Single-use technology, designed for the manufacturing of biopharmaceutical products, has made major inroads over the last 30 years. First introduced in the late 1970s in the form of disposable capsules and a range of filters, single-use technologies were revolutionized in the late 2000s with the introduction of single-use 2D and 3D process containers and filter assemblies for mixing and storage systems. Today, these technologies have been adopted across the upstream manufacturing process, downstream purification and fill-finish of entire classes of biologic drugs.
The adoption of single-use technology is especially growing in the development and manufacturing of biologics and complex drugs like Antibody-drug Conjugates (ADCs).
ADCs are highly potent biopharmaceutical drugs designed as a targeted therapy in the treatment of cancer. They are highly hazardous materials, often with occupational exposure limits (OEL) below 100ng/M³/8Hr work day.
The acute potency of ADCs creates a significant risk to personnel involved with the various manufacturing stages. The accepted method to counter the risk of exposure to ADCs is the implementation of so-called barrier isolation systems. These systems are recognized as the highest level of current containment technology, creating both respiratory and dermal protection.
While the use of glass or stainless-steel legacy systems may effectively protect operators, significant equipment decontamination is required. Since most ADCs are produced on a small (production) run/campaign with manufacturing typically taking days rather than months, the cleaning validation burden associated with a hard-shell glass or stainless-steel isolator can be an issue.
Alternative to traditional technology
“Single-use technologies are an alternative to traditional glass or stainless-steel manufacturing with the key difference in their materials of construction. Glass and stainless-steel equipment have decades of historical data and, as a result, their use is well characterized,” noted Karen Green, product manager for single-use assemblies at MilliporeSigma.
“Single-use systems are commonly composed of polymeric materials, which are not as well-known or characterized for biologics processing. These differences result in different approaches to validation and qualification,” she added.
In the manufacturing of highly complex active pharmaceutical ingredients (APIs) such as ADCs, single-use technologies offer specific benefits in the upstream manufacturing and production of monoclonal antibodies (mAbs) and downstream bioconjugation.
For example, single-use technology enables faster process changeover and facility flexibility that is not possible when traditional equipment is used.
“Since each single-use system is pre-sterilized and used only once, there is no need to sterilize or clean systems between batches, saving time and enabling manufacturers to produce multiple products within the same facility. Furthermore, single-use systems are often mobile, allowing them to be moved within the facility as needed, enabling additional facility flexibility,” explained Mary Robinette, principal project engineer at MilliporeSigma.
Contract development and manufacturing organizations
According to various reports, 70-80% of the manufacturing of ADCs is outsourced to contract development and manufacturing organizations (CDMOs).
“Due to [this] increased outsourcing pattern, CDMOs entertain many different types of ADCs. The use of single-use technology by CDMOs will help speed up the product change over time, avoiding time spent in establishing cleaning methods for each product that is produced, and eliminating upfront investment for expensive capital equipment such as reactors for each product,” said Gang Yao, Ph.D., principal scientist, process & analytical development at MilliporeSigma.
“In the end, customers benefit from lower manufacturing costs and speed to market. The faster turnover will result in more batches made to meet the commercial demand,” he added.
Implementation of single-use technology
Single-use technologies have advanced in several ways over the past decade. Their materials of construction are better known and have established leachables and extractables profiles, and manufacturing techniques have evolved leading to cleaner and more robust films.
Due to these advancements, the adoption rate of single-use has steadily increased across the biopharmaceutical industry, including ADC manufacturing. However, ADC manufacturers will need to be assured of solvent compatibility with bag liners and other single-use components since the manufacturing of ADCs often involves either dimethyl sulfoxide (DMSO) or dimethylacetamide (DMA) for the conjugation process.
They also will need to trust that the potential for a leak during the conjugation process is extremely low and that they can successfully scale from a smaller development scale to large-scale GMP production.
Single-use technology suppliers, like MilliporeSigma, have recognized these concerns and have demonstrated that the materials in single-use technologies are indeed compatible with two commonly used solvents (DMSO and DMA) at the temperatures and duration typically used for ADC processing.
Addressing the aggressive conditions used during bioconjugation to ensure compatibility with the polymeric materials used in single-use assemblies and understanding extractables and leachables under these conditions are vital. MilliporeSigma provides supporting data to ensure that the use of solvent during the manufacturing process will not negatively impact the conjugate by demonstrating solvent compatibility as well as sharing representative leachable and extractable data.
MilliporeSigma also has demonstrated that small-scale development batches can be successfully scaled up to large-scale GMP batches using a completely single-use process, guaranteeing operator safety at all steps in the manufacturing. In this single-use process, the fluid contact materials do not change, only the size of the components of the process assemblies. “However, operator safety becomes very critical with the use of more potent linker payloads that typically demonstrate IC50 values in the low-to-mid picomolar range,” Yao added.
Mobius® FlexReady Solution with Smart Flexware™ Assemblies for Chromatography and TFF
Mobius® Single-use Bioreactors
Pellicon® Capsules with Ultracel® Membrane
Tangential flow filtration Tangential flow filtration (TFF) is a common unit operation in ADC manufacturing and enables concentration and exchange to pre-formulation buffer.
The presence of toxic linker-payloads following conjugation presents challenges in traditional TFF operations. The scale of TFF also can be a challenge.
“MilliporeSigma has developed a completely enclosed single-use TFF capsule. This device is shipped gamma sterilized with RO (reverse osmosis) water, which reduces flushing requirements and enables faster batch turnaround while utilizing the same Ultracel 30 kDa membrane found in our traditional flat-sheet devices,” noted Nicholas Landry, group product manager ultrafiltration at MilliporeSigma.
“The device was engineered with operator safety and containment in ADC processes as design principles,” he added.
Upstream and downstream processing
While single-use technology has generally been used in upstream processing in the manufacturing of mAbs, the technology is now also available in downstream bioconjugation.
One of the major benefits of single-use technology in downstream processing is bioburden control. Single-use technology offers a more closed processing opportunity compared to traditional glass or stainless-steel reactors, thus reducing the opportunities for bioburden growth.
Another significant benefit of single-use technology is that there is no cross-contamination from inefficient cleaning, allowing faster turnover between process changeovers in a biopharmaceutical manufacturing facility, while at the same time, reducing cleaning validation requirements.
In the final verdict, single-use technology has proven, compared to traditional methods, to be a flexible, cost-effective and efficient alternative that provides improved safety. There is no cross-contamination from inefficient cleaning and no cleaning required between batches, resulting in a quicker turnover of the facility.
 Roots Analysis, Antibody Drug Conjugates Market (2nd Edition), 2014 – 2024.
 Czapkowski B, Steen J, et al. “Trial of High Efficiency TFF Capsule Prototype for ADC Purification,” ADC Review, April 12, 2017. [Article]
Lonza, a specialty contract development and manufacturing (CDMO) partner to the biopharma industry, will add new highly potent API (HPAPI) manufacturing suites at its site in Visp, Switzerland. The expanded capacity is for the specific support of antibody-drug conjugate (ADC) payload manufacturing.
By leveraging the company’s more than 100-year experience in chemistry, biopharmaceuticals and small molecule drug process development and scale-up, Lonza as developed a reputation in manufacturing and support of both clinical development and commercial licensing of antibody-drug conjugates (ADCs).
The expansion is based on a tailored business agreement with a major biopharmaceutical partner that ensures ADC payload supply continuity and flexibility at reduced cost of goods
This latest expansion includes two new manufacturing suites. These new suites enable handling of a variety of highly potent products with occupational exposure levels down to 1ng/m3 and strengthen the overall bioconjugation capabilities of the company.
The expansion underlines the strategic position of antibody-drug conjugates in the Lonza Pharma & Biotech portfolio, with the company developing and producing all components of this increasingly important cancer treatment: cytotoxic payloads, antibodies and the required linkers.
The first of the two new HPAPI suites specifically supports a global biopharmaceutical partner by securing the long-term supply of highly potent ADC payloads.
The second suite will be available to other customers for similar HPAPI and payload development and manufacturing programs. The expansion also increases Lonza’s capabilities in providing fully scalable HPAPI and ADC solutions from lab to commercialization, which supports the accelerated timelines that many drug programs in this category require.
“By ensuring critical supply for the treatment of cancer patients, we are supporting one of our global partners in the oncology field,” said Maurits Janssen, Head of Commercial Development of the API Business Unit at Lonza Pharma & Biotech.
“Oncology continues to be the leading indication in biopharma and the main driver for bioconjugates. We continue to increase capabilities and capacity to meet the HPAPI development and manufacturing needs of our partners,” Janssen added.
Lonza is an established partner in developing and manufacturing HPAPI, with more than 20 years’ experience in safely progressing more than 30 products from early-stage work to late-stage clinical or commercialization. The company has the capabilities in place to safely handle HPAPIs to exposure levels down to 100ng/m3 across all manufacturing scales. These new suites will extend the options for companies developing APIs with even higher potencies.
“Our customers developing highly potent medicines need a partner whom they can trust to handle these toxic substances and to deliver in sync with their needs, whether for clinical or commercial supply,” said Gordon Bates, President Chemical Division at Lonza Pharma & Biotech.
“Combined with our expertise in biologics development, manufacturing, bioconjugation and sterile fill/finish, this new capability will offer further solutions for companies developing complex therapies,” Bates concluded.
Future of ADCs
The expansion confirms Lonza’s belief in the growing global therapeutic potential of ADCs which is, according to experts expected to grow to US $ 4bn by 2023, with double digit approvals within 3-years.
As part of this growth, novel payloads that target tumor-initiating cells on third generation antibody-drug conjugates or ADCs could come to market in the next couple of years. Driven by a healthy late stage pipeline, experts confirm that they expect the market for antibody-drug conjugates to expand at around 19% compounded annual growth rate (CAGR) between 2017 and 2030.
These predictions are based on a new analysis published in the 2018 edition of the CPhI Annual Report – the complete findings of which were released earlier this month at CPhI Worldwide in Madrid, Spain, the global pharmaceutical event held October 9 – 11, 2018.
Lonza’s HPAPI and ADC payload expansion, which is, in part, based on these expectations, is expected to be on-line by the end of 2019.
Disclosure: Lonza is one of the underwriting sponsors of ADC Review | Journal of Antibody-drug Conjugates.
WuXi Biologics, a Hong Kong-listed, open-access biologics technology platform company offering end-to-end solutions for biologics discovery, development and manufacturing, has started the construction of a state-of-the-art integrated biologics conjugate solution center in Wuxi, a city near Shanghai in eastern province of Jiangsu, on the banks of Taihu, one of China’s largest freshwater lakes.
This $20 million 6,000 square meter facility will be operational in 2019 and provide integrated solutions from concept to commercialization for biologics conjugates including Antibody-Drug Conjugates (ADCs) and other protein conjugates.
Antibody-drug Conjugates or ADCs are complex molecules composed of an antibody linked to a biologically active cytotoxic agent. Over the last decades these drug, 4 of which have been approved by the U.S. Food and Drug Administration (FDA), have emerged as targeted treatments for patients with various forms of cancer.
WuXi Biologics plans to build this site into a world-class antibody-drug conjugate research and development and manufacturing platform which will meet cGMP standards from the United States, Europe and China.
“I am very excited about this new investment in ADCs,” Dr. Chris Zhisheng Chen, Chief Executive Officer of WuXi Biologics noted.
“In collaboration with chemistry division of WuXi AppTec Group, WuXi Biologics is one of the few global companies that can provide the one-stop service to global partners for antibodies, small molecule payloads, ADCs drug substance and drug products,” he added.
“Our vision is to empower any global partners to develop any ADC to benefit patients,” Chen observed.
United States Expansion
Earlier this month, WuXi Biologics announced that it is to invest $60 million and hire approximately 150 employees to establish a state-of-the-art biologics clinical and commercial manufacturing facility in Worcester, Massachusetts in the United States.
Supported by the Government of Massachusetts, the Worcester Business Development Corporation (WBDC) and the Massachusetts Life Sciences Center (MLSC), this facility will be WuXi Biologics‘ 11th global drug substance manufacturing facility, the company’s first overseas site in the United States, as well as the third outside China subsequent to Ireland and Singapore.
“Metropolitan Boston is acknowledged as a leader in the biopharmaceutical industry. The new site plays a key role in WuXi Biologics’ global bio-manufacturing network to ensure that biologics are manufactured at the highest quality and within a robust supply chain to benefit patients worldwide. We are grateful for all the support local agencies and the talented people here have provided for us. We believe we can quickly push forward this exciting project,” explained Ge Li, Ph.D, Chairman of WuXi Biologics.
“The new site will undoubtedly meet WuXi Biologics’ growing need for biologics development and manufacturing in the near future. Many partners of WuXi Biologics are located within two hours of this new site,” Chen added.
“We are all very excited to initiate our first US site to enable local companies and expedite biologics development in the United States. We are committed to becoming the most comprehensive capability and technology platform in the global biologics industry to enable both local and global partners,” he concluded.
In April 2018 WuXi Biologics also confirmed that it is to build a €325 million biologics development and manufacuturing plant in Dundalk, County Louth, Ireland. The city is located on the Castletown River, which flows into Dundalk Bay, and is near the border with Northern Ireland, halfway between Dublin and Belfast. The new facility will be built on a green field site at Mullagharlin.
The investment is expected to create 400 permanent jobs and 700 temporary construction positions.
This state-of-the-art facility of the future will be based on the novel approach WuXi Biologics has pioneered deploying multiple single-use bioreactors for commercial biomanufacturing. The facility is also designed to be able to run continuous bioprocessing, a next generation manufacturing technology to be first implemented globally in this 26-hectare campus, the company’s first site outside of China, which is supported by the Irish Government through IDA Ireland.
A total of 48,000 L fed-batch and 6,000 L perfusion bioreactor capacity will be installed, representing the world’s largest facility using single-use bioreactors.
Christoph Rader, PhD, associate professor at the Florida campus of The Scripps Research Institute (TSRI) , has been awarded a $2.875 million, five-year grant from the National Cancer Institute (NCI) to develop unique antibody-drug conjugates engineered to eradicate one of the most common forms of leukemia, chronic lymphocytic leukemia (CLL).
“We want to attack the cancer without harming healthy cells and tissues,” Rader says. “To do this, we attach a highly potent drug to an antibody and then use the antibody to lead the drug payload to the cellular target.”
Doctors diagnose more than 20,000 people a year in the United States with chronic lymphocytic leukemia. The blood cancer originates in a type of white blood cells called lymphocytes, born in bone marrow. As the condition worsens over time, the cancerous cells accumulate, crowding out healthy blood cells. When they move into the blood stream, the malignant cells can spread to other organs and disrupt their healthy function. The illness can cause fatigue, fever and infections, swelling of the lymph nodes and weight loss. More than 4,500 people die each year of CLL in the United States.
The central challenge in fighting all cancers is attacking the malignancy without hurting other parts of the body. Antibodies, the immune system’s adaptable targeting system, recognize and bind to specific threats.
Using them to attack cancer requires designing ways to attach drug payloads, and then identifying ideal points of attack. Rader’s team discovered a binding site on the surface of CLL lymphocytes, called FCMR, which pulls antibodies into the cells in a matter of minutes.
“This particular target is selectively expressed in CLL,” Rader says, which means antibodies that bind to the cancer won’t attack other, healthy cells.
Attaching the drug payload to the antibody requires a third element, a linking molecule. Working with Scripps Research chemists, including Assistant Professor Hans Renata, PhD, and Professor Emeritus William Roush, PhD, Rader’s group has devised several approaches that perform well.
“This draws on the unique interface of biology and chemistry we have here at Scripps Florida. We are creating new molecules with precise designs that are now able to selectively target CLL cells,” Rader noted.
“There is a dire need for the development of new, effective and safe therapies against chronic lymphocytic leukemia,” he added.
Antibody-drug conjugates or ADCs have emerged as a powerful and strategy tool in the targeted treatment of cancer. These relatively novel agents combine the ability of monoclonal antibodies to specifically target tumor cells, which express specific antigens on their surface, with the highly potent killing activity of a cytotoxic drug with payloads which is generally too toxic for systemic administration. In contrast to conventional, standard, treatments, antibody-drug conjugates cause less damage to healthy tissues.
This approach, has, over the last two decades led to a paradigm shift in cancer chemotherapy.
Today, a number of different ADC-based treatments options are available for both including hematological malignancies and solid tumors. These options have dramatically increased the efficacy of treatment and are now considered among the most promising strategies used for targeted therapy of patients with a variety of malignancies.
Although much progress has been made, the therapeutic success of future antibody-drug conjugates depends on closely choosing the target antigen, increasing the potency of the cytotoxic cargo, improving the properties of the linker, and reducing drug resistance.
Antibody-drug Conjugates are an integral part of an evolving cancer treatment paradigm, and we are committed to bringing important new treatments to patients in need…
Today, there are 4 antibody-drug conjugates approved and commercially available in the United States. Until the summer of 2017 brentuximab vedotin (Adcetris®; Seattle Genetics) and ado-trastuzumab entansine (Kadcyla®; Genetech/Roche) were the only commercially available ADCs. Then, on August 17, 2017, the U.S. Food and Drug Administration (FDA) approved inotuzumab ozogamicin (Besponsa™, Wyeth Pharmaceuticals Inc., a subsidiary of Pfizer Inc.) for the treatment of adults with relapsed or refractory B-cell precursor acute lymphoblastic leukemia (ALL) and only weeks later, gemtuzumab ozogamicin (Mylotarg™, previously known as CMA-676; Wyeth Pharmaceuticals, a subsidiary of Pfizer) for the treatment of adults with newly diagnosed CD33-positive acute myeloid leukemia or AML, and adults and children 2 years and older with relapsed or refractory CD33-positive AML was again approved, bringing the number of commercially available ADCs to four.
In addition, there are nearly 175 investigational ADCs in development – from early discovery to pivotal, late stage, clinical phase III studies (see Drugmap in ADC Review | Journal of Antibody-drug Conjugates).
J.P. Morgan Healthcare Conference
Earlier this year, during the 36th Annual J.P. Morgan Healthcare Conference in San Francisco, Seattle Genetics highlighted the progress of its pipeline of antibody-drug conjugates.
Through both internal efforts and efforts of its collaborators, Seattle Genetics’ Antibody-drug Conjugate technology is being employed in more than 20 clinical trial programs. Some of these study programs include a number of late-state development programs across both hematologic malignancies and solid tumors.
Important therapeutic modality
“ADCs continue to advance as an important therapeutic modality, both as single agents and as part of various combination regimens, across hematologic malignancies and solid tumors,” noted Clay Siegall, Ph.D., President and Chief Executive Officer of Seattle Genetics.
“We are the industry leader in ADC technology driven by our scientific expertise in monoclonal antibodies, drug payloads and stable linker technologies. Our leadership is further illustrated by the continued clinical and commercial expansion of brentuximab vedotin (Adcetris®; Seattle Genetics), progress with our late-stage programs enfortumab vedotin and tisotumab vedotin, and the breadth of our pipeline of other ADCs and empowered antibodies,” Siegall further noted.
Addressing the success of the company’s partners, Siegal observed: “Our collaborators are making significant advances with several programs using our technology. Antibody0drug Conjugates ADCs are an integral part of an evolving cancer treatment paradigm, and we are committed to bringing important new treatments to patients in need,”
Overexpression of CD30, a 120-kDa type I trans-membrane glycoprotein belonging to the tumor necrosis factor (TNF) receptor superfamily, has been reported in Hodgkin lymphoma (HL) and anaplastic large cell lymphoma (ALCL). Treatment with CD30-targeted antibody-drugconjugates, including brentuximab vedotincan lead to promising clinical benefit.
Brentuximab vedotin, which is developed by Seattle Genetics and Takeda Pharmaceuticals on a 50:50 basis is commercially available in 70 countries worldwide and generated more than $600 million in global sales in 2017.
On January 2, 2018 the U.S. Food and Drug Administration (FDA) accepted Seattle Genetics’ filing for supplemental Biologics License Application (BLA) of brentuximab vedotin in combination with chemotherapy for the frontline treatment of patients with advanced classical Hodgkin lymphoma.
The FDA granted Priority Review for the application, and the Prescription Drug User Fee Act (PDUFA) target action date is May 1, 2018. The submission of the supplemental BLA is based on positive results from a phase III clinical trial called ECHELON-1. In October 2017, the FDA granted Breakthrough Therapy Designation (BTD) for brentuximab vedotin in frontline advanced Hodgkin lymphoma based on the ECHELON-1 study results.
In addition to advancing brentuximab vedotin, Seattle Genetics and its collaborator Astellas have initiated a pivotal phase II clinical trial of enfortumab vedotin for patients with locally advanced or metastatic urothelial cancer who have been previously treated with checkpoint inhibitor (CPI) therapy. The study is designed to support potential registration under the FDA’s accelerated approval regulations.
Seattle Genetics, in collaboration with its development partner Genmab, also plans to initiate a phase II clinical trial of tisotumab vedotin for patients with recurrent and/or metastatic cervical cancer. This study is intended to support potential registration under the FDA’s accelerated approval regulations.
Late stage trials
A number of companies, including GlaxoSmithKline, Genentech/Roche and AbbVie are including Seattle Genetics’ proprietary ADC-technologies in the development of their ADC-programs. These programs include:
GSK2857916, an ADC being developed by GlaxoSmithKline (GSK) for multiple myeloma. GSK recently reported encouraging data from the program at the 59th American Society of Hematology (ASH) annual meeting in December 2017;
Polatuzumab vedotin, an ADC being developed by Genentech/Roche. Positive results were presented at ASH from a phase 2 trial in advanced-stage diffuse large B-cell lymphoma. A phase 3 trial is underway; and,
Depatuxizumab mafodotin, an ADC for glioblastoma in development by AbbVie. Encouraging data have been reported from this ADC, which is currently in a phase 3 clinical trial.
Genentech/Roche’s Polatuzumab vedotin and GlaxoSmithKline’s GSK2857916 have both received Breakthrough Therapy Designation from the FDA and PRIority MEDicines (PRIME) designations from the European Medicines Agency. These designations signify the importance of therapies such as these in addressing significant unmet medical need.
“Through our robust internal development efforts and our strong licensing and co-development agreements, we are extending the potential of ADCs globally. We look forward to future results of studies that include Seattle Genetics’ novel technologies both as monotherapies, as well as in combination with checkpoint inhibitors and other agents,” said Siegall concluded.
The development of novel antibody-drug conjugates is rapidly expanding. Researchers at Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences and Peking Union Medical College in Beijing, China, are working on the development of a novel enediyne-integrated antibody-drug conjugate.
This development involves lidamycin or LDM, which consists of an apoprotein LDP and an active enediyne chromaphore AE. Lidamycin is a member of the enediyne antibiotic family and one of the most potent antitumor agents. Researchers consider lidamycin to be an ideal payload for the preparation of ADCs.
In one study, the researchers demonstrated that the anti-CD30-LDM ADC, a novel ADC consisting of the intact anti-CD30 antibody and lidamycin, is highly cytotoxic to Hodgkin lymphoma and anaplastic large cell lymphoma cell lines with IC50 values of 5~50 pM. In using a Karpas299 xenograft model, the ADC inhibited tumor growth by 87.76% in mice treated with the investigational agent. Interestingly, the researchers did not observe discernible adverse effects.
Based on the results of their study, the researchers concluded that the anti-CD30-LDM offers attractive tumor targeting capability and anti-tumor efficacy both in vitro and in vivo and could be a promising candidate for the treatment of CD30+ lymphomas.
Altough the first-generation ADCs have been commercialized, researchers around the globe are concerned that that the amount of the cytotoxic payload that can be loaded onto a single antibody molecule is still relatively low. Theeir concern also includes the fact that synthetic linkers used in some antibody-drug conjugates may be unstable, and, that as a result the cytotoxic payload may become detached, leading to the onset of adverse drug reactions. As such, ADC technologies are still evolving, and many companies are currently working to develop next-generation ADC technologies.
Among these next generation ADCs is trastuzumab deruxtecan (also known as DS-8201), being developed by Daiichi Sankyo. Trastuzumab deruxtecan is an antibody-drug conjugate comprised of a humanised antibody against HER2, a novel enzyme-cleavable linker and irinotecan, a topoisomerase I inhibitor, payload, which stimulates DNA synthesis.
Daiichi Sankyo’s ADCs also utilize proprietary technologies characterized by a structure of unique linkers connecting the drug and the antibody. The technology being developed also allows for the linker and the payload to be combined with various antibodies. By capitalizing on this characteristic, researchers at the company aim to maximize the value of these technologies through internal efforts and possibly through external collaboration
During the 2018 36th Annual J.P. Morgan Healthcare Conference, Anna Protopapas, President and Chief Executive Office of Mersana Therapeutics outlined her company’s goals. The company is a clinical-stage biopharmaceutical company focused on discovering and developing a pipeline of antibody drug conjugates (ADCs) based on its Dolaflexin® and other proprietary platforms.
“2017 was a year of exceptional execution as we positioned the company for achieving key clinical milestones in 2018 and beyond. Last year, we advanced two lead ADC product candidates, XMT-1522 and XMT-1536, into the clinic and supported our partner Takeda in selecting its first Dolaflexin-based ADC for initiation of IND enabling studies,” Protopapas said.
“We’re looking forward to 2018, as we plan to complete the dose escalation phase of the Phase I study for XMT-1522 and present the data at a scientific conference, as well as substantially complete recruitment of the dose expansion cohorts for XMT-1522. We also expect to continue dose escalation for XMT-1536 and select our next ADC candidate for clinical development. We will persist in building a strong organization that is passionately dedicated to scientific excellence, focused execution and addressing patient needs,” she added.
Mersana’s pipeline includes two compounds in Phase I clinical trials:
XMT-1522, a Dolaflexin ADC targeting HER2-expressing breast cancer, non-small cell lung cancer (NSCLC) and gastric cancer, which, in dose escalation studies, has been administered to six dose cohorts with the sixth dose cohort currently in safety evaluation. Preclinical data on XMT-1522 presented at AACR 2017 supported potential synergy with immune checkpoint inhibitors, and
XMT-1536, a first-in-class Dolaflexin ADC targeting NaPi2b, a clinically validated ADC target broadly expressed in epithelial ovarian cancer and non-squamous NSCLC, as well as a number of other tumor types. In dose escalation studies, XMT-1536 has enrolled and cleared the first dose level.
Protopapas explained that she expects to continue the dose escalation study to establish Maximum Tolerated Dose (MTD) for XMT-1522, and will be able to select Recommended Phase II Dose (RP2D) and substantially enroll dose expansion cohorts. She also expects to continue the dose escalation study to establish MTD for XMT-1536.
New platform technologies
In addition to the results of these investigational agents, Protopapas confirmed that the company has ongoing, robust research programs in place, which positions Mersana to deliver an additional investigational new drug (IND) every 12-24 months. She expects that the company will be able to disclose pre-clinical data of the next ADC clinical candidate at an upcoming scientific meeting. More excitedly, she also hopes to disclose new proprietary platform technologies at an upcoming scientific meeting.
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.
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.
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 involvedin 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.
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).
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.
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.
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.).
Research by Rice University scientists, supported by the National Science Foundation and the Robert A. Welch Foundation, shows the developed a method to efficiently modify natural antibodies that can deliver drugs to target cells. The key for success is adding a little extra metal.
Zachary Ball and graduate student and lead author Jun Ohata discovered that rhodium, a rare, silvery-white, hard, corrosion resistant and chemically inert transition metal, can be a useful element in the design and preparation of antibody-drug conjugates that have become a standard tool for targeted delivery of highly cytotoxic ‘payload’ drugs for the treatment of patients with a number of solid cancers and hematological malignancies.
They developed a unique multimetallic protein that acts like an enzyme to catalyze the action of a wide variety of antibodies. The simple process will allow labs to test the relative function of a variety of antibody sources and antigen targets to see which will work best on a tumor cell.
The key to Ball and Ohata’s design is having three rhodium complexes attached to specific sites of a protein that binds to the constant (Fc) antibody region. Once bound, this multimetallic peptide catalyzes site-specific attachment of therapeutic agents with minimal disruption to the antibody itself. The lab tested its complexes on breast cancer cells and confirmed that the modified antibodies retained their antigen-binding properties.
“The beauty of this catalyst is that it binds to the constant region of the antibody, so it should be broadly general for all human antibodies,” explained Ball, an associate professor of chemistry and director of Rice’s Institute of Biosciences and Bioengineering.
“We have a single, universal cassette system that plugs into antibodies to make drug conjugates fairly quickly and easily,” Ball added.
Simplifying chemistry The technique is meant to simplify what has been a complicated path to antibody-drug conjugates. “To do selective chemistry on natural antibodies without first engineering their sequences has been an unsolved problem,” Ball said.
“Purely random conjugation can be valuable, but it’s hard to understand structure-activity relationships when you don’t have a single structure; you get an ensemble of molecules with an ensemble of properties.” He said homogeneous conjugates are more desirable from a regulatory perspective as well.
His lab has extensive experience with the interplay of proteins and transition metals, a group of elements in the center of the periodic table, including rhodium, with diverse chemical reactivity.
The rhodium complexes in Ball and Ohata’s metalloprotein play multiple roles.
“At least one of the rhodium complexes binds to and helps orient the system properly, and a second one does the bond-forming chemistry,” Ball noted.
“It’s just a fascinating chemical problem,” he said. “We’ve solved a lot of small-molecule selectivity problems, but when chemists move to bigger and bigger systems, the traditional approaches aren’t sufficient.”
A new approach
“Our studies in the past have focused on doing the chemistry to put something onto proteins, but here we had to use the produced proteins in further biological studies, which we had never attempted to do before,” Ohata said. “It took me almost two years to finish these biology-related experiments.”
“We think of this as the frontier of chemical selectivity,” Ball said. “We’ve got this massive molecule that weighs 150,000 kilodaltons. How do we find one hydroxyl group in that massive structure and do chemistry on it? These are the kind of fundamental things that chemists love to think about.”
Ball’s lab is beginning to work with Texas Medical Center collaborators to test the new catalyst.
“We want to get these in the hands of clinicians and drug development people to see what these conjugates can do,” he concluded.
Less than 3 decades old, antibody-drug conjugate or ADC-technology is a relatively new. Due to many technological advances, recognition of appropriate target antigens, success in the development on novel monoclonal antibodies (mAbs) and increasing demand for biologics and biotherapeutics the market of targeted therapies, including ADCs, is rapidly increasing.
This week, ReportLinker, an award-winning market research organization published the latest industry data covering ADCs. According to the authors of the report, developed by BCC research, the global market for antibody drug conjugates was valued at $1.3 billion in 2016 and is expected to reach $4.2 billion by 2021, growing at a compound annual growth rate or CAGR of 25.5% from 2016 to 2021. 
In 2016, the market for ADCs in North American was valued at $588.6 million and should reach $2.0 billion by 2021, growing at a CAGR of 27.2% from 2016 to 2021. In Europe this market was valued $395.0 million in 2016 and is expected to reach $1.2 billion by 2021, growing at a CAGR of 24.1% from 2016 to 2021.
Currently approved ADCs
Advances in targeting antibodies, potent payloads and drug-linker technologies that facilitate improved ADC stability, potency and targeting efficiency have led to the development of two commercially viable ADCs. BCC Research’s goal in conducting this study is to provide an overview of the current and future characteristics of the global market for antibody drug conjugates.
The new report explores present and future strategies within the antibody-drug conjugates market, which includes, by type of payload (cytotoxic agent), by type of monoclonal antibodies and by type of linker. The inception of the market, and its demands and restraints are discussed in this report. Classification, comparisons and usage of ADC products are also presented in this report.
The authors analyzed the structure of the antibody-drug conjugate industry and broke down revenues by region, with sales estimated for the five-year period from 2016 through 2021. Applications of antibody drug conjugates and significant patents and their allotments in each category discussed.
Advancements in research have changed the way many diseases are treated. ADCs represent an innovative class of drugs that are mainly developed by conjugating already-developed or marketed small molecules and biologics. ADCs have shown great potential in cancer therapy. ADC products are becoming an important part of the biomedical industry and have the potential to replace conventional treatment options.
Research & Development spending, along with increasing competition, patent expires and new technologies are providing a new direction to the market. Advancements, new product launches and changing lifestyles are expected to influence the future growth of the market. This study looks at the majority of the systems affected by these factors.
Acquisition strategies and collaborations by companies are also covered in this report. This study also discusses the strength and weaknesses of each type company in light of the new technologies, growing competition and changing customer needs.
Antibody drug conjugates are mainly used to treat cancer and are safer and more effective than many other cancer therapies. This report focuses on the global market for antibody drug conjugate products and provides an updated review, including their basic design and application in various areas of the biomedical sciences.
The report covers three main areas of application, breast cancer, lymphoma and other cancers, including acute myeloid leukemia or AML. The scope of this study includes the current market for ADCs. The report also discusses regulatory aspects, current and developing technologies, market projections and market shares. An analysis of clinical trials, innovations and opportunities and the latest trends in ADC market are also discussed in the report.
Also included in the report is an analysis of relevant patents and profiles of companies, including Seattle Genetics, Takeda Pharmaceuticals and Genentech/Roche that lead the antibody-drug conjugate product market.
Sales data for the global and regional markets were corroborated for the present and forecasted values via statistical analysis, and sales are broken down geographically into North America, Europe, Asia- Pacific and the emerging markets. The application of ADCs in various types of cancer is discussed from both a commercial perspective and that of a research and development (R&D) perspective.
The report only covers antibody-drug conjugates in which an antibody is conjugated with small-molecule cytotoxins (payload) through a linker. Other forms of antibody conjugates such as radioisotopes conjugated with an antibody are beyond the scope of this report.
For this report, the authors surveyed many companies to obtain data for this study. This included manufacturers and end users of antibody-drug conjugate products. Data was also gathered from various industry sources. The authors spoke with officials within the industry, consulted newsletters, company literature, product literature and a host of technical articles, journals, indexes and abstracts. Exhaustive database searches were conducted using key terminology. In addition, data were compiled from current financial, trade and government sources.
Both primary and secondary research methodologies were used in preparing this study. The authors also conducted a comprehensive literature search, which included technical newsletters and journals, including ADC Review | Journal of Antibody-drug Conjugates, and many other sources and conducted interviews experts and key opinion leaders. Projections were based on estimates such as the current number of end users, potential end users, mergers and acquisitions, and market trends.
Antibody-drug conjugates, representing the convergence of chemistry with biology, include an antibody linked with a cytotoxic drug called payload. They combine the extraordinary affinity and specificity of antibodies with the anticancer potential of payloads. Continuous efforts to improve the therapeutic potential of biologics and to develop novel efficacious drugs either by modification or derivatization led to the development of ADCs.
Over the last decades, ADCs have revolutionized the field of cancer treatment. Unlike conventional chemotherapeutics, which damage normal cells along with the cancer cells, ADCs target only cancer cells. Through the synergistic combination of monoclonal antibody with the cytotoxic drug, via a stable linker, an extremely efficacious class of anticancer drugs has been emerged. To date, three ADCs have gained entry into the market, of which only two remain. Gemtuzumab ozogamicin (Mylotarg®), marketed by Pfizer, became the first FDA approved ADC in 2000.
This drug was approved for the treatment of relapsed acute myeloid leukemia. In 2010, a decade after its approval, gemtuzumab ozogamicin was withdrawn from the market due to serious hepatotoxicity issues.
However, in late January 2017 Pfizer’s Biologics License Application (BLA) for gemtuzumab ozogamicin (Mylotarg®; previously known as CMA-676) was accepted for filing by the U.S. Food and Drug Administration (FDA). And a Marketing Authorization Application (MAA) for review by the European Medicines Agency (EMA) was validated in December 2016.
The Biological License Application (BLA) was based on additional data from a Phase III study that evaluated the potential benefits of adding gemtuzumab ozogamicin to standard induction chemotherapy in the treatment of patients with acute myeloid leukemia aged 50–70 years old. The FDA’s decision on the application is expected sometime in September 2017.
Only brentuximab vedotin (Adcetris®; marketed by Seattle Genetics and Takeda Pharmaceutical) and ado-trastuzumab emtansine (Kadcyla®; marketed by Genentech/Roche), are commercially available. Brentuximab vedotin was approved in 2011 for relapsed Hodgkin lymphoma and relapsed anaplastic large-cell lymphoma, and ado-trastuzumab emtansine was approved in 2013 for human epidermal growth factor receptor 2 (HER2)-expressing breast cancer.
Technological advancements, the growing number of cancer patients and increasing demand for biologics for the treatment of chronic diseases are the prime factors that are driving the market for ADCs.
North America continues to lead the market for ADCs as it has the advanced technologies needed to develop ADCs. In addition, rising healthcare expenditures and huge government initiatives are also driving the North American market. Improving economic conditions, demand for better healthcare facilities, increasing health awareness, increasing incidence of chronic diseases and growing R&D activities will help the market for ADCs grow in Asia-Pacific.
The ADC industry involves a specialization business model, more specifically a technology licensing model. In specialization models, certain companies discover and license its ADC technology to pharmaceutical companies. The two main ADC technology companies in terms of sheer numbers of licensing deals to date are ImmunoGen and Seattle Genetics. ImmunoGen, with its maytansinoid-based targeted antibody payload (TAP-) technology, produced ado-trastuzumab emtansine with Genentech.
Brentuximab vedotin is developed by Seattle Genetics and includes the company’s ADC linker and cytotoxin expertise coupled with an antibody from Millennium Pharmaceuticals, now part of the Takeda Pharmaceutical.
Innovation in ADCs typically occur through the development of new cytotoxic agents as well as new linkers that are adequately stable and at the same time can be cleaved efficiently to deliver the cytotoxic drug. Thus, key future trends in the market for ADCs include the development of novel payloads, new linker chemistry and the site-specific conjugation technology. All these advancements are expected to lead to the development of more specialized, personalized and targeted ADCs.
The manufacturing of antibody-drug conjugates requires specific manufacturing facilities. In turn, this requires high capital investment and extensive specialized training of operators and both of these requirements indicates the trend towards the contract development and manufacturing of ADCs.
The product pipeline is a key determinant of any industry’s future growth. And that is also the case with antibody-drug conjugates. The industry’s acceptance of ADC technology is evident from the continual increase in novel ADCs entering clinical trials during the past few years. During 2003-2007, 10 ADCs reached Phase I trials and this number increased to 30 during 2008-2012. About 24 novel ADCs entered Phase I trials during 2012- 2016.
Inotuzumab ozogamicin, an anti-CD22 ADC being developed by Pfizer for the treatment of relapsed or refractory acute lymphoblastic leukemia, is expected to be approved by FDA at the end of 2017. It received priority review designation from the FDA in February 2017. Through the FDA’s priority review program, Pfizer is expected to receive the FDA’s decision on inotuzumab ozogamicin with breakthrough therapy designation within six months.
In October 2016 rovalpituzumab tesirine, also known as Rova-T, an antibody-drug conjugate being developed by AbbVie/Stemcentrx, was recognized at the 7th Annual World Antibody Drug Conjugate (ADC) Awards as the “Most Promising Clinical Candidate” for fighting cancer. The novel biomarker-specific ‘smart-bomb’ antibody-drug conjugate targets the delta-like protein 3 or DLL3 protein, expressed in more than 80% of small-cell lung cancers (SCLC) patient tumors, appears to be safe and shows efficacy in treating patients with advanced SCLC. The authors expect this investigational agent to also reach the market during the forecast period.
The market for ADCs was worth approximately $1.3 billion in 2016 with just two approved drugs, and its potential remains very large. Total revenues, representing product sales (collaboration and royalty revenues are not considered), are expected to be $4.2 billion worldwide by 2021 at a CAGR of 25.5% from 2016 through 2021.
These revenues reflect the estimated addition of other ADCs that are directed toward acute lymphocytic leukemia and ovarian cancer. Much of the market growth is expected to come from added indications for both the marketed ADCs. In addition, the expected approval of several other antibody-drug conjugates, such as Pfizer’s gemtuzumab ozogamicin and inotuzumab ozogamicin, during the forecast period will help the market for ADCs to grow significantly.
North America led the antibody drug conjugate market due to the presence of major pharmaceutical companies working on the development of antibody drug conjugate drugs there. Both the North American and European markets benefited from the fast track approval of ADCs. Expanded access to ADCs in Asia-Pacific and the emerging markets drove the market for ADCs in these geographies.
The two most common therapeutic areas for ADCs from 2014 to 2016 were lymphoma and breast cancer, with breast cancer representing 61.3% of ADC revenues in 2016. By 2021, with the approval of two novel ADCs to treat acute myeloid leukemia and ovarian cancer, breast cancer ADCs will represent a market share of 47.1%.
EAG Laboratories is a global scientific services company providing testing, analytical and characterization services to clients across a vast array of technology- and life-science-related industries. The company has recently made significant investments to support its growing life science offering and customer base, including the recent expansion of its cGMP pharmaceutical laboratory in Columbia, Missouri.
This expansion is directly related to the biotech and pharmaceutical industry’s critical need for high-quality contract laboratory partners who understand the regulatory guidelines, can perform required risk assessments and have the capacity to execute validated analytical procedures. But it also gives the company’s experienced and dedicated team of highly skilled scientists a state-or-the-art environment to assist customers in successfully execute drug development projects.
To see how these developments impact the development of novel drugs, including ADCs, we sat down with Glenn Petrie, Ph.D., Senior Scientific Advisor at EAG Laboratories.
With over 20 years of experience in support of biotechnology projects, Petrie helps EAG Laboratories’ clients find answer to challenging development questions unique to large molecule development. He serves as the primary business development contact for the company’s biopharmaceutical development projects.
PH: In your experience, what are some of the unique challenges presented by the complex nature of antibody-drug conjugates?
GP: Understanding biopharmaceutical stability and demonstrating biological activity are some of the most critical and challenging aspects of the development of novel therapeutic agents. This is, however, becoming increasingly difficult as we move towards molecules with multiple mechanisms, such antibody-drug conjugates or ADCs. Antibody-drug conjugates combine the target specificity of a monoclonal antibody with the therapeutic activity of a highly potent cytotoxic anticancer agent utilizing a variety of (linker-) chemistries. This results in an extremely complex structure.
Our team of highly dedicated and experienced scientists collaborate with our clients, offering them their experience and expertise in developing and optimizing a variety of bioassay methods for product potency and stability.
“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…”
PH: What are some of the special considerations when developing analytical methods for ADCs?
GP: When developing methods for the analysis of ADCs our scientists take into account the unique properties of a specific ADC, including the drug-antibody ratio or DAR and drug load distribution.
DAR and drug load distribution are critical product quality attributes. A hydrophobic interaction chromatography or HIC method has been developed to determine the drug load distribution and DAR for a variety of ADCs. This is important, because, in general terms, DAR and drug load distribution determine the drug quantity to which a patient is exposed. In addition, each of these various drug loaded forms may differ in their pharmacokinetic/pharmacodynamic (PK/PD) characteristics.
Another important aspect to consider is that the linker chemistry applied and the cytoxin included in a specific ADC will modify the chemistry of the monoclonal antibody. As a result of changes to the surface of the antibody protein, this modification may result in increased antibody aggregation and/or decreased binding and cytotoxicity decreasing the overall stability and efficacy of the antibody-drug conjugate. SEC, antigen binding and cytotoxicity reflect overall 3-dimensional structure and are therefore Critical Quality Attributes.
PH: In March you presented a talk during BioPharma Asia 2017 in Singapore* discussing “ADC Development: Keys to Rapid IND Submission and Approval.” During the presentation you discussed the unique analytical challenges presented by the complex structure of antibody drug conjugates (ADCs) and the myriad of analyses required in support of a successful Investigational New Drug application (IND). How do you support your clients with an IND submission?
GP: One of the most critical aspects of an IND submission is to address all the the unique issues involved; to be complete, correct, and submit the IND in a timely fashion. Incomplete or incorrect information can cause delays in submission and may even result in a rejection of the IND. We use our extensive experience and expertise to support in our clients in submitting successful INDs. And we do that in an accelerated time frame.
During my presentation in Singapore I also highlighted proven ways to maximize the probability of a successful IND, while minimizing the time and effort required. This included critical biopharmaceutical characterization parameters and critical quality attributes or CQAs, but I also discussed studies that may be frequently overlooked, such as compatibility and residual solvents/metals/
PH: What makes an IND-submission for an ADC complex?
GP: It’s good to keep in mind there is no specific regulatory guidance to industry for ADC development. In their process to regulate ADCs, the FDA follows existing guidelines for both small drugs and monoclonal antibodies. As such, this process is a collaborative effort across product quality FDA-offices, including the Office of Biotechnology Products (OBP) and the Office of Pharmaceutical Quality (OPQ). OBP and OPQ primarily focus on the manufacturing of the antibody component of the ADC and the control strategy for the antibody intermediate, as well as for the drug substance and drug product. In addition, the small molecule review group at the OPQ is primarily responsibility for review of the adequacy of the payload and linker, conjugation reaction and aspects of the control strategy.
PH: What is the foremost important aspect the FDA – and other regulators are looking at?
GP: The FDA’s primary concern is safety. This is especially important for ADCs. These novel drugs contain one of many different cytotoxic agents that are far more potent than standard anticancer agents. And as a result of their cytotoxicity, with IC50 in the picomolar range. Consequently, to ensure the drug product, it is critically important to determine the concentration of unconjugated drug. The level of free, unconjugated, drug is usually in the 1-10 ng/mL range, making it very difficult to detect. Typically Liquid Chromatography-Multiple Reaction Monitoring/Mass Spectroscopy or LC-MRM-MS has the necessary sensitivity and specificity and will suffice. But ocassionally you’ll have to push sensitivity even further to determine free or conjugated drug down to 1 ng/mL or less.
PH: As part of your work, what should companies note about working with regulatory agencies – whether this involves the FDA or EMEA?
GP: One of the key aspects is to ask questions. Don’t be afraid to ask for clarification if the advice given is not clear. It will help you submit the correct information and avoid unnecessary and expensive mistakes.
But it is also important to understand the difference in the requirements of the different agencies. The EMEA, for example, places an emphasis on cell bioassays as part of their equivalent of an IND; the FDA does not. Generally the European requirements are more rigorous early in the process, but that difference quickly disappears in the following phases of the process.
PH: In your experience, why are pharma and biotechnology companies eager to work with companies like EAG?
GP:We’re scientists, not only by training, but as part of our natural curiosity. When we talk with a client, we speak scientist to scientist – and that is a real benefit because the biotech and pharmaceutical industries have a critical need for high-quality scientific partners who truly understand analytical methods and regulatory guidelines and can execute complex study designs. Our team of highly skilled scientists has a proven track record for efficiently advancing complex programs through the regulatory process. They bring deep insight to the analysis and characterization of ADCs, monoclonal antibodies, bispecifics, biosimilars, fusion proteins, pegylated proteins and other biotherapeutics.
When we start working with a client early in the development process we truly become an extension of their team. We are not just performing our analysis. It’s not just “throwing a report over the fence… ” as one might say. We become true collaborators. As a result we sometimes know more about our client’s molecules than the client.
In the end, I think that the reason why our industry partners want to work with us is our unique experience and dedicated – collaborating approach. That is what our clients are looking for and what makes EAG unique in the industry.
PH: What does the future of ADCs hold?
GP: Today there are only two ADCs on the market. But I expect that this will change quickly. When speaking with our clients my understanding is that most of them have very aggressive timelines. One of our clients mentioned that they expect submitting 2 INDs per year – each year – for years to come.
PH:…. that is a really big push…
GP: Yes it is. But according to some analysts this is still a conservative estimate. Several months ago, during World ADC Summit in San Diego, California, expert opinion seemed to suggest that there will be 15 ADCs on the market by 2020.
PH: How does that impact your work?
GP: Some of our clients have voiced legitimate concern when discussing the available capacity. But in reality, I don’t think that they need to worry. Earlier this year we started to increase our staff of scientists. We expect to increase the number of scientists by 35 – 40% this year and triple our dedicated cell bioassay capability in Columbia, Missouri.
With the strong commitment of our senior management team we expect to be ahead of the curve.
PH: Looking back over the last decade – what are some of the major accomplishments that excite you about the development of ADCs?
GP: The diversity in the development and the differences in the various platforms is exciting. For example, there are now two well established platforms developed by Seattle Genetics and the other by Immunogen. There is also considerable invested in the development of new cytotoxic payloads, additional linker technologies, and site-specific attachment.
I’m also excited about the improvement in controlling DAR. All these developments may help us to improve the efficacy and decreases the side effects of novel ADCs.
Looking towards the future, I can see the potential for applications beyond oncology and hematology.
That really excites me.
Last Editorial Review: March 27, 2017
* BioPharma Asia 2017, March 21 – 23, 2017, Suntec Convention, Singapore, Singapore
Scientists from the Florida campus of The Scripps Research Institute (TSRI), one of the world’s largest independent, not-for-profit organizations focusing on research in the biomedical sciences, have developed a new drug delivery method that produces strong results in treating cancers in animal models, including some hard-to-treat solid and liquid tumors.
The study, led by Christoph Rader, Ph.D. Associate Professor Department of Immunology and Microbiology at TSRI, was published March 16, 2017, online ahead of print in the journal Cell Chemical Biology.
The new method involves a class of pharmaceuticals known as antibody-drug conjugates or ADCs, which include some of the most promising next-generation antibody therapeutics for cancer. ADCs can deliver a cytotoxic payload in a way that is remarkably tumor-selective. So far, three ADCs have been approved by the U.S. Food and Drug Administration (FDA), but neither attaches the drug to a defined site on the antibody.
“We’ve been working on this technology for some time,” Rader said. “It’s based on the rarely used natural amino acid selenocysteine, which we insert into our antibodies. We refer to these engineered antibodies as selenomabs.”
Antibodies are large immune system proteins that recognize unique molecular markers on tumor cells called antigens.
On their own, Rader noted, antibodies are usually not potent enough to eradicate cancer. However, their high specificity for antigens makes them ideal vehicles for drug delivery straight to tumor cells.
“We now show for the first time that selenomab-drug conjugates, which are ADCs that utilize the unique reactivity of selenocysteine for drug attachment, are highly precise, stable and potent compositions and promise broad utility for cancer therapy.”
Along with its potency, Rader noted, the ADC’s stability is critical to its effectiveness. The researchers found that their new ADCs showed excellent stability in human blood in vitro and in circulating blood in animal models. Moreover, the new ADCs were highly effective against HER2 breast cancer, a particularly difficult cancer to treat, and against CD138 multiple myeloma. Importantly, the ADCs did not harm healthy cells and tissues.
“The selenomab-drug conjugate significantly inhibited the growth of an aggressive breast cancer,” explained TSRI Research Associate Xiuling Li, first author of the study. “Four of the five mice tested were tumor-free at the end of the experiment, a full six weeks after their last treatment.” 
The researchers plan to investigate similar ADCs going forward. Rader, along with TSRI Professor Ben Shen, was recently awarded $3.3 million from the National Cancer Institute of the National Institutes of Health to test highly cytotoxic natural products discovered in the Shen lab using selenomabs as drug delivery vehicles.
The study was supported by the National Institutes of Health, the Intramural Research Program of the National Cancer Institute, the Lymphoma Research Foundation, the Klorfine Foundation and the Holm Charitable Trust.