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

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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Antibody Drug Conjugate Development: Keys to Rapid IND Submission and Approval

Antibody drug conjugates (ADCs) are a relatively new type of drug that combines the targeting ability of a biologic with a highly potent cytotoxic agent.

This powerful combination promises to become a game-changer in the fight against cancer—potentially replacing broad spectrum chemotherapies with more specific, less damaging options. At the same time, because ADCs’ cell-killing drug payloads are thousands of times more toxic than conventional treatments, safety concerns are proportionally amplified. That makes gaining regulatory approval for first-in-man studies far more demanding than with a traditional biopharmaceutical.

While it’s natural for pharmaceutical developers to focus on toxicological and pharmacological findings from animal studies, far too often, early stage ADC developers underestimate the importance of their filing’s Chemistry Manufacturing and Controls (CMC) section. This may result in regulatory requests for additional information or unanticipated studies, which can delay or even permanently derail a promising program.

This white paper discusses a pragmatic approach to helping ADC developers ensure IND success. It highlights two main challenges:

  1. Complexity of the ADC molecule
  2. Insufficient CMC data

This publication outlines strategic and analytical approaches that can save time and effort, and help ensure that regulatory requirements for CMC data are satisfied. It suggests that the best way to accelerate the regulatory path to first-in-man studies is to focus the CMC development plan on three areas:

  1. Critical Quality Attributes (CQA)
  2. Frequently overlooked studies
  3. Platform approaches

1.0 Antibody-drug Conjugates and the IND Process
Before human clinical trials can commence in the United States, new drugs must go through a complicated and time-consuming Investigational New Drug (IND) application and approval process. An IND application must demonstrate complete pharmaceutical or biopharmaceutical analyses. In addition to extensive data from animal pharmacology, toxicology studies, clinical protocols and investigator information, it must include detailed Chemistry, Manufacturing and Controls (CMC) information on the manufacturing and stability of the clinical trial material (CTM).[3]

When it comes to clinical studies with ADCs, additional scrutiny of CTM is to be expected. The inherent instability of biologics, together with the level of toxicity associated with an ADC’s small molecule payload have grave implications on patient safety. It is not surprising, then, that CMC data requirements and the level of analytical support needed to support an ADC program are substantially greater than with more traditional therapies.

According to the editors of ADC Review / Journal of Antibody Drug Conjugates, “One of the most critical aspects is to address all the unique issues involved in the submission of an IND completely, correctly, and in a timely fashion…” [2]

Incomplete or incorrect information can result in requests for additional studies, delaying the filing of a successful IND or worse—the financially motivated end to an otherwise promising program. But with a well-planned approach to testing and diverse technical/analytical expertise on your team, ADC developers can avoid these pitfalls and help ensure a seamless path to the clinic.


2.0 Why ADC development is so hard
According to the 2016 Nice Insight CDMO Outsourcing Survey, 57% of companies surveyed said they were developing ADCs, compared to 51% who said they have naked monoclonal antibodies (mAbs) in development.[4][5] Another source states that 182 companies around the world have ADCs in their pipeline.[6] Despite this surge, only four ADCs have been licensed to date. Plenty of examples exist of drugs that showed potential in early pre-clinical stages, but didn’t progress, and were terminated. Many of these failures were due to toxicity or incomplete characterization data.[7][8]

This white paper deals with two of the most common challenges relating to IND approval for ADCs. These are:

  1. The complexity of the ADC molecule itself, which is critical, as analysis of this complex structure informs decisions about its design and manufacture.
  2. Lack of necessary CMC data on the clinical trial Material

2.1 Challenge #1 – The complexity of the ADC molecule
The analytical challenges unique to ADC development are numerous, but chief among them are the complexity and stability of the mAb, the very difficult synthesis and characterization of the small molecule payload (cytotoxic agent) and linker, the chemical linking chemistry, and different conjugations that may be involved. [9][10][13]

Figure 1.0: Schematic showing the complexity and various components of an antibody drug conjugate.

Understanding the structure and behavior of biologically derived molecules–and interpreting analytical findings to inform development decisions—requires a myriad of analytical techniques and experienced biopharmaceutical scientists.[12]

Few Contract Manufacturing Organizations (CMOs) have the breadth of testing services required for full biopharmaceutical analysis. Not surprisingly, an estimated 70%-80% of ADC analysis is outsourced.[6]

ADC analysis also requires expertise handling highly cytotoxic compounds. Because the potency of ADC payloads is much greater than biologic drugs, it is crucial to truly understand the role that each part of the ADC – mAb, linker and cytotoxic agent – plays in the toxicity, stability and safety of a new drug.[7]

Linkers: improvements in linker design focus on serum stability and drug-to-antibody ratio (DAR). The overall concern with linkers is to produce more homogenous ADC populations by studying the conjugation between linker and mAb.

Payloads: choosing the right payload involves certain basic criteria, such as solubility, stability, and the likelihood of conjugation.[11] But ascertaining the correct drug potency also has proven to be a critical factor. According to McCombs et al, “poor clinical efficacy of first-generation ADCs is attributed to sub-therapeutic levels of drug reaching the target.”[10]

The IND analytical package must include not only assays and purity analyses, but also the drug-to-antibody ratio (DAR) and site(s) of conjugation. Only advanced biopharmaceutical analysis can supply this information.

Selecting the right analytical techniques is critical.[13] Valliere- Douglass et al. suggest that conventional analytical methods used for standard biopharma characterization are not sufficient for ADCs.[14] They outline the latest methods in mass spectrometry that have helped scientists fully characterize ADC drugs when conventional techniques fall short.

A list of analytical services and techniques necessary for ADC characterization is given in Part 4 of this white paper.


2.2 Challenge #2 – Failure to provide sufficient CMC data 
One of the primary reasons IND submissions for new ADCs are delayed is because the biopharma company (or their contract service provider) fails to perform analyses in accordance with Chemistry, Manufacturing and Controls (CMC) guidelines.[15]

This is because nine times out of ten, the drug developer lacks a clear plan for meeting CMC data requirements when mapping the development process.16 In fact, a key factor in streamlining your IND submission for a new ADC is finding a development partner who can help you articulate a well-planned CMC strategy early in the project.

Complete structural characterization, physico-chemical testing, and biophysical analysis of the antibody-drug conjugate are required. This includes the parent monoclonal antibody, as well as analysis of biological activity, toxicity, and stability of the drug product. Table 1 on the following page shows the structural analysis needed for the mAb intermediate.

As already mentioned, ADC analysis is more complex than traditional biopharmaceutical analysis. Multiple biopharma studies and analytical methods are required, as well as concurrent expertise in performing these techniques and interpreting the data.

Analysis Needed Appropriate Analytical Technique
Primary Structure (Complete Sequence) Peptide map-UPLC-UHR QToF
Disulfide linkage Peptide map-UPLC/MS/MS
Secondary/tertiary structure CD, Fluorescence, HDX-MS
Fragments Aggregates SEC-MALS, MFI
Charge icIEF
Glycosylation Peptide map-UPLC/MS/MS or cleavage/labeling/UPLC
Ohter post translational modifications Peptide map-UPLC-UHR-QToF
Antigen binding ELISA, ECL, SPR
Biological activity, as appropriate Cell bioassay (proliferation, cytotoxicity, affector)
Table : Necessary analysis of mAb to meet CMC guidelines, and corresponding analytical techniques

Bottom line: you may find traditional techniques used for biopharmaceutical analyses are quickly becoming obsolete. New, highly sensitive and specific technologies are becoming the standard, and are indispensable if you are to progress through the clinic ahead of your competition.[17]


3.0 Why traditional approaches fall short
The complexity of the ADC molecule and lack of emphasis on CMC development strategy are the primary causes for delays in ADC IND approvals. But since most early stage developers lack internal analytical resources, they must partner with consultants or CROs who understand regulatory guidance and can help them navigate the IND process. They also need access to a full suite of cGLP and cGMP-compliant analytical testing services. But it can be difficult to find a partner with the experience and capabilities necessary to step into this role.

There are two primary reasons why the choice of outsourcing partners can be especially critical for ADC developers:[17]

Analytical Capabilities
Older techniques are unable to provide the analyses necessary for ADC molecules – the stability of specific molecules cannot be determined, and a deep understanding of the molecule may not be possible.

Absence of a Plan
All too often, early stage developers lack a defined CMC strategy. When this is the case, archived samples often aren’t set aside, validation reports and studies are inconclusive, and compatibility studies are overlooked—all of which can lead to delays and/or insufficient data. In the absence of a clearly defined testing strategy, analytical methods are not in place to ensure the identity, strength, quality, purity and potency of the drug. These are required for every New Drug Application (NDA).[18]

Finally, according to an article by Amer Alghabban in Pharmaceutical Outsourcing: “The way a pharmaceutical company contracts CROs/ CMOs has a critical and direct impact on a company’s realization of its goal”[19]

Alghabban states that many manufacturers – 45.6% in one survey–have reported quality problems with their vendors, inexperience with regulatory requirements, and 49.1% of vendors were not able to keep their promises.[19][20]

Ultimately, current practices fail to overcome the two challenges outlined in section 2 because ADC developers partner with the wrong CRO.


4.0 Three ways to streamline the IND Process for ADCs
There are proven ways to increase your chances of successfully filing an IND for a new ADC, and at the same time reduce the amount of effort and expense involved.

Complete characterization and protein analysis play the most important part in this process.[13] This means characterizing attributes such as the drug-to-antibody ratio (DAR) and sites of conjugation. DAR is a critical factor for ADCs, because it represents the average number of drugs conjugated to the mAb. The DAR value influences the drug’s effectiveness, as low toxin loading lowers potency, and high toxin loading can negatively affect pharmacokinetics (PK) and toxicity. Sites of conjugation are important, because improving site-specific drug attachment can result in more homogeneous conjugates and allow control of the site of drug attachment.[21]

There are several considerations that can accelerate time-toclinical trials for an ADC. These include:

  • Analyzing critical quality attributes, or CQA
  • Developing a defined testing plan to ensure no necessary studies are overlooked, such as compatibility and residual solvent analysis—and a schedule that ensures the most efficient and timely completion
  • Adopting platform approaches to ADC development
  • The following sub-sections will address each of these in turn.

4.1 Conduct Detailed Studies of Critical Quality
Attributes
Critical quality attributes (CQA) are biological, chemical and physical attributes that are measured to ensure the final drug product maintains its quality, safety, and potency. The precursor to defining CQAs is complete characterization of the drug product and intermediates.

Currently, characterization of the mAb intermediate is already well defined, and includes studies such as:

  • Mass Analysis — Intact, reduced, deglycosylated
  • Peptide Map (UPLC–UHR QTof MS): sequencing, Post Translational Modifications (PTMs) and disulfide linkages
  • N-Glycan Profile Site, extent and structure of glycosylation
  • Circular dichroism
  • Differential scanning calorimetry

CQAs (relating to safety and efficacy of the drug) for an ADC product also include the following additional assays:

Analysis Needed Appropriate  analytical techniques
Drug-to-antibody ratio (DAR) HIC
Drug load distribution Peptide map-UPLC-UHR QToF
Linkage sites Peptide map-UPLC-UHR QToF
Linker payload structure FTIR, UPLC/MS/MS, NMR
Table 2: CQAs for an ADC relating to safety and efficacy, and corresponding analytical techniques

Additional attributes considered CQA, due to their impact on health and efficacy include:

  • Free drug concentration
  • Antigen binding
  • Cytotoxic assays
  • Free Drug Concentration

As mentioned earlier, the FDA is concerned primarily with human safety in regards to an IND submission. With ADCs, this means they are concerned with the concentration of free drug (toxin) in the final product — both on release and on stability. While the main advantage of ADCs is their targeted specificity, any free toxin introduced into the bloodstream is a serious threat to human health and safety. Therefore, any assay used to measure free drug concentration must be exceptionally sensitive (≤1 ng/ mL). This is typically performed by UPLC/MRM/MS.

Antigen Binding
Antigen binding is vital to the efficacy and specificity of an ADC. Non-specific binding results in the death of healthy cells and toxicity. Techniques to measure binding include:

  • Enzyme-linked immunosorbent assay (ELISA) – a biochemical technique for detecting and quantifying peptides, proteins and antibodies. Multiple formats can be utilized, but all incorporate binding of an antibody to the analyte resulting in a subsequent signal (UV, fluorescence, phosphorescence).
  • Electro-chemiluminescence (ECL) – a detection method based on luminescence from electrochemical reactions. ELISA and ECL can be used interchangeably, but ECL’s greater sensitivity allows it to be used in other studies, streamlining the IND process.
  • Surface Plasmon Resonance (SPR) – a label-free method used to monitor noncovalent molecular interactions in real time. Generally considered a poor candidate for antigen binding, due to poor inter-day precision.

Cytotoxic Assays
While all of the physico-chemical analyses (CE, icIEF, SEC, etc.) provide an idea of the purity and stability of a single aspect of an ADC, they do not provide a measure of the functional stability of the entire molecule. Cell bioassays are the ultimate measure of an ADC’s activity, stability and 3-dimensional structure, as they measure the effect of all degradation pathways. Bioassays, by their very nature, are variable and are technique-dependent, making them difficult to utilize as part of your IND submission. While research quality bioassays are sufficient for drug development; a qualified, accurate cell bioassay is an absolute requirement for an IND application. Optimizing these assays to make them precise and robust requires expert and experienced scientists. They provide a method that can be confidently used for stability and post-IND formulation development. Upon IND approval, these studies should be initiated immediately, shortening formulation/ process optimization.


4.2 Perform Studies that are often overlooked
A successful IND depends on multiple studies – particularly relating to toxicology – that are often overlooked, or even neglected. This is due to a lack of planning early on in the process. And these oversights can result in delays of several months.

A number of overlooked studies should be performed prior to initiation of toxicology and other early clinical tests. These include:

  • Dose formulation
  • Infusion set/syringe compatibility
  • In-use stability
  • Residual cytotoxins
  • Dose Formulation

Toxicology studies are performed at low doses and require greater sensitivity than release/stability assays. As required by the FDA, dose formulations must be assayed for toxicology studies, to ensure the correct dose is being delivered. The typical approach is ECL or ELISA. If ECL is developed for release, it is easily adapted to these studies, streamlining the overall IND process.

Infusion Set/Syringe Compatibility
Concern has been raised about the occurrence of critical incidents related to infusion sets. Every drug developer and CRO needs to establish a set of procedures to evaluate infusion sets from their vendors, particularly in terms of drug loss to surfaces. This includes filters, pre- and post-IV bags, and tubing. Multiple concentrations and durations should be tested.

In-use Stability
According to the FDA: “The purpose of in-use stability testing is to establish a period of time during which a multiple-dose drug product may be used while retaining acceptable quality specifications once the container is opened.” [22]

The FDA recently announced a draft GIF #242 entitled “In- Use Stability Studies and Associated Labeling Statements for Multiple-Dose Injectable Animal Drug Products”. The draft will outline how to design and carry out in-use stability studies to support the in-use statements, for multiple-dose injectable drug products.22 While this focuses on animal and multi-dose studies, the draft also reflects the importance the FDA places on in-use stability for human trials, and yet they are often neglected during the IND process.

Multiple stability-indicating assays are required, including:

  • DAR
  • ECL
  • Size Exclusion Chromatography (SEC)
  • Micro Flow Imaging (MFI)
  • Residual Cytotoxins

The linkage of the payload to the monoclonal antibody is an organic chemical event involving many of the typical solvents and catalysts. Therefore, similar to traditional pharmaceuticals, both residual solvents and heavy metals must be monitored on release of the drug substance. Typical assays include:

  • DMA (Dimethylacetone)
  • DMF (Dimethylforamide)
  • THF (Tetrahydrofuran)
  • Palladium
  • Platinum

4.3 Adopt a “Platform’ Approach
The basic idea behind a platform approach is to leverage “prior knowledge” to reduce the effort needed to start clinical trials. It begins with identifying a class of molecules that show comparable characteristics, such as physico-chemical properties and stability profiles.[23]

New candidates with characteristics that match known molecules can be treated as a “next-in-class” candidates. Once comparable characteristics are validated, developers can focus additional testing on areas of difference between the new candidate and historical likenesses—reducing testing requirements and at the same time further adding to the body of shared knowledge related to the platform, and increasing the platform’s robustness. Adopting a platform approach can significantly streamline IND testing requirements, accelerating time to clinic and reducing costs. According to Bradl et al., the platform approach enabled biopharmaceutical development for toxicological studies within 14 months after receiving DNA sequences. [24] After another six months, material from GMP facilities was provided for clinical studies. This resulted in a time requirement of 20 months from DNA to Investigational Medicinal Product Dossier.[24]

Of course, a key element is actually identifying those molecules that match the definition of a “next-in-class” candidate. Careful planning in regards to methods, data, and documentation will provide a universal approach applicable to other antibody drug conjugates.

Standardization of instrumental parameters, data collection and data manipulation can speed up characterization. The necessary studies include:

1. QToF – An ultra-high resolution Quadrupole Time of Flight MS, coupled to a UPLC can provide the vast majority of characterization data. Powerful QToF software, designed specifically for proteins, deconvolutes complicated mass spectra, simplifying data interpretation. The QToF can determine:

  • Complete sequence
  • Post translational modifications
  • Glycan profiles
  • Payload linkage sites
  • Disulfide linkages

2. Release and Stability:
The majority of assays are similar for all ADCs: SDS CE, icIEF, SEC, UV, and DAR. Generic assays can be qualified directly and only modified/optimized if qualification criteria are not met.

Design method qualifications appropriate to Phase I and template protocols
Binding assays should all utilize ECL. The sensitivity of this technique allows it to be used for toxicology and compatibility studies, as well as release and stability.

Other investigations typically include prophylactic studies in anticipation of agency questions. While they are not necessarily required for the IND filing, having data to support responses to agency questions will prevent delays. By preparing data in an IND-ready format, you’ll ensure “drag and drop” of the data, greatly facilitating the process in the typical last minute rush to complete the IND.


5.0 Buyer’s Guide: Choosing the right CRO for Fast IND Submission and Approval
According to a report by Global Industry Analysts, Inc., the global biopharma market is estimated to reach U.S. $ 306 billion by the year 2020.25

With this continued market expansion, including antibody drug conjugate development, there is a greater need for contract lab support. Not only this, but there is a critical need for high-quality contract laboratory partners who understand the regulatory guidelines, can perform required risk assessments, and can develop, validate and execute challenging analytical procedures.

If you’re looking for help from a CRO to reduce risk, and increase your chances of a successful IND submission, here’s what you need to look for:

True loyalty and partnership
You need a CRO that will take complete ownership of your product, and not just treat it like another sample. A CRO that partners with you closely – and isn’t simply a vendor – means they form a core part of your team, and have a personal stake in your success. They’re hands-on, and keep you updated every step of the way. Whatever CRO you choose, be sure they make their experts available to you at all times. They should take part in meetings, telecons, kickoff calls, and be involved in every stage of the process.

Scientific expertise
Significant scientific expertise in biopharmaceutical development and biopharma services is a must. A large proportion of the CRO staff should be made up of Ph.D. scientists and biopharma veterans. The CRO should assign scientific advisors that act as connections between your team and theirs. Their expertise and scientific background means they can accurately map out the entire process, from development to IND submission.

The right experience
Ideally, your CRO should have experience supporting successful IND submissions under tight deadlines. They should also have a solid track record of working on multiple biopharma products over several years. These drugs should span a wide range, from monoclonal antibodies and antibody-drug conjugates, to biosimilars and pegylated proteins. All projects need to be backed by an exceptional regulatory record.

Flexibility
Flexibility is important when the unexpected happens. Your CRO needs to work closely with you to determine the best analytical approaches. Their flexibility (and scientific expertise) means the CRO can think outside the box when things don’t go according to plan. They can quickly identify alternative ways of getting things done. In fact, finding novel ways to characterize and understand biopharmaceutical behavior is often necessary to file a successful IND.

Full range of analytical biopharma services. The complexity and heterogeneity of ADCs mean they are exceptionally challenging to characterize. A full suite of analytical services is necessary to do this. Be sure to ask your CRO about their capabilities, and what biopharma services they offer. As mentioned in this white paper, you need to be sure your CRO won’t overlook anything, and can help you meet CMC regulations. Their scientists should be experts in these techniques and interpretation of their data. At a minimum, these techniques should include cell-based bioassay development and analysis by ultra high resolution QToF, as well as routine release and stability testing.


6.0 Case Study: CMC Suport for ADC Development
Situation
Virtual client had very aggressive timelines for submitting INDs for two antibody drug conjugates within 12 months. The Client requested complete chemistry support for the CMC section of the IND
Solution

In collaboration with the client’s scientists, EAG proposed a fast-tracked method development and validation program to meet their timelines. EAG scientists performed complete characterization of the mAb and drug product, including complete sequencing, PTMs, and glycan analysis. Developed and validated multiple methods for release and stability including: icIEF, ELISA, cell bioassay, DAR, free drug, N-linked Glycan, SEC, CE-SDS, and HCP

Outcome
All data was delivered to the client within the deadline, and both INDs were submitted on schedule
Both INDs were successful, and the FDA had no observations/ remarks regarding the EAG’s portion of the IND. Our client’s priorities changed during the study, requiring additional studies beyond the scope of the original project. We were able to accommodate these changes and still meet their deadlines. EAG scientists were fully involved in project kick-offs.


7.0 Conclusion…
Finding a CRO who can partner with you to accelerate your antibody drug conjugate IND submission is challenging. It’s not easy to determine which CROs can truly partner with you to help you achieve your objectives.

This white paper has outlined two critical challenges with ADC development. Specifically, these challenges relate to successfully filing an IND. They are:

  • The complexity of the ADC molecule
  • Failing to meet CMC regulations
  • Given these challenges, there are 3 ways to streamline the IND process:
    • Characterize all critical quality attributes
    • Perform studies that are often overlooked
    • Adopt a platform approach

Abbreviations:
ADC, antibody drug conjugate; DAR, drug-to-antibody ratio; CMC, Chemistry Manufacturing and Controls; IND, Investigational New Drug; ELISA, Enzyme-linked immunosorbent assay; ECL, Electro-chemiluminescence; SPR, Surface Plasmon Resonance.

Keywords:
ADCs, Antibody-drug Conjugates, Characterization, Chemistry Manufacturing and Controls (CMC)


August 1, 2017 | Corresponding Author:
* Glenn Petrie, Ph.D. gpetrie@eag.com

How to cite:
Petrie G, Antibody Drug Conjugate Development: Keys to Rapid IND Submission and Approval (2017), DOI: 10.14229/jadc.2017.08.04.002.


Original manuscript received: April 12, 2017 | Manuscript accepted for Publication: July 3,  2017 | Published online September 4, 2017 | DOI: 10.14229/jadc.2016.09.04.001.

Last Editorial Review: August 17, 2017

Featured Image: Capped vials on an analysis autosampler – selective focus. Courtesy: © Fotolia. Used with permission.

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Preclinical Studies Show Significant Improved Therapeutic Index

Synaffix, a Netherlands-based biotechnology company exclusively focusing on the continued advancement of best-in-class and industry leading antibody-drug conjugate (ADC) technology platforms, has competed a new set of preclinical studies that further supports the potential for technology developed by the company to enable safer and more effective targeted cancer therapeutics.

Antibody-drug conjugates use monoclonal antibodies (mAb) to deliver highly potent cytotoxic chemotherapeutic agents targeted to specific tumor cells.  Compared to unconjugated cytotoxic chemotherapy, antibody-drug conjugates improve the therapeutic index or TI, the relationship between (the highest) exposure of a cytotoxic agent and the therapeutic dose, of an anti-cancer agent.[1]  In drug discovery and development, this pharmacodynamic parameter is relevant because it establishes how safe (or toxic) a specific drug is, leading to an appropriately balanced safety–efficacy profile for a given indication.


…[New] experimental findings… highlight the potential…  to address the persistent unmet medical need across a wide variety of cancer types…


Traditional conjugation process
Today, the majority of antibody-drug conjugates in the clinic are based on the conjugation of payload to naturally available amino acid side-chains (i.e. lysine, cysteine). While the majority of these ADCs use a linkage to the thiol of cysteines on the antibody, a lesser number of these drug candidates utilize chemistry to surface lysines of the antibody. This generally results in a stochastic distribution of drug−antibody ratio or DAR between 0 and 8. [1][2]

synaffix-illustration-ADCs1
Figure 1.0: With a suite of advanced tools for the design and development of antibody-drug conjugates Synaffix offers scientists a technology that can be used to develop ADCs targeted against a wide variety of cancer types.

Emerging technologies
A better understanding of conjugation chemistry and the underlying biologies have helped scientists advance the technologies used in the development of first- and second-generation antibody-drug conjugates, leading to new approaches, including considerable emphasis on site-specific conjugation, to ensure homogenous ADCs with well-defined DARs. [3][4]

New site-specific approaches being developped not only increase the homogeneity of antibody-drug conjugates, they also enable novel bio-orthogonal chemistries* based on reactive moieties other than thiol or amine.  In turn, these novel approaches broaden the diversity of linkers used, leading to better linker design for future generations of ADCs. [2][8]

Among these emerging technologies is Synaffix’s novel, proprietary, approach, which, for example, includes a robust, generally applicable, nongenetic technology designed to convert monoclonal antibodies into stable and homogeneous ADCs.[4]

The data in Synafix’ preclinical studies, based on the company’s latest R&D efforts, demonstrates that the company’s proprietary platform technologies, GlycoConnect™ and HydraSpace™, generate ADCs with significantly improved therapeutic index when directly compared to brentuximab vedotin (Adcetris®; Seattle Genetics/Takeda) and ado-trastuzumab emtansine (Kadcyla®; Genentech/Roche), two approved ADCs for the treatment of multiple lymphoma indications and HER2-positive breast cancer, respectively.[5]

synaffix-illustration-GlycoConnect2
Figure 2.0: GlycoConnect™ chemoenzymatic antibody remodeling and conjugation process developed by Synaffix.

Technology Platforms
GlycoConnect, Synaffix’ robust chemoenzymatic technology platform, is a site-specific and stable antibody conjugation technology that allows for efficient antibody-to-ADC conversion by anchoring a payload to the antibody’s glycan at asparagine-297 (Asn-297).

Human immunoglobulins, including Immunoglobulin G (IgG), the most prominent antibody in humans, are mainly glycosylated at the asparagine residue at position 297 (Asn 297) of the heavy chain CH2 domain.

Synaffix’ process involves proprietary enzymatic N-glycan remodeling with one azide, forming an anchor point for the copper-free click attachment of a cytotoxic payload.

The antibody remodeling includes a two-step approach.  In the first step the enzyme trims the glycan. In the second step the enzyme installs a proprietary small molecule substrate bearing a functional handle, which will be used during subsequent conjugation. In this process, the proprietary azide-based enzymatic substrate preserves the high reactivity and selectivity afforded by conjugation via click chemistry.

Since aromatically stabilized structures typically come with an order of magnitude higher stability than non-aromatic structures, the aromatically-stabilized triazole linker, formed during the second reaction, offers improved safety and efficacy profiles. As a result, a higher level of cytotoxic payloads reach the targeted cancer cell, increasing efficacy, while minimizing the potential of premature detachment in circulation and improving the safety profile.

Enhancing therapeutic index
GlycoConnect was shown to be capable of significantly enhancing the therapeutic index of an antibody-drug conjugate on its own.

Using novel proprietary linkers, the highly polar properties of HydraSpace-technology, an ADC-enhancing spacer technology which enables conjugation of highly hydrophobic payloads, improves the solubility and stability of the payload.

One of the challenges in the development of antibody-drug conjugates, is that most of the cytotoxic payloads are hydrophobic. As a result, linking them to a monoclonal antibody with an additional hydrophobic moiety may create problems due to aggregation. [6]

Since ADC aggregates are insoluble, such aggregates can limit achievable drug loading onto the antibody. In addition, some studies suggest that ADC aggregates are sequestered in the liver, leading to hepatotoxicity and is linked to increased immunogenicity.[6]

However, in contrast to standard approaches, the highly polar properties of HydraSpace-technology enables the most challenging hydrophobic payloads to be efficiently conjugated to antibodies.

According to Synaffix’ s scientists, the result is the generation of stable ADCs at the desired drug-to-antibody ratio (a homogeneous DAR 2 or DAR 4).  This novel technology makes it possible to increase drug loading using two different drugs with varying mechanism of action (MOA) to be incorporated into a single therapeutic ADC (DAR 2+2 “dual-payload” ADCs) by a single conjugation event. [4][7]

Metal-free Click Chemistry
Metal-free click chemistry is widely used by researchers in pharma, biotech and academia.  This chemistry offers a unique capability for rapid, selective and stable conjugation of complex macromolecules.

Synaffix’ scientists have extensively optimized metal-free click chemistry between cyclooctynes and azides in conjunction with GlycoConnect for conjugation of potent cytotoxins site-specifically to antibodies.

The resulting antibody-drug conjugates feature an aromatically stabilized triazole. Given its high stability, the resulting chemistry provides a powerful alternative to cysteine-maleimide conjugation chemistry currently used in the majority of antibody-drug conjugates in the clinic.

Furthermore, pre-clinical studies have demonstrated the versatility of GlycoConnect across a range of different antibody isotypes and linker-to-payload combinations as well as excellent in vivo efficacy and high tolerability.  This approach paves the way for the next generation of antibody-drug conjugates with an improved therapeutic index.[7]

Synaffix’ scientists were also able to seamlessly upscale GlycoConnect, further confirming manufacturability.

Key metric
“Improvement in the therapeutic index is a key metric in the quest for superior ADCs. What is exciting about our technology is that we can now consistently demonstrate in preclinical models of both liquid and solid tumors that if we connect the same antibody and payload from each [of the] commercially-available ADC products using our proprietary technology, we are able to increase the efficacy of the drug as well as its safety and tolerability,” noted Floris van Delft, PhD, co-founder and Chief Scientific Office at Synaffix.

“Our experimental findings to date … highlights the potential of our technology to address the persistent unmet medical need across a wide variety of cancer types,” Van Delft added.


Last Editorial Review: July 28, 2016

Note: * Coined by Carolyn R. Bertozzi, the term bio-orthogonal chemistries refer to chemical reactions occurring inside of living systems without interfering. These reactions neither interact with nor interfere with native biochemical processes. [8]

Featured Image: Scientists in Research Laboratories. Courtesy: © Fotolia Photo. Used with permission. Figure 1: Suite of Advanced tools for the development of antibody-drug conjugates. Figure 2: GlycoConnect chemoenzymatic antibody remodeling and conjugation process. Courtesy Figure 1 and Figure 2: © Synaffix BV, The Netherlands.  Used with permission.

Copyright © 2016 InPress Media Group. All rights reserved. Republication or redistribution of InPress Media Group content, including by framing or similar means, is expressly prohibited without the prior written consent of InPress Media Group. InPress Media Group shall not be liable for any errors or delays in the content, or for any actions taken in reliance thereon. ADC Review / Journal of Antibody-drug Conjugates is a registered trademarks and trademarks of InPress Media Group around the world.

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Avacta and Glythera Partner to Develop Novel, Highly Targeted, Drugs

Avacta Life Sciences, the developer of Affimer® biotherapeutics and research reagents will collaborate with Glythera a developer of advanced, stable conjugation chemistries and novel, ultra-potent toxin payloads, to evaluate the use of the Avacta’s Affimer® technology in combination with Glythera’s PermaLink™ conjugation chemistry. The partners announced that the ultimate goal is to develop a new class of of highly targeted bio-therapeutics which may have the potential to be a superior alternative to antibody-drug conjugates or ADCs.

Today two ADCs are approved by regulators in the United States and Europe and more than 50 are currently in clinical development. Approximately a quarter of the investigational agents are in phase II or Phase III trials. [1] Analysts estimate the market to be worth around US $ 1 billion today from two approved antibody-drug conjugates. They expected it to be worth US $ 10 billion annually by 2024.


The combination of the two companies’ technologies has the potential to deliver … best-in-class solutions…  opening additional avenues for bringing novel therapeutic to market… which could lead to … improved patient outcomes…


Increased therapeutic activity
Antibody-drug conjugates are highly potent biologics composed of a tumor specific monoclonal antibody linked via a linker to a cytotoxic drug.  By combining the unique targeting ability of monoclonal antibodies to discriminate between normal, healthy tissue and cancer cells, they are able to considerably reduce damage to healthy, normal tissues.

ADCs are being developed with the goal of increasing, and achieve, increased therapeutic efficacy by delivering highly potent cytotoxic molecules (with the cancer-killing ability of highly potent cytotoxic drugs with cellular IC50 values in the pM range).

Critical aspects in the development of successful ADCs include the selection of the targeting antigen, the monoclonal antibody against the target, the cytotoxic molecule or payload, the linker bridging the cytotoxic molecule and the antibody, and, finally, the conjugation chemistry.

Linker technology
Linkers are small organic chemical moieties or peptide of several amino acids required for the specific attachment of a highly potent cytotoxic payload to the antibody. Stable linkers play a crucial role in antibody-drug conjugates, and linker properties greatly influence the ADC’s pharmacokinetics, therapeutic index and efficacy.  The ideal linker is systemically stable so that biophysiochemcial property of the antibody-drug conjugate are similar to that of the unconjugated antibody. At the same time, linkers should still be able to release the payload at the target site. [2][3]

Challenging
Despite key advances made in linker chemistries, off-target toxicities, toxicities other than in cancer cells, are reported in several ADCs in clinical development. Off-target toxicities me be caused as a result of the limited stability of chemical linkages between antibody and cytotoxin, resulting in the the payload coming off the antibody and causing off-target toxicity and often severe, side effects.

This remains as a challenge, creating a need to improve linker chemistries.

Scientists are conducting extensive research to develop novel linkers utilizing linker platforms that include both cleavable and non-cleavable linkers. Linker technology is also crucial for improving the therapeutic window of an antibody-drug conjugates.[3]

Scaffolding technology
The collaboration between Avacta and Glythera aims to develop technologies that have the potential to create an analogous leading protein drug conjugate platform with a number of benefits over current ADC offerings.

Avacta’s Affimer technology is based on the cystatin protein fold. It has high affinity and high specificity. Affimer reagents are selected from libraries in which 12 – 36 amino acids are diversified giving a predicted total binding surface area of 650-1000 Å2. Unlike antibodies, Affimer reagents and biotherapeutics are produced in vitro.[4]

The reagents contain no disulphide bonds, are expressed easily in E. coli and have no batch to batch variability. One of the unique characteristics is that they can distinguish between proteins that differ by only a single amino acid.  Furthermore, they can be generated against targets which are intractable for antibodies and can even detect whether a protein is in an active or inactive conformation.[4]

Being proteins Affimer reagents don’t have the problems associated with aptamers, a special class of small RNA/DNA molecules which can form secondary and tertiary structures capable of specifically binding proteins or other cellular targets and essentially a chemical equivalent of antibodies.[4][5]

The Affimer scaffold has been engineered so that it does not binds to proteins found in human cells, serum or plasma. As a result,  interaction with an Affimer molecules are specifically defined by the engineered peptide loops made up of 19 naturally occurring amino acid side chains.[4]

The technology offers scientists the ability to closely control the position and number of cytotoxins in the payload. One of the benefits is that the technology has much shorter development times, allows for flexibility to “design-in” the required pharmacokinetics (i.e. the time the drug spends in the blood stream), and is much easier, more consistent and has lower cost production. The small size of the Affimer molecule is likely to also improve tumour penetration compared with antibodies which are ten times larger in size.

Exceptionally stable
PermaLink is Glythera’s highly specific proprietary cysteine linker technology that generates exceptionally stable antibody-drug conjugates with enhanced selectivity and specificity. Efficacy was demonstrated in both in vitro and in vivo for trastuzumab/monomethyl auristatin E (MMAE) based ADCs using various accepted cancer cell line models.  These studies demonstrates that the direct substitution of maleimide for an alternative conjugation technology has resulted in enhanced anti-cancer activity in a xenograft model,  providing a more stable attachment of the cytotoxic payload.  These studies further show that efficacy outperforms maleimide-based linkers in a mouse xenograft models. This approach can  potentially reduce off-target toxicity effects.[6]

PermaLink is highly specific for the sulfhydryl groups of cysteine residues which are a primary site for cytotoxic drug attachment in many antibody-drug conjugates currently in clinical development
The novel technology enhances stability provided by a stable thioether bond which is resistant to biological and chemical degradation. Furthermore, because PermaLink can be tailored to generate both “non-cleavable” and “cleavable” linkers for efficient release of active drug following antigen-mediated internalization, the technology is compatible with a diverse range of cytotoxic payloads. [6]

Agreement
Under the terms of the agreement, the companies will develop materials and methods to be used in the generation of Affimer-drug conjugates. The proof of concept study aims to demonstrate the key technical and commercial benefits of the combination over traditional antibody and linker approaches. The two companies will partner to offer Affimer-drug conjugate development services, and licensing of the combined platform, to pharmaceutical developers.

“We set out a detailed commercial strategy for Affimer technology, and [our new] collaboration with Glythera in the area of ADCs is another important application area,” Alastair Smith, Chief Executive Officer of Avacta, said.

“The combination of the two companies’ technologies has the potential to deliver a best-in-class solution. We’re  confident that the partnership will demonstrate the utility of the Affimer platform as a powerful approach to generating a broad range of biotherapeutics, creating opportunities for third party licensing of the platform with the potential to generate long-term value for both companies,” Smith noted.

“[I expect that] combining PermaLink conjugation chemistry with the Affimer technology will demonstrate the benefits of PermaLink across a new targeting molecule class, opening additional avenues for bringing novel therapeutic to market.  [I think that] the is a step forward in bio-therapeutic development which could lead to[novel agents] and improved patient outcomes,” Dave Simpson, Chief Executive Officer of Glythera added.


Last Editorial Review: July 14, 2016

Featured Image: Scientist with equipment and science experiments ,Laboratory glassware containing chemical liquid, science research,science background. Courtesy: © 2016 Fotolia. Used with permission.

Copyright © 2016 InPress Media Group. All rights reserved. Republication or redistribution of InPress Media Group content, including by framing or similar means, is expressly prohibited without the prior written consent of InPress Media Group. InPress Media Group shall not be liable for any errors or delays in the content, or for any actions taken in reliance thereon. ADC Review / Journal of Antibody-drug Conjugates is a registered trademarks and trademarks of InPress Media Group around the world.

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Linkers for Antibody Drug Conjugates: Current Role and Advancements

Advancements in research have shifted the way we think of combating cancer, and traditional treatment options are on the path to being replaced by safer and more effective methods.

Antibody-drug conjugates, or ADCs, are at the forefront of this change. They and are being developed to meet the challenges that cancer treatment has continually faced.

The chemistry that is used to attach an antibody, via a linker, to an cytotoxic agent affects the performance and efficacy of an ADC. That’s why linker chemistries have become an important target for scientists involved in the development of novel antibody-drug conjugates.

There are several requirements for the successful developments of antibody-drug conjugates, much of which has to do with the use of chemical linkers that hold an antibody and cytotoxin together. Linker research is aiming to produce linkers that suit the particular antibody and cytotoxin being used, provide stability before entering the cell, and provide efficient payload release once inside the target cel.

With traditional chemotherapy drugs, cancer cells are only killed slightly faster than normal cells, making treatment harmful and often ineffective. This lack of specificity was addressed by the development of mAbs that aimed to target antigens present on the surface of tumors, which allowed drugs to be targeted to specific regions and avoid contact with healthy cells. However, the use of mAbs alone has generally been unsuccessful due to their large size and poor penetrability.  [1] [2]

Better understanding of the biology of cancer
Now, as technology and our understanding of the biology of cancer and other diseases has advanced, targeted therapies like antibody-drug conjugates (ADCs) are paving the way for next generation cancer treatment. ADCs are able to take potent cytotoxic agents – up to a thousand times more powerful that traditional chemotherapeutic  drugs – and conjugate them to a monoclonal antibody that can specifically target a tumor antigen. This conjugation is done through the use of a chemical linker, which can undergo endosomal or lysosomal degradation and release the cytotoxin once inside the cell.[3]

Because the cytotoxic agent is released only inside the targeted cancer cell, there is possibility for highly tumor-targeted specificity, which enables the use of more powerful drugs while reducing off target toxicity. However, in order to prevent the cytotoxic agent from being released before reaching the cell, as well as to ensure that the payload is efficiently released, the development of linkers must be optimized.  There are a variety of linkers that have been developed for ADCs, all of which fall into the two general categories of cleavable and non-cleavable linkers. [4]

Cleavable vs. Non-Cleavable
Non-cleavable linkers are broken down once inside in order to release the active cytotoxic agent. After being internalized, they generate metabolites containing the cytotoxin and may or may not contain a portion of the linker as well.

One advantage of non-cleavable linkers is that they possess a greater degree of plasma stability. Additionally, they can potentially provide a greater therapeutic window due to the fact that they may carry a more potent cytotoxin, since internalization is required for any payload release.

Cleavable linkers rely on the physiological environment and release drug payload by either hydrolyzation or proteolysis. There are various types of cleavable linkers that have been developed for ADCs, which either fall into the category of chemically labile or enzyme cleavable linkers. [4]

In the past, several in vivo studies have shown non-cleavable linkers to outperform their cleavable counterparts. In fact, in a study of huC242-SMCC-DM1 (Immunogen), which uses the non-cleavable thioether linker N-succinimidly-4-(N-maleimidomethyl) cylcohexane-1-carboxylate (SMCC), has shown  that the ADC was only effective for tumors in which all proliferating cells expressed the target antigen. This was not the case for huC242-DM1 which contained a cleavable disulfide linker, which displayed higher in vivo activity in multiple xenograph tumor models as compared to its non-cleavable counterpart. [4] [5]

Chemically Labile Linkers
Chemically labile linkers include acid cleavable and reducible linkers, and they have been extensively applied in the manufacturing of ADCs.

Acid-cleavable linkers such as hydrazones and silyl ethers at the forefront of ADC development. Acid cleavable linkers are cleavable under acidic conditions in the cell, but they are designed to remain stable at the pH of the blood. However, non-specific drug release has remained a challenge for acid cleavable linkers, since they have often been associated with releasing cytotoxin in other acidic parts of the body.

Reducible linkers, on the other hand, take advantage of the cellular reducing environment. Reduced glutathione in tumor cells cytoplasm is very high compared to that of normal cells, and this is able to act on the disulfide bonds that hold these linkers together.

Chemically labile linkers have been used since the first approved ADC gemtuzumab ozogamicin (Mylotarg®; Pfizer/Wyeth). Gemtuzumab ozogamicin was withdrawn from the market in 2010 for toxicities related to poor plasma stability, leading to further research for this linker variety. That being said, inotuzumab ozogamicin (CMC-544; Pfizer), which has a structure closely related to gemtuzumab ozogamicin, has recently shown good stability in human plasma and serum with the use of acid labile 4-(4’-acetylphenoxy) butanoic acid linker for targeting CD22 expressing B-lymphoid malignancies. [4] [6]

Currently, Immunomedic’s IMMU-110, which uses an acid-labile linker to release doxorubicin (DOX), has shown high activity against multiple myeloma (MM; also called Kahler disease), a cancer that begins in the blood’s plasma cells, and appeared to be safe in monkey models, and is in now in phase I and II studies.

Milatuzumab (IMMU-115), as a doxorubicin conjugate currently in a Phase I/II clinical trial for the treatment of patients with relapsed multiple myeloma and also DOX based, uses a hydrazone linker and providing a basis for novel therapeutics against B-cell malignancies. [4] [7]

For disulfide linker based conjugates, which include the cytotoxic maytansinoids, progress is being seen through the development of the novel antibody-drug conjugate, IMGN242, which has shown excellent efficacy and clearance rates, about four times faster, when compared to its antibody component alone. [4]

Enzyme Cleavable Linkers
Enzyme cleavable linkers are different from chemically-cleavable linkers in that they rely on the presence of hydrolytic enzymes in the cell. These linkers can be peptide based or include a beta-glucuronide linker.

Peptide-based linkers, including valine-citrulline (Val-Cit) dipeptide linkers and phenylalanine-lysine (Phe-Lys) dipeptide linkers have been used in many antibody-drug conjugates. Designed to keep antibody-drug conjugates intact in systemic circulation, cleavage by specific intracellular proteases provide an excellent balance between plasma stability and intracellular protease cleavage.

Currently, AGS-5ME (Astellas Pharma) is an ADC based on a valine-citrulline (Val-Cit) depeptide linker, a substrate of cathepsin B, that is in Phase I clinical trials for the treatment of pancreatic and prostate cancer.

Beta-glucuronide linkers rely on cleavage by the enzyme β-glucuromidase, which is over expressed in the lysosome of many tumor cell types. These linkers have hydrophilic properties, which allow them to promote solubility of the ADC when compared to their dipeptide-based counterparts.  [4] [8]

New Approaches:  Quaternary Ammonium Linker
Despite recent progression, linker development remains limited in scope. Drugs that are conjugated as part of an antibody-drug conjugate must have certain reactive functional groups present in order to fit the drug linker chemistries that already exist.  Functional groups, including primary and secondary amines, phenols, and sulfhydryls, are commonly used for linker attachment and have been developed in recent years.

However, the scope of ADC payloads has recently been expanded by development of quaternary ammonium linkers. This novel linker can expand ADC payloads to include tertiary amines, a functional group commonly present in biologically active compounds, but that had not been used as a linker element thus far.

The conjugate for which this novel strategy is being used is a monomethyl auristatin E (MMAE) construct which uses a β-glucuronidase–cleavable linker which is showing impressive plasma stability thus far. Anti-CD30 conjugates comprised of the glucuronide-MMAE linker were potent and immunologically specific in vitro and in vivo, and the pharmacologic properties were similar to the carbamate-linked glucuronide-MMAE construct that was used as a comparison.

The novel linker was then used for a tubulysin antimitotic drug that contained an N-terminal tertiary amine. When the glucuronide-tubulysin quaternary ammonium linker was synthesized and evaluated as a payload, the resulting conjugates displayed a high level of activity in a Hodgkin lymphoma xenograft. This conjugate was potent and immunologically specific in vitro as well. These results were superior to those obtained with a related tubulysin derivative that contained a secondary amine N-terminus for conjugation, and which was developed using previous linker technologies.

The development of quaternary ammonium linker is currently being expanded to include new tertiary amine containing compounds. Researchers are hoping that this new strategy will allow for antibodies to combine with tertiary amine containing payloads and provide highly plasma stable, potent and better targeted ADCs that can contribute to the rapidly expanding ADC effort for cancer treatment. [9]


Last Editorial Review: May 31, 2016

Featured Image: Blood testing in laboratory Courtesy: © Fotolia. Used with permission.

Copyright © 2016 InPress Media Group. All rights reserved. Republication or redistribution of InPress Media Group content, including by framing or similar means, is expressly prohibited without the prior written consent of InPress Media Group. InPress Media Group shall not be liable for any errors or delays in the content, or for any actions taken in reliance thereon. ADC Review / Journal of Antibody-drug Conjugates is a registered trademarks and trademarks of InPress Media Group around the world.

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Kairos and Zymeworks Bring Together Complementary Technologies for the Development of Novel Antibody-drug Conjugates

Zymeworks, a privately held biotherapeutics company developing best-in-class Azymetric™ bi-specific antibodies, multi-specific antibodies and antibody drug conjugates for the treatment of cancer, and Kairos Therapeutics, a biopharmaceutical company with a proprietary next-generation antibody-drug conjugate platform based on novel toxin, linker, and site-specific conjugation technology, have entered into a strategic partnership whereby Zymeworks, has made an undisclosed equity investment in Kairos.  The company is a spin-out of The Centre for Drug Research and Development (CDRD), Canada’s national drug development and commercialization organization addressing one of the biggest challenges facing the life sciences sector today: how to translate commercially promising health research conducted at the university level into innovative new therapies that improve and save lives. Both companies and the CDRD are headquartered in Vancouver, Canada.

Under the terms of this agreement, Zymeworks and Kairos also have the option to merge to further integrate their respective platforms, resources and pipelines to accelerate the development of novel anti-cancer biotherapeutics.

Collaborations
Kairos Therapeutics is developing a pipeline of antibody-drug conjugate therapeutics based on a proprietary toxin, linker and site-specific conjugation platform. The platform, which is currently partnered through numerous collaborations, is a key contributor to personalized medicine as it allows scientists to develop therapeutics that target multiple forms of cancer with increased potency and efficacy while reducing toxic side-effects.

Complementary technologies
“We are excited to work with the team at Kairos in bringing together complementary technologies for the creation of novel and highly efficacious therapies for cancer patients,” noted Ali Tehrani, Ph.D., President and CEO of Zymeworks. “This is an excellent opportunity to leverage the therapeutic potential of ADCs in combination with our Azymetric™, AlbuCORE™, and EFECT™ platforms to help us create first-in-class biotherapeutics. This strategic investment and opportunity to integrate Kairos’ ADC platform and expertise furthers our strategy of acquiring innovative technologies that can augment internal capabilities and accelerate development programs.”

“We believe we have developed a superior antibody-drug conjugate platform which has demonstrated significant advantages over existing ADC platforms, and our proprietary approach shows promise in the development of treatments for a range of different cancers,” said John Babcook, President and Chief Scientific Officer of Kairos. “I’m excited to bring together the complementary technologies of Kairos and Zymeworks to create cancer therapeutics that have the potential to be transformative to the lives of patients.”

Canada’s drug development engine
The Centre for Drug Research and Development (CDRD), which works in partnership with academia, industry, government and foundations, provides the specialized expertise and infrastructure to identify and de-risk promising discoveries, and transform them into commercially viable investment opportunities for the private sector – and ultimately into innovative new therapies for patients. In doing so, CDRD is actively growing Canada’s national health sciences industry into a wholly-optimized generator of economic prosperity for the country.

“We are proud of the Kairos [antibody-drug conjugate development] platform and the work that has led to this agreement with Zymeworks. As Canada’s national drug development and commercialization centre, CDRD is in a unique position to provide world-class drug development infrastructure to incubate many exciting technologies, and this enabled and accelerated the development of Kairos’ novel platform. The combined forces of these two BC-based Canadian companies is a testament to the strength of this cluster and the innovation and translation capabilities in British Columbia – and across Canada,” explained CDRD President and CEO, Karimah Es Sabar.


Last Editorial Review: January 8, 2016

Featured Image: Science World at Telus World of Science, Vancouver, British Columbia, Canada, is a science centre run by a not-for-profit organization. It is located at the end of False Creek, and features many permanent interactive exhibits and displays, as well as areas with varying topics throughout the years. The center was originally developed as a part of the World Fair ‘Expo 86’ in 1986. When Vancouver was awarded to host the transportation-themed 1986 World’s Fair, a Buckminster Fuller-inspired geodesic dome was designed by Expo’s chief architect Bruno Freschi to serve as the fair’s Expo Centre. Construction began in 1984 and was completed by early 1985. After Expo closed its gates in October of that year, an intensive lobbying campaign was launched to secure the landmark building, relocate the Arts, Sciences and Technology Centre into the post-expo dome, and convert the Expo Centre into Science World.
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Copyright © 2016 InPress Media Group. All rights reserved. Republication or redistribution of InPress Media Group content, including by framing or similar means, is expressly prohibited without the prior written consent of InPress Media Group. InPress Media Group shall not be liable for any errors or delays in the content, or for any actions taken in reliance thereon. ADC Review / Journal of Antibody-drug Conjugates is a registered trademarks and trademarks of InPress Media Group around the world.

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