehensive understanding of every aspect of their processes.

Implementation of ICH guidelines for biologics manufacturing also affects ADC developers because the requirements detail insights right back to preclinical stages.

It is important to realize that the conjugation to form an ADC is not the only part that must be controlled, and that final product is not the only one that must meet regulatory requirements.

Question: What is your role in this process?

Answer: Along with our clients, we agree that having best practice guidelines and creating regulations is necessary as the sector matures, in order to ensure the safety of professionals and the surrounding environment. Hence, we engage with them and experts in the field to ensure that our in house guidelines are consistent with best practice in the sector.

Question: We discussed some of the manufacturing challenges. Based on the challenges, dedicated facilities are required. What are some of the bottlenecks for your clients?

Answer: The cost of developing ADCs is high, and one that only a few pharmaceutical companies can afford. And there are only a limited number of companies in a position to make the huge capital investments required for the safe manufacture of ADCs.

This is in part due to the complexity of the process, but also because of the costly manufacturing capacity, the high-containment equipment needed to handle the cytotoxic payloads, and the high operational and maintenance costs of the specialized equipment.

Current Good Manufacturing Practice (cGMP) capabilities are required long before a drug reaches commercialization. And as cytotoxic payloads become ever more potent, the capital investment required in equipment and containment will inevitably rise.

Question: How does this impact what you do?

Answer: We currently only offer pre-clinical chemistry services on a relatively small, laboratory scale. To offer cGMP synthesis services by adding a regulatory wrap around our services would require another level of investment to build a specialist scale up facility and the recruitment of the regulatory expertise to install the required processes and procedures. We expect to do this alongside our customers, as products move into the clinic.

Question: In the development of ADCs, or other complex drugs, it is suggested that a specific molecule may look great in early pre-clinical development. But later on, it may be found impossible to further develop. How are you helping your clients avoid manufacturing process errors or issues related to scale-up and manufacturability?

Answer: With a background in process chemistry, we can examine a customer’s process for the synthesis of payload-linkers and can identify potential process improvements to scale up synthesis. Doing this at as early a stage as possible allows us to bank associated process efficiency improvements and safety improvements.

An example is to look at telescoping two reactions together and use a common solvent for both. This reduces the synthesis time and more importantly avoids the isolation of a solid cytotoxic intermediate.

Question: How do you help your clients with risk assessment of the manufacturing process to identify any issues prior to scale-up?

Answer: This is something we carry out for all our projects, whether standard or high potency chemistry.

It is essential to understand the hazards before starting any process and to mitigate any potential hazardous events before they can occur.

Assessment may also result in the design of a new process to be tested ahead of scale up, but this is largely dependent on the specific customer requirements. Whether time to delivery or process efficiency is the driver for a project. Either scenario does not compromise on safety.

Question: … and training?

Answer: As independent consultants we advise on procedures and processes, and help implement SOPs for specific pieces of equipment or processes. Our staff is trained on safe handling procedures and hazard assessments, and all hazard assessments are checked and signed off prior to initiating work.

Potential of novel drugs like ADCs
Question: What excites you the most about the potential of novel drugs such as ADC?

Answer: These novel drugs have only really had their first wave applied to the oncology area. We are seeing more advanced technologies progressing into the clinic and potentially another 5 FDA approved drugs coming off the pipeline within the next ten years.

That can only be good news for patients.

The technology developed for cancer treatment can and is starting to be used in other disease areas. The targeting ability of the antibody is being coupled to different payloads to develop potential treatments for other diseases.

Looking at some of the drugs that were initially developed for the treatment of cancer and hematological malignancies, it’s interesting to note that a number of ‘technologies’ are now moving to other therapeutic areas. For example, monoclonal antibodies as a class of drugs were initially only available in the oncology setting. But today, monoclonal antibodies are being used in a variety of non-cancer areas and the same might be true for ADCs.

Merck (MSD) is one of the companies developing a new approach to take ADCs out of the realm of cancer, but have become aware of a number of technical issues, including the need to develop new linker chemistries.

I expect that our expertise in chemical synthesis, payloads, linkers and the synthesis of linker-payloads can be directly applied to new areas of ADC.

Question: Overall…What do you see is the biggest challenge in the (future) development of ADCs?

Answer: Improving preclinical methods to reduce the failure rate of ADCs in the clinic. The main reasons for this are lack of therapeutic window or no efficacy at the maximum tolerated dose, which suggests that current preclinical methods are not accurately predicting clinical results.

Figure 4.0: Senior Scientist in YProtech’s facilities.

The future
Question: What are your company’s major accomplishments over the past 12 months?

Answer: Over the last 12 months we have increased the size of the company by 50%, doubled revenues and opened the high potency facility and established the high potency business.

Our customer base has expanded 2-3 fold in recent years and we have a very high rate of repeat business from our customers. This is a huge achievement for us as a company

Question: … and what are your expectations for the next 12 months?

Over the next 12 months we have ambitious targets to again increase the size of the company by a further 50% and double the revenues. Both our standard and high potency chemistry services are expanding as the outsourcing model for R&D continues and YProtech’s reputation in the sector increases.

We are continually requesting feedback from our customers to ensure that our offering remains relevant and reflects the sectoral needs. We will also continue to expand our product offering for linkers and toxins to provide more choice to our customers.

Economy
During the last meeting of the Bio Innovation Organization in San Diego, CA, (June 2017), former prime minister David Cameron addressed Britain leaving the EU by advising biotech executives on how they should handle the Brexit process when it comes to their business.

Cameron mentioned that they should not worry over EU nationals who are working in the UK, as they will eventually have their rights to work in Britain guaranteed, even though this process is still being worked out. Additionally, he urged companies based in the UK not to concern themselves over the ability to hire from the EU.

While admitting that it would not be easy, Cameron said that a mechanism will be put into place in order to hire European workers.

In his speech at BIO, he urged that most of the concern should actually be placed on lobbying and worrying about the exact nature of the UK’s trading relationship after Brexit, which includes the impact of pulling the UK out from drug regulation by the European Medicines Industry.

Question: What are your expectations when it comes to BREXIT, the challenges involved and the (potential) opportunities it may give your company?

Answer: The challenges associated with BREXIT are undoubtedly significant, but there will also be opportunities. Since we operate at the pre-clinical stage the potential regulatory changes will not directly affect us – but it will affect our customers and the indirect effect on us remains to be seen.

As the economy changes and currencies fluctuate, it is currently more economical for US companies to work with UK companies and in the short term, that can help us in developing International business. But whether BREXIT will have an effect or not, the key is having an experienced management team and dedicated staff and a flexible approach to the economic challenges we must face.

I’m convinced that with our excellent Management Team – experienced in the growth and development in multiple CRO businesses and our highly experienced and skilled chemistry team – we can ensure that we can help our customers select and apply the correct technology solution to meet their specific needs.


[a] As of September 1, 2017 four antibody-drug conjugates have been approved by the U.S. Food and Drug Administration (FDA) and are currently commercially available in the United States. These ADCs include Brentuximab Vedotin (Adcetris®; Seattle Genetics), Ado-trastuzumab emtansine (Kadcyla®; Genentech/Roche),  Gemtuzumab Ozogamicin (Mylotarg™, previously known as CMA-676; Wyeth Pharmaceuticals, a subsidiary of Pfizer); and Inotuzumab Ozogamicin (Besponsa™, Wyeth Pharmaceuticals Inc., a subsidiary of Pfizer Inc.).

Last Editorial Review: September 7, 2017

Featured Image: Working with fluorescent microscope Courtesy: © 2017 Fotolia. Used with permission. Photo 1.0: In 2015 YProtech relocated to the BioHub at Alderley Park in Cheshire, UK, where the company operates a high potency facility that allows them to offer dedicated chemistry services for the non-GMP synthesis and manufacture of cytotoxic compounds on multigram scale to support pre-clinical development for its pharmaceutical and biotech clients.  Courtesy: © 2017 YProtech. Used with permission. Photo 2.0” …We focus on early research and development pipelines, from milligram scale to small grams scale synthesis of high potency small molecules.” Courtesy: © 2017 YProtech. Used with permission. Photo 3.0Effective containment is imperative to make the highly potent small-molecule cytotoxic payload as well as to have the ability to carry out complex chemical reactions. It’s essential to protect both operators and the environment around a manufacturing suite. YProtech’s Cleanroom with Isolator (Envair) allows for safe reconstitution and dispensing of cytotoxic compounds. while a separate wet chemistry lab is dedicated to cytotoxic chemistry. Courtesy: © 2017 YProtech. Used with permission. Photo 4.0: Senior Scientist in Yprotech’s facilitiesCourtesy: © 2017 YProtech. Used with permission.

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