Antibody-drug Conjugates (ADCs) have evolved since the initial approval of gemtuzumab ozogamicin (Mylotarg®) in 2000, with respect to conjugation, linker and toxin chemistries and processing. With the current availability of 4 commercially approved drugs and approximately 80 programs in various clinical trials, there has been a significant interest in simplifying the complex supply chain.
With approximately 80% of the programs outsourced to Contract Development and Manufacturing Organizations (CDMOs), a transparent and integrated supply chain is critical for the success of ADC projects.
This white paper will describe how chemistry and manufacturing have evolved over the past 10 years globally and how MilliporeSigma, as a CDMO, has adapted to these changes to meet customer’s needs.
During all stages of development, including expression, refolding, downstream processing, formulation, sterilization, and storage, biotherapeutic proteins are subjected to aggregation and degradation. In the development of antibody-drug conjugates or ADCs, the attachment of hydrophobic payload to form the an ADC also enhances hydrophobicity-driven aggregation. And while aggregates/degradants may be present in low concentrations, there is real evidence that this may have a big impact on the quality of biotherapeutic agent, leading to activity loss, decreased solubility, and enhanced immunogenicity 
Now leading experts in the development of antibody-drug conjugates at ADC Biotechnology warn that best in class ADCs are being overlooked due to critical aggregation control problems.
Contract Development and Manufacturing Organizations or CDMOs may be unable to develop products which are capable of working successfully in clinical testing or which are economically viable. The warning comes as more and more full service CDMOs are investing in the development of conjugation and ADC facilities.
A major challenge
“There is a major challenge in the ADC pipeline that conventional manufacturers have not addressed and which pharma companies are obliged to work around.
The ultimate problem is that you have a candidate that may look promising but in practice it can’t be commercialized – unless aggregation control systems are put in place,” noted Charlie Johnson, Chief Executive Officer at ADC Bio, a specialist ADC contract services company which has developed an innovative new process technology to speed up, simplify and significantly lower the production costs of antibody-drug conjugates.
“We are seeing a great deal of excitement from bio-pharmaceutical companies seeking to invest in ADC therapeutics. But applying conventional manufacturing techniques will see the drugs fail or endure very long periods in development. From the vendor side, there is considerable investment across the industry in facilities – but that alone will not give you the capabilities to commercialize optimal ADC therapeutics and that is ultimately a failure to patients desperately in need of new life-saving therapies,” Johnson added.
This is especially the case with best in class ADCs – predominantly ADC with either pyrrolobenzodiazepine (PBD) or duocarmycin as the cytotoxic drug payloads.
The development of these ADCs is very complex, primarily because these payloads are very hydrophobic and despite only comprising 2% of the ADC, they dramatically effect the propensity to aggregate. Consequently, effective aggregation control solutions are critical – without which such ADCs can’t be manufactured.
Control of aggregation
Control of aggregation can be achieved by physically segregating antibodies from each other during the critical conjugation steps. To accomplish this, ADC Bio has developed a proprietary process that can achieve the optimal molecular formulation.
Called “lock-release,” the company’s technology platform allows immobilisation of antibodies onto a solid-phase support, thereby segregating them and preventing aggregation during the critical conjugation steps.
This is accomplished by assembling – covalently ‘locking’ – ADCs to solid polymer beads, prior to conjugation, in a highly stable form. Following this step conjugates are washed free of residual toxin-linker, capping agent and solvent, prior to being released as a clean drug substance. This, in turn, enables manufacturers to evaluate the most suitable stabilizers, buffers and excipients to determine the best aggregate free formulation for release.
Following conjugation to the payload, the ADCs are subsequently released into an optimal formulation containing stabilizing excipients that suppress aggregation.
The ADC pipeline faces a quality issue bottleneck which, if not addressed, will prevent drugs reaching the market. There is an urgent need to adopt techniques that prevent the formation of soluble high-molecular weight (HMG) aggregate in ADCs – thereby preventing severe adverse immune responses in patients that renders drugs unusable.
Turning to the early stages of ADC development, scientists require much greater certainty that read-outs from initial in vitro panels are accurate and reliably predicative of in vivo efficacy and safety. Consequently, technology is needed that guarantees that ADCs are free of residuals, in particular free cytotoxic payloads and solvents – each of which impact negatively on in vitro assays.
Today, ADC Bio’s “lock-release” technology platform is the only commercially available system that controls aggregation at source and that is scaleable and capable of meeting the regulatory requirements of Good Manufacturing Practice (GMP) required to produce materials for use in human clinical trials.
Using the company’s proprietary technology, is a fast, simple, cost efficient and robust system that guarantees the consistent production of high quality, purified bulk drug substance.
In the development of ADCs new techniques are also needed to minimize risk to high value drug components and lower production costs. To help in this process, ADC Bio has developed a technology that can achieve this by eliminating the number of process steps and conventional purification equipment – ensuring that there are fewer points in the process chain at which physical losses of the antibodies can occur. Interestingly, this technique can prevent batch loss caused by charging reactants and reagents in the wrong order.
Reducing material wastage in ADC production is also essential – as unless sufficient quantities are recovered, ADC production is too uneconomic to carry out.
Success or failure
“Effective aggregation control technologies are now essential and can be the difference between whether an ADC makes it to the market as a commercially viable product or fails. Indeed, much of our future customer base will come in as the industry realizes that not all CDMOs are equal and you require not just facilities, but also highly specialist technologies when it comes to aggregation control,” Johnson said.
“We’re coming to the ADC market from a completely different direction – we are not an all purpose CDMO. We realized that there was a problem and consequently developed a proprietary technology. As a result, we are expanding our facilities to meet ADC production demand,” Johnson concluded.
Lock-release will ultimately provide better patient outcomes by allowing tumor-biology to select the best available payloads and ADC formats rather than allowing manufacturability to determine what products are possible. Manufacturers and innovators will be able to select the optimal ADC concepts that can be manufactured to a meaningful scale – making the best and most efficacious ADC products possible. It is a step change technology that is set to provide the market with the best process solutions.
UK-based ADC Biotechnology has secured investment for the construction of an $11 million* bioconjugation facility at its new site in Deeside, North Wales, UK.
The specialist antibody-drug conjugate contract services company with proprietary conjugation technology designed to overcome process and aggregation challenges during the development of new antibody-drug conjugates,
The new 6,500 m2 facility – scheduled to be operational by December 2018 – is expected to support manufacturing in all clinical phases and small-scale commercial production of antibody-drug conjugates. The new facility includes GMP production suites equipped with vessels of 10 up to a few hundred liters for batch sizes from 100 grams up to a kilo. The integrated facility is also expected to complement ADC Biotechnology’s long established technical services business that provides small scale R&D through to preclinical testing, with three on site laboratories and analytical testing capabilities.
The company’s move into clinical and commercial ADC manufacturing is particularly significant as it already boasts a strong pipeline of customers – thanks to its patented ‘Lock-Release’ technology and the extensive experience of its senior scientists.
The aggregation control platform is currently used by over 20 customers, including a number of ‘big pharma’ as well as smaller biotechnology companies. The ‘Lock-Release’ technology results in fast, simple and robust conjugation processes with the potential to eliminate several process steps while, at the same time, enhancing product quality.
This process is expected to help overcome aggregation challenges from the more complex, potent and hydrophobic payloads increasingly coming through discovery and development. The ADC Biotechnology technology immobilizes protein elements, keeping them separated up to the point they are conjugated – ensuring that much cleaner drug products are ultimately released and that the quality and yield of highly aggregated systems are managed in one single step. The technology will also be available for licensing and sub-licensing in the future.
“We already have confirmation that many of our existing customers will use the facility for clinical development and we anticipate adding a number of the new targets entering clinical development from customers in the USA and Europe – especially in light of the added value we can provide through Lock-Release. For many of the newer types of payload this could well be the difference between a viable product and not,” noted Charlie Johnson, Chief Executive Officer of ADC Biotechnology.
The purpose-built, dual stream bioconjugation facility will provide a suite of capabilities ranging from R&D technical services, quality control, QA, warehousing, and process development through to manufacturing – all of which will occupy just 50% of the unit’s footprint. Consequently, ADC Bio will have free capacity to upscale quickly from early clinical phases into late phase and commercial manufacturing within the same footprint at the new facility.
Subsequent phases are planned for 2018 and beyond and will add further capacity for large scale clinical and commercial, and potentially, dosage form production (fill/finish).
“We are already preparing for future phases of development and the medium-term manufacturing pipeline for the business looks extremely strong. But longer term, we also have a lot of USPs – as a standalone site with patented Lock-Release technology – which makes us extremely attractive.” added Johnson.
ADC Biotechnology’s senior management and scientific team have decades of professional experience of developing ADCs both at ADC Bio and at rival CDMOs. Several of the company’s senior management were pivotal to the development and commercialization of Adcetris – the world’s first approved ADC. And, the company is already an integral part of the growing North West pharmaceutical manufacturing hub.
With a population of 1.4 billion [*] and a rapidly expanding economy, China has become a manufacturing powerhouse. In addition, China is pursuing a goal of becoming a major hub for international bio-pharmaceutical product research, development and manufacturing. In realizing the first steps in this ambitious goal, China has, over the past decade, become a major destination for the global pharmaceutical industry to conduct R&D activities. This growth has drastically changed the pharmaceutical landscape, challenging Chinese companies in raising the quality of their products, while, at the same time, challenging them in expanding their development and manufacturing capacity to serve both global and national markets. 
Partly the results of China’s population growth and increasing domestic medical needs, the country has, according to a recent report published by UBM’s CPhI China, become the world’s biggest producer and exporter of active pharmaceutical ingredients or APIs. Today, the country is responsible for nearly 40% of global API production. But the Chinese pharmaceutical market has still huge opportunities for growth.
With government’s increasing investment in healthcare and R&D, China offers unique opportunities for innovative products and technologies, and collaboration between global and domestic pharmaceutical companies.
According to the China Food and Drug Administration (CFDA), the government’s significant investment in healthcare led to an increased – and more innovative – R&D pipeline and a growing importance of China as center of bio-pharmaceutical development and manufacturing. The government’s investment has also cultivated companies with capabilities that are comparable – and competitive – with North American and European R&D, putting high-cost, global-centric R&D models at a real disadvantage.
The growth of China’s bio-pharmaceutical industry is also the result of effectively securing Intellectual Property (IP) rights. IP rights are among the most valuable resources for pharmaceutical and biotech companies, and their protection often dictates the future success of the companies involved. While poor IP protection and enforcement have often been cited as limiting factors in the growth of pharmaceutical companies’ drive to carry out R&D in China, recently revised patent laws have increased overall global trust and are expected to effectively deter copycat drug makers. And while, according to the US-China Business Council, some concern remains, China’s IP laws and regulations increasingly reflect international standards, allowing Chinese authorities to better protect and enforce IP rights.
According to a study about the business of life sciences, pharmaceuticals and healthcare sector in China, published by Deloitte China Life Sciences and Health Care in Shanghai, the increased IP protection and enforcement has resulted in a growing number of global pharmaceutical companies being increasingly attracted to the idea of having a R&D center in China or, alternatively, partnering with Chinese partners.
Furthermore, a general low cost base, a large pool of highly qualified research subjects, increasing scientific capabilities, the local industry’s knowledge, a general lack of regulatory and cultural impediments often found in other countries and insight into the country’s growing drug markets have made China an attractive country for R&D.
In China, regulatory approval for pharmaceutical agents is based on clinical trials that have been carried out in the country. This requirement has also contributed to the global pharmaceutical industry’s interest in conducting clinical trials in China – and, as a result, work with a Chinese contract research organization (CRO) and contract (development) and manufacturing organizations (C(D)MO).
The regulatory environment has, no doubt, boosted China’s ambitions plans to be a primary market for CROs and CDMOs. Most of the top 20 multinational pharmaceutical companies have been expanding their footprint in China by setting up R&D facilities through various enterprise structures. Large companies including Bristol-Myers Squibb (BMS), Pfizer, Roche, GlaxoSmithKline (GSK), Johnson & Johnson and Novo Nordisk continue to develop partnerships with Chinese companies.
This approach mitigates traditional development risks but also leverageg local efficiencies, allowing companies to add operational value due to familiarity with the market and regulatory requirements, leading to shortened approval times and reduced development costs. In turn, Chinese CROs are recruiting expert Chinese nationals with research experienced nurtured at top Western pharmaceuticals companies to staff domestic CROs.
Moreover, global pharmaceutical companies are starting to conduct R&D activity specifically related to Asian markets. The specificity is linked to the environmental, cultural and genetic factors, liver disease, certain cancers, and some communicable diseases that are more common in Asian countries, such as China and Thailand than in other countries around the world.
Among the growing CRO/CDMOs in China is MabPlex International. Based in Yantai, a port city in Shandong province, China, and founded in 2013, the company specializes in the development and GMP manufacturing of recombinant proteins, antibody therapeutics and antibody-drug conjugates for its global customers. To accommodate growing demand, MabPlex, in October 2016, broke ground on the expansion of its bio-manufacturing facilities.
The construction of company’s new 428,000 sq. ft. facility is expected to be completed by August of 2017, with utility and HVAC validation finished by December 2017. The fill/finish facility will be completely validated by March of 2018.
Earlier this year we interviewed Andrew C. Huang, MabPlex’ Senior Vice President of R&D. Huang has developed a robust and proprietary technology platform for the manufacturing antibody-drug conjugates based on covalent thiol conjugation Technology. The resulting Hertuzumab Vedotin, the first ADC being developed in China, has entered Phase I and Phase II clinical trials.
Prior to joining MabPlex International, Huang served for more than 17 years as a biomedical researcher at the University of California, Los Angeles (UCLA), a public research university in the Westwood district of Los Angeles, engaging in molecular medicine, including brain aging, diabetes, stem cells and protein folding research. He has published near 100 research articles, journal reviews and book chapters. During our interview we asked him about his company, the role his company plays in global bio-pharmaceutical development and manufacturing, the current expansion, the potential for antibody-drug conjugates and the regulatory env
Question/Peter Hofland: What excites you the most about the potential of ADCs?
Answer/Andrew Huang: Antibody drug conjugates are one form of combinatorial therapy that uses tumor-targeting antibodies and high-potency chemical drugs. Most antibodies alone have limited efficacy against malignant cancers. The efficacy of an antibody often increases synergistically when conjugated to a high-potency chemical drug. In addition to the enhancement efficacy, the ADC platform can rescue some cytotoxic drugs, which are too toxic or have poor bioavailability on their own.
PH: What are your company’s major accomplishments over the past 12 months?
AH: We have completed several ADC projects, including providing ADCs for phase II clinical trials and one successful IND with better than expected results.
PH: … and what are your expectations for the next 12 months?
AH: Our ADC projects from US-based clients gradually increased over the last 12 months. And we expect that this will continue in the foreseeable future. That’s why we are expanding our ADC manufacturing capacity to accommodate [the doubling of the number of ADC projects].
PH: As a CDMO, what are the top three things that sets your company’s next-generation ADC platform apart?
AH: I think that there are three things that set us apart. The first thing includes our cysteine conjugate platform and our product quality in terms of conjugation efficiency and fraction of DAR4. The second differentiator is our proprietary thiol covalent conjugation technology and finally, our faster speed and efficiency of completing client’s task as compared to (other) leaders in the field.
Pharma/Industry Questions PH:MabPlex International is based in China. How big is the role of Chinese CDMOs in the world?
AH: The Chinese are gradually increasing their role as a worldwide CDMO family. However, right now, Chinese CDMO companies are limited in capacity because most Chinese companies focus mainly on Chinese business and they are not familiar with rules and business outside China. But that’s changing. Currently, more and more Chinese companies are starting (representative) offices in the United States and Europe to explore opportunities.
PH: How is the approach of Chinese companies different (or similar) to the approach of CDMOs in North America and Europe?
AH: Most CDMO companies in China are led by US/Europe “returnees” so most approaches are likely to be the same or (very) similar. The significant difference will be to fit Chinese “culture” and how to bridge the Eastern culture to Western one.
Regulatory landscape PH: The unique properties of ADCs create technical challenges that require careful CMC considerations. Based on your experience in the development of ADCs what are some of the current regulatory challenges (with special focus on CMC)?
AH: A few years ago, during the Cambridge Healthtech Institute’s inaugural CMC Strategies for Antibody-Drug Conjugates meeting in Boston, Massachusetts, someone answered the same question by saying that antibody-drug conjugates are conceptually, very simple, but in practice, extremely complicated. And I must agree with that. In it’s ‘simple’ complexity ADCs combine a monoclonal antibody, a chemical linker and a cytotoxic drug. Simply stated, as a result of the complex nature of an ADC, we need triple the amount of control and characterization to achieve the right formulation, stability and consistency for effective scale up and manufacturing if we want to meet the regulatory requirements.
And with the increased number of ADCs coming down the pipeline, it becomes imperative for pharmaceutical and biotechnology companies to consider the manufacturability of the ADCs. This means that they have to incorporate process design and CMC strategies early on in the development stage of an ADC.
Looking at our experience, some of the technical challenges require careful CMC considerations include homogeneousdrug distribution, the highest possible fraction of DAR4 and the lowest possible fraction of DAR6 or higher with cysteine conjugation.
PH: Overall…What do you see is the biggest challenge in the development of ADCs?
AH:That’s the degree of homogeneous drug distribution.
But manufacturing ADCs not only involves technical challenges but also challenges in the areas of externalization of manufacturing, supply chain management and new technology considerations. That’s why regulators, looking at the highly toxic nature of ADC payloads, as well as the monoclonal antibody and linker chemistry thta make up an ADC, are concerned about the safety, potency and stability of the product and the workers involved in manufacturing it.
Regulatory implications PH: How is the regulatory landscape in China different than the European of North American regulatory landscape?
AH: A few years ago, regulations in China for CDMOs were significantly different when compared to Western regulations. At that time the drug license and MFG (Drug Manufacturing) license had to be the same. This greatly limited Chinese CDMO development. However, after November 2015, China adopted a new policy for Marketing Authorization Holders (MAH). This new policy is similar to policies in the United States and Europe: the licenses for marketing authorization and manufacturing are separate.
PH: How has the creation of the China Food and Drug Administration (CFDA) and a restructuring of its regulatory system benefited Chinese CDMOs and in particular, your company?
AH: As mentioned, starting in November 2015, China enforced a new policy for Marketing Authorization Holders similar to policies in the United States and Europe. Prior to 2015, all bio-pharmaceutical companies were required by the China Food and Drug Administration (SFDA) to complete the biologic drug CMC and formulation-fill-finish by themselves. Only a chemical drug could be outsourced or contracted out to CRO/CDMOs. Now, biologics, like any chemical drugs, can be outsourced to CRO-CDMO, like MabPlex. This includes R&D and CMC, formulation, fill-finish and even IND submissions.
PH: One often heard concern from companies in North America and Europe is that despite vast improvements, concerns still persist about enforcement of intellectual property (IP) and patent laws in China. How does that impact CDMO business in China?
AH: These concerns have a deep impact on CDMO’s in China. We believe the only thing we can do is to continuously improve our IP enforcement, which is already at Western standards. In addition to our secure enforcement of IP protection, MabPlex has a morning meeting each day to emphasize to all our employees three things: IP, GMP and Safety!
PH: … and how does this, specifically, impact your business?
AH: Companies, especially North American and European companies, are still a little hesitant in dealing with new companies like us. However, we see more and more companies from the United States starting ADC business with us. We are confident that we will prove to our US and European colleagues that we are a trustful and reliable partner.
PH: Your company is experienced in ADC development and manufacturing. Are you planning to expand with additional development and manufacturing facilities in North America and Europe?
AH: We already established a branch (MabPlex Inc. USA) in USA last year. But our US branch will not include manufacturing.
Earlier this week, Evans Analytical Group®, better known as EAG, a global scientific services company offering testing, analysis and characterization to technology- and life-science-related industries, announced that it has combined its 11 corporate brands, including ABC Laboratories, under a new, singular, entity: EAG Laboratories.
Following a number of acquisitions in recent years, the move is designed to bring together broad capabilities in the materials, engineering and life sciences sectors. The new company expects to leverage scientific talent in its 20 locations in the United States, Europe and Asia-Pacific regions, strengthening its offering for industries including pharmaceutical, biopharmaceutical, medical devices, crop protection, aerospace, defense, semiconductor, wearables (and other consumer products), among others.
“Over the last decade, EAG Laboratories has quietly added capabilities through complementary acquisitions and service line expansions in the high-growth contract research and testing space,” explained Siddhartha Kadia, PhD, president and CEO of EAG Laboratories.
Following the discovery of a potential therapeutic drug or biologic, regulatory agencies around the world are requiring an increasingly complex and demanding process of pre-clinical and clinical trials. A large part of this development process is required to demonstrate drug safety and therapeutic efficacy.
“We’ve built a problem-solving culture in which our scientists and engineers go beyond simply delivering data. Our scientists interpret results and find answers that support our clients’ commercial success. That is something today’s technology-driven companies need from their outsourcing partners, and it makes EAG unique in the scientific services arena. By unifying multidisciplinary expertise under one brand, we simplify delivery of our services to enhance our customer relationships,” Kadia further noted.
“With our unique, multidisciplinary, expertise in the life-, materials- and engineering-sciences, we help our clients innovate and improve their products, ensure quality and safety, protect intellectual property and comply with the ever evolving global regulatory demands,” Kadia added.
One of the original EAG companies, ABC Laboratories (Columbia, MO), a GLP and cGMP-compliant Contract Research Organization (CRO), established 1968 and acquired by EAG in 2015, offers a range of product development, structural characterization, analytical testing, custom synthesis and radio-labeling services, as well as testing capabilities for small- and large-molecules.
Following the discovery of a potential therapeutic drug or biologic, regulatory agencies around the world are requiring an increasingly complex and demanding process of pre-clinical and clinical trials. A large part of this development process is required to demonstrate drug safety and therapeutic efficacy.
With a large number of antibody-drug conjugates (ADCs) in development, companies require extensive characterization and analytical services in order for a novel (ADC) drug candidate to enter a clinical trail. Because of the relatively low odds of success in the development of novel therapeutic agents and the large investments required, biotechnology companies are generally focusing on potential therapies with the highest likelihood of generating commercial success. 
This is where EAG Laboratories plays a role.
“We have a thorough knowledge of the regulatory landscape in a various global jurisdictions as well product-specific knowledge and understanding of the (clinical) drug development process,” explained Glenn Petrie, PhD, EAG Laboratories’ Senior Scientific Advisor. “This gives us the unique opportunity to support our clients’ and help them find specific answers and, ultimately, help them reach commercial succes,” he added.
Characterization and analysis
The physico-chemical properties influencing the safety and therapeutic efficacy of novel biologics are their Critical Quality Attributes or CQAs. For therapeutic monoclonal antibodies there is an increasing number of studies explaining which attributes are really critical.
Because conjugation methods can influence heterogeneity, and therefore impact the pharmacokinetic, safety and therapeutic efficacy of an ADC, the Critical Quality Attributes for ADCs may overlap those of the monoclonal antibody intermediate, while others involve size variants (aggregates and fragments), drug distribution, average drug-to-antibody ration or DAR, and free drug level.
Other Critical Quality Attributes may include charged variants associated with the monoclonal antibodies, as well as process impurities such as those related to the cytotoxic anti-cancer drug, the linker chemistry, conjugation and product isoforms. Each of these Critical Quality Attributes can be used during the development of antibody-drug conjugates to demonstrate that a manufacturing process can reproducibly meet defined criteria.
“Using state-of-the art instrumentation and a pioneer approach to methodologies, we’re a highly technical, experienced and innovative partner for companies seeking characterization and analytical services for their antibody-drug conjugates development tracts,” Petrie noted.
“The combination of analytical as well as process knowledge, helps us to support our clients develop antibody-drug conjugates with consistent quality, safety, and therapeutic efficacy for both clinical and commercial use,” Petrie added.
Small and large
“While we work for a large number of biotechnology companies involved in the development of antibody-drug conjugates, some of our smaller clients may involve ‘virtual’ companies. These clients may be working with Contract (Development) Manufacturing Organization (CDMO), but they don’t have their own (production) facilities or laboratories. Others may have an extensive infrastructure. But overal, our clients tell us that while they may have a great relationship with their CDMO, given the complex supply chain involving multiple partners, each with their own, specific, expertise, they prefer outsourcing characterization and analysis to us,” Petrie concluded.
“Since [the] acquisition, we have been following an aggressive strategy in adding some of the world’s most trusted names in contract research, development and testing. While the puzzle is not yet complete, our clients see us as a global scientific services company with industry-leading expertise in testing, analysis and characterization services, bringing significant customer value to multiple markets,” Kadia said.
“Since day one, we’ve pursued our vision of being a world-class testing and analytical services company by adding more and more expertise and capability to a company we believed to have the best and brightest people in the industry,” added Randy Paulson, a managing principal at Odyssey Investment Partners, EAG Laboratories’ majority owner.
“We now have expanded services that match all our clients’ testing and analysis requirements, and also have been aggressive in augmenting our executive team in the last 18 months. We have all of the pieces in place to help grow EAG Laboratories, creating even more value for our worldwide customer base,” he concluded.
The new company employs 1,200+ employees across 20 laboratories in seven countries, serving more than 7,000 clients worldwide.
Often described as target-seeking molecular missiles with a lethal warhead, antibody-drug conjugates have, over the last 15 years, shown to have staying power. With two approved antibody-drug conjugates currently available and more than 50 in clinical trial programs, some experts believe that a number of ADCs may hit blockbuster status in the next 5 – 10 years.
The regulatory approval of antibody-drug conjugates as well as successes in clinical dervelopment of ADCs, have clearly confirmed that developing and manufacturing novel, targeted, therapeutics is technically feasible and that regulatory approval is possible. However, while the idea behind ADCs seem relatively straightforward, developing and manufacturing these drugs requires understanding – and overcoming – technically challenging problems involving biology and chemistry.
In December 2015 we asked Ekaterina (Kate) Dadachova, PhD, Professor of Radiology, Microbiology and Immunology Sylvia and Robert S. Olnick Faculty Scholar in Cancer Research, Albert Einstein College of Medicine, Muctarr Sesay, PhD, Chief Scientific Officer and Vice President of Bioconjugation at Goodwin Biotechnology, Inc. and Dave Cunningham, Director, Corporate Development at Goodwin Biotechnology, Inc., a number of questions about their expectations of the industry and the future of antibody-drug conjugates.
With more than a decade of experience and multiple patents pending in protein modifications through chemical bioconjugation of novel cancer drugs, protein toxins, bifunctional ligands and metal chelates (for radio-isotope labeling), antibodies and other biological molecules onto monoclonal antibodies and recombinant proteins, the company has a unique and unrivaled expertise in the research, development, validation and multi-gram manufacture of Antibody-drug Conjugates, radioimmunoconjugates, and other protein bioconjugates.
Successful development of novel Antibody-drug Conjugates is not only exciting for scientists and researchers in the field. It offers especially good news for patients and their physicians who are trying to help find solutions for, so far, unmet medical needs.
Question: The ADC market is a growing market. What is your expectation for the ADC market in the next 5-10 years? In particular, with 2 currently approved drugs, and more than 50 ADCs in clinical trials (a number that is growing every month), what do projections look like?
Answer: We’ve seen data from a couple of sources that suggest the current ADC market was valued to have been in excess of $500 million in 2014 and will grow to $10 to $12 billion by 2024. In 2014, there were around 238 Phase I to Phase IV clinical trials underway involving 45 ADCs in the pipeline and the majority of these trials were Phase I and Phase II studies. The results of an industry survey suggest that there will be 11+ ADCs on the market by 2024.
Many of these projections are based on a strict definition of antibody: drug conjugates, which tend to focus on antibodies linked to cytotoxic drugs. When adding other types of conjugations such as linking radioisotopes, nanoparticles or photo-sensitive dyes to antibodies, the market projections could increase significantly.
These projections and data support our contention that bioconjugation is still in its infancy with tremendous upside potential, and Goodwin Biotechnology is uniquely qualified and well suited to partner with clients to help them capitalize on the opportunities with their product candidates.
Question: How is the development of ADCs, and other targeted therapies, such as CAR-T, PD-L1s andnanodrugs, changing medicine? What does this means for the industry? How does this impact the need for specialized companies like Goodwin?
Answer: Monoclonal antibodies (mAbs) conjugated with a payload have shown some promise based on the antibody’s ability to target diseased cells. However, one significant finding is impacting the growth of the ADC market. Some researchers have reported that upwards of 95% of ADCs don’t affect the target cell. These researchers explain that this problem is based on the complexity of the antibody:linker:payload conjugate, premature cleavage of the payload from the conjugate, binding to non‐target sites, and/or getting eliminated from the body prematurely.
Further, internalization adds another level of complexity to the biology of ADCs with some researchers suggesting that greater than 95% of the administered dose never reaches the intracellular target. This is primarily because the majority of antibodies selected are based on their ability to target receptors on the cell surface. Therefore, all too often neither the conjugate nor payload are internalized into the cell where they can do their work.
Therefore, in an attempt to counter these challenges, many are looking at other means to make ADCs more effective. For example, payloads with greater cytotoxicity are being studied. However, this strategy requires higher drug doses, which increase the cost of therapy and the potential adverse effect profile of the treatment.
Goodwin Biotechnology has conducted development and manufacturing of novel therapeutic targeting technologies. For example, we have had a significant amount of success conjugating radioisotopes and photosensitive dyes to antibodies for different modes of action. We have also received interest in miniaturized biologic drug conjugates (mBDCs) comprised of nanoparticles and small molecule drug conjugates (SMDCs). Both are designed to enable the penetration of the conjugates deep into the tumor tissue where they selectively bind to tumor cells, become internalized, and release their potent cell killing payload.
It is also important to note that we are exploring a novel approach and the preliminary findings are encouraging. Goodwin Biotechnology and Transporin, a Silicon Valley R&D company with a broad array of life science proprietary technologies, are collaborating on exploring and functionalizing Transporin’s proprietary metal-binding domain transporter technology in the development of antibody and peptide-based biopharmaceutical drugs.
Goodwin Biotechnology will utilize the proprietary metal-binding domain of human insulin‐like growth factor binding protein‐3 conjugated to monoclonal antibodies or antibody fusion proteins, and perform process development and manufacturing services using such conjugates for research, evaluation, and clinical trial purposes.
We are currently investigating the metal-binding domain or MBD-peptide sequence when covalently or genetically linked to the antibody can enhance the ability of the antibody to target diseased cells and improve targeting specificity an estimated 3x to 10x fold by binding to the cell surface transferrin receptor and integrin beta‐3. Hence, it can help reduce the off-target effects of the conjugate and increase the speed of the agent to the target.
What’s more important is that the MBD peptide carrier may also provide active transport into the target cell to help ensure that the payload does its job. MBD uptake correlates with the expression of genes associated with cellular stress‐coping mechanisms commonly up‐regulated in cancer (nuclear factor‐kappaB and HSP‐70B), for example. Once inside the cell, the payload can then modify the disease process.
As a contract manufacturer, we welcome the opportunity to partner with our clients on these and other methodologies designed to enhance the ability of conjugates to effectively target and deliver payloads directly to tumor cells.
Question: Based on the previous question. In therapeutic areas like oncology and hematology, there is a drive towards personalization/individualization of therapies. How does this change medicine? What role, if any, does Goodwin play – and, how may this change the role of CDMOs in general. What can Goodwin offer to help their (pharmaceutical) clients to be successful in this unique market?
Much optimism and promise supports the focus on precision medicine as an approach for understanding diseases and developing targeted therapies. Advances in genomic sequences and the development of tools to analyze genetic variations to model disease physiology and the efficacy of treatments are moving the world of precision and personalized medicine forward at a rapid pace. The possibility of improving the selectivity of therapy for a number of diseases may be enhanced by the use of targeting strategies. Some are exploring CAR-T, PD-L1s, nanodrugs, prodrugs, nanoparticle delivery, etc.
The trend towards personalized and individualized medicine focuses on segmenting the patient population for a certain disease to better customize a specific treatment for a subset of patients with that ailment, and has had and will continue to have a significant impact on the therapeutic approach to certain diseases. As a result, the large blockbuster drugs developed to treat the full universe of patients with a specific disease are becoming a thing of the past.
Goodwin Biotechnology, has been one of the pioneers in bioconjugation and has nearly 15 years of experience in this field. Over that time, we have developed the “know how” that help us design and successful produce robust conjugates for our clients.
This has helped us partner with our clients to fulfill the promise of bioconjugation in advancing a number of bioconjugation strategies, including antibody:drug, antibody:dye, antibody:peptide, and antibody:radioisotope conjugates for diagnostic, therapeutic, and theranostic (treatment and monitoring) applications.
As the cost of ADCs is much higher than that of the small molecule drugs, it seems very important to be able to image the binding of the ADC to its respective target by attaching a PET or SPECT radioisotope to the ADC before making individualized treatment decisions.
Towards that end and as noted previously, we can also offer our clients the value associated with MBD:Peptide technologies, as well as miniaturized biologic drug conjugates (mBDCs) and small molecule drug conjugates (SMDCs) that are designed to enhance the ability of ADCs to target and deliver payloads into diseased cells!
Question: Ongoing research points to new developments in ADCs (different linkers, payloads and monoclonal antibodies– a good example is the work of Aspyrian). How does Goodwin expect this to impact the market? And, how does Goodwin’s experience benefit industry How is this different from other industry players?
Answer: Over the last 15 years, we have adopted a solutions-oriented approach to help our clients overcome significant challenges, including aggregation, especially that associated with IgM antibodies and conjugates, multiparameter optimization, optimizing drug-to-antibody ratios (DAR), working with antibody fragments, purification challenges, etc. We have developed proprietary processes to help address many of those challenges. We have also overcome the challenges associated with random conjugations with site-directed conjugation of radionuclide chelators and other payloads to antibodies which results in narrower DAR (drug-to-antibody mole ratios) and improved conjugate binding and, hopefully, an enhanced therapeutic index. For example, we are working on developing linkers that will have higher solubilizing properties for the cytotoxic drugs most of which are highly insoluble in an aqueous environment, thereby, minimizing the use of high quantities of organic solvents as well as minimizing the potential for aggregation and other deleterious effects on the antibody.
In addition to our bioconjugation experience, Goodwin Biotechnology has over 23 years of experience in manufacturing mAbs through mammalian cell culture expression systems. So, not only can Goodwin do the bioconjugation work, we can also manufacture the “naked” antibodies our clients need.
As a testament to our commitment and dedication, Goodwin Biotechnology recently receive Frost & Sullivan’s 2014 Global Customer Value Leadership Award for demonstrating Best Practices in Biologics Contract Manufacturing. In addition, we were recently notified that Goodwin Biotechnology has received the 2015 Best in Sector: Biopharmaceutical Contract Development & Manufacturing award from Acquisition International.
Question: How does Goodwin see the future or these novel drugs and what is the role does Goodwin plays in shaping the future of ADC and other targeted therapies?
Answer: We feel that the future of the ADC market will be focused on finding the best combination of antibody, linker, and payload to effectively treat a specific disease and minimize the off-target effects of the conjugate.
Goodwin Biotechnology is uniquely qualified to develop the next generation of ADCs and antibody:cytotoxic drug conjugates, as well as antibody:dye, antibody:peptide, and antibody:radioisotope conjugates, as well as miniaturized biologic drug conjugates (mBDCs) and small molecule drug conjugates (SMDCs).
In short, we offer a Single Source Solution™ to take a client’s product candidate from cell line development and/or proof-of-concept process development and optimization through to the delivery of early- and late-stage clinical trial material of not only the “naked” antibody but also the bioconjugated ADC.
We’re a relatively small CDMO and we pride ourselves in being flexible and agile. What’s more, we focus on a solutions-oriented approach to every project. Over the last 23 years, we have worked on nearly 400 projects for over 100 clients, and that experience has enabled us to be able to identify and overcome many challenges in developing and manufacturing biologics, in general, and, specifically, ADCs
Question: How do those changes impact health policy in the US and abroad? How does this impact treatment and treatment “value” and, finally, how does this impact medical technology?
Ekaterina (Kate) Dadachova, PhD, Professor of Radiology, Microbiology and Immunology Sylvia and Robert S. Olnick Faculty Scholar in Cancer Research, Albert Einstein College of Medicine
Muctarr Sesay, PhD, Chief Scientific Officer and Vice President of Bioconjugation at Goodwin Biotechnology, Inc.
Dave Cunningham, Director, Corporate Development at Goodwin Biotechnology, Inc.
Answer: Enhancing target cell specificity and enabling the payload to affect the target cell will improve therapy, minimize side effects, and lower the cost of therapy. Further, many of the applications associated with bioconjugation can help in the diagnosis and monitoring of diseases in order to improve treatment plans.
All aspects of bioconjugation promise to have a positive impact on patient care as well as health care systems in general. Converting the promise into reality has been the challenge. That’s where the experience and expertise of a company like Goodwin Biotechnology can make the difference between success and failure.
Question: There are only a few facilities/companies around the world capable of offering a“one-stop shop” for the development of ADCs (from monoclonal antibody development/production to linker technology, cytotoxins, fill/finish, regulatory services, etc.). How does Goodwin support their clients in this important therapeutic area and how does the company help customers seamlessly scale ADC production from preclinical to commercial phases?
Answer: It’s important to note that we manage all aspects of biopharmaceutical manufacturing whether it’s developing the protein from the DNA sequence and/or fully optimizing a bioconjugation project. While all aspects of a project may not be done under one roof at Goodwin Biotechnology, we offer one point of contact throughout the length of the project in that we have collaborations in place to perform the requisite activities to deliver the highest quality product candidates rapidly and cost effectively
What’s more, we have a strong Quality Assurance program in place that not only assures compliance to the most rigorous regulatory standards, but our staff has the regulatory experience that has helped many of our clients successfully submit INDs.
Question: Given the announcements and media attention SAFC (a business unit of Sigma Aldrich) received last year when it announced the expansion of their production facility, offering a fully commercial development and commercial production in the US, how important is geography? How is a US based competitor facility expected to impact Goodwin? What is Goodwin doing to counter/address this?
Answer: Over the last 23 plus years as an independent CDMO, we’ve had clients from Eastern and Western Europe, Asia, as well as North America, so geography is not of critical importance. What remains important is the quality of work and the level of service our clients receive. Our clients come to us based on our unique level of experience and expertise as a biopharmaceutical CDMO and in bioconjugation, and they stay with us because we partner with them by nurturing an environment of total transparency that our clients find refreshing.
For every project, Goodwin Biotechnology assembles a Project Team with a single Project Manager (PM) as the point-of-contact. The PMs are experienced veterans in biological manufacturing and are the advocates for our clients within Goodwin Biotechnology. They will ensure that project timelines are met and that information is communicated in a timely manner. Beginning with the Tech Transfer meetings, we listen to our clients to understand the challenges they face and their objectives, then we develop solutions jointly to meet their technical as well as budgetary goals. Throughout all phases of the project, the PM coordinates weekly or biweekly meetings with the clients and the Goodwin Biotechnology Project Team as appropriate in order to communicate the progress of the project and discuss the path forward. To ensure adherence to set schedules and timelines (e.g., Gantt charts) for completion of the project, the PM uses systems for internal project monitoring such as project status meetings and project checklist, among other tools.
Question: Can you describe some of the developments and additional services/updates created by Goodwin, and how does this set the companyapart? What is new, unique? What has worked and what did not?
First of all, Goodwin Biotechnology has 23 years of experience and expertise in the contract bioprocess development and cGMP manufacturing of cell culture-derived Monoclonal Antibodies, Recombinant Proteins, and Vaccines. Therefore, we can develop the “naked” antibody and optimize it through our Process Development department for efficient scale up and cGMP manufacturing. Our solutions-oriented approach to all projects has paid handsome dividends, even with the most challenging projects.
Goodwin Biotechnology is one of the pioneers in providing development and GMP manufacturing of ADCs, Radioimmunoconjugates, Peptide:Immunoconjugates, and other Bioconjugates for over 15 years.
Our Bioconjugation services include:
Exploratory Proof-of-Concept Studies
Process Development and Scale Up of Bioconjugation Processes
Scale Up Manufacturing Process and Production of Tox Material
cGMP Manufacturing of Clinical Trial Supplies
GMP Aseptic Fill & Finish of Bioconjugates and cytotoxic drugs
Site-directed conjugation of radionuclide chelators to antibodies to improve conjugate binding
Metal Binding Domain-peptide technology to enhance the ability of ADCs to target and deliver payloads into diseased cells.
FlexReleaseTM Cleavable Linker (Disulfide based)
In summary, we are a fully-integrated, customer-focused, and highly-flexible contract development and manufacturing organization that delivers high-quality, timely, and cost-effective services to our clients. In recognition of this, we recently received Frost & Sullivan’s 2014 Global Customer Value Leadership Award for demonstrating Best Practices in Biologics Contract Manufacturing. Also as noted, Goodwin Biotechnology has received the 2015 Best in Sector: Biopharmaceutical Contract Development & Manufacturing award from Acquisition International.
Question: In a conversation late last year with representatives from Merck KgaA, it was made clear that Merck is expanding its offerings in targeted therapies. In 2014 Merck took over Sigma Aldrich (now Millipore Sigma). How important is this development? How does Goodwin view this? Is there a benefit to be part of large pharmaceutical company (such as in the case of Merck or Pfizer) or are there more benefits to operate independently (like Goodwin is doing today)? How does Goodwin feel, will this ‘merger’ change the (CDMO) industry?
Answer: There are benefits and drawbacks when dealing with a contract manufacturer who is part of a large pharmaceutical firm. Certainly, the deep pockets of a large, multinational pharmaceutical firm help enhance the investment in the facility and retain skilled personnel even during the down times.
However, a significant drawback to those seeking a contract development and manufacturing organization (CDMO) is that large pharmas tend to be less flexible and responsive. They prioritize their facility’s production capacity for their own products leaving excess capacity, if any, to the contracted clients. They tend to be very rigid in their approach with contracted projects and their decision making is slow due to the many layers of bureaucracy.
As an independent CDMO, our clients don’t have those problems. Our clients know well in advance when they are scheduled for bioreactor production, for example, and we don’t deviate from that schedule.
There’s no question that mergers are affecting the CDMO industry. There are fewer and fewer independent biological CDMOs every day, but it’s important to recognize that mergers can change the culture of an organization. Management changes, deletion of redundancies, shifting and / or evolving focus, etc. can cause a lot of distractions and have a negative impact on the quality of work that they can provide.
Goodwin Biotechnology has been a relatively small, independent CDMO for 23 years. Throughout this period of time, we have been consistent with a laser focus on our clients and their products.
Question: What are some other changes (industry and market developments) that will impact the industry and market in the (near) future – 2015– 2020 – 2025?
Answer: We anticipate that there will be increased competition from developing countries like China, India, South Korea, and other Asian countries, but a number of questions remain. They may have impressive facilities, but there are distance and language barriers for effective communication and timely decision making, and it can be a challenge for them to recruit the highly skilled technical expertise required to successfully perform complex biological processes. Further, many clients prefer the quality that is required for contract manufacturers who operate under strict FDA compliance guidelines.
Another trend, as we have discussed, is overcoming the challenges noted earlier to improve cell targeting and killing strategies, as well as reducing off-target effects of ADCs. This includes:
Optimizing each part of the ADC to specifically target and impact the diseased cell
Finding and validating new targets
Overcoming drug/mAb resistance
Controlling development costs by overcoming the lack of preclinical predictability based on multivariable aspects of the target cell and heterogeneity of the tumor, aspects of the tumor microenvironment, etc., especially in rodent models
Exploring alternative delivery routes as well as multiple or different payloads
Addressing unwanted toxicity which is linked to the antibody half-life and renal toxicity of small conjugates
Developing ADCs with cytotoxic, diagnostic, and theranostic (treatment and disease monitoring) capabilities
Adding imaging capabilities to ADCs
We’ve also seen concerns about which medical discipline will drive the usage of conjugates with radioisotopes. The challenge for each institution is to determine if the treatment is under the auspices of medical oncology or does it fall under the radiology department. As the value of radioisotope conjugates is demonstrated, cooperation between these two groups will be enhanced and the treatment pathways will be more clearly defined.
In short, changes in the ADC industry have been constant, and the challenges create many opportunities for innovation and product differentiation. Given the growth potential, the winners in the CDMO business will be companies like Goodwin Biotechnology who can remain flexible and leverage their experience and technical expertise to capitalize on opportunities. These types of companies will be on the forefront of new developments in the bioconjugation business.
This article is based on interviews with:
Ekaterina (Kate) Dadachova, PhD, Professor of Radiology, Microbiology and Immunology Sylvia and Robert S. Olnick Faculty Scholar in Cancer Research, Albert Einstein College of Medicine (Photo 1)
Muctarr Sesay, PhD, Chief Scientific Officer and Vice President of Bioconjugation at Goodwin Biotechnology, Inc. (Photo 2)
Dave Cunningham, Director, Corporate Development at Goodwin Biotechnology, Inc. (Photo 3)
Antibody-drug Conjugates or ADCs are among the most exciting drug developments of the last decade. The combination of potent, small molecule drugs with the highly target specificity of monoclonal antibodies allows sensitive discrimination between healthy and diseased tissue. This approach has demonstrated great efficacy – and safety – in the fight against cancer and hematological malignancies. Antibody-drug Conjugates are part of a specialized subset of highly potent active pharmaceutical ingredients (APIs).
Today, the development of this technically challenging new class of highly potent biopharmaceutical drugs is rapidly expanding. On average, each month more than one new ADC is entering a clinical trial. This progress, as well as the increased development of innovative payloads, novel linkers chemistry and new site-specific conjugation technologies, is creating much excitement among scientists and researchers involved in the development of these specialized, personalized and targeted therapeutics. But, looking ahead, the excitement among researchers and scientists is especially good news for patients and their physicians who are trying to help find solutions for, so far, unmet medical needs.
This interview is the first in a series with experts involved in the research, development and manufacturing of Antibody-drug Conjugates. We will be talking to individual scientists and researchers involved in the development process as well as key employees of pharmaceutical companies, contract (development) manufacturing organizations and physicians involved in clinical trials with ADCs.
In this interview we discussed a variety of subjects related to the development of ADCs, how market conditions and the industry are changing, the impact of personalized and targeted therapies as well as expectations of approved drugs, drugs in the growing pipeline of novel ADC and how this is impacting medicine.
Projections ADC Review (Question): The ADC market is a growing market. What is your expectation for the ADC market in the next 5-10 years? In particular, with 2 currently approved drugs, and more than 40+ in clinical trials (a number that is growing every month), what do projections look like?
Laurent Ducry (Answer): We expect to see significant growth in what we call targeted drugs and bioconjugates/ADCs are certainly within that category. At ASCO this year, we did see some very promising data from ADCs in the clinical pipeline and we definitely expect to see them in the cancer therapy toolbox in the next 5-10 years. Also, the pipeline is expected to grow considerably, which is evidenced by the significant activity we see in both in-house research and licensing activities.
Changing medicine Question: How is the development of ADCs, and other targeted therapies, such as CAR-T, PD-L1s and nanodrugs, changing medicine? What does this means for the industry? How does this impact the need for specialized companies like Lonza?
Answer: This is an exciting time for our company. We are the leading CMO in the world with substantial experience in manufacturing targeted therapeutics technologies and bringing them to the market. Cell and viral therapies, monoclonal antibodies, and bioconjugates all fall under our areas of expertise. Companies like ours that are already well positioned to provide development and manufacturing services for these therapies will benefit from these trends.
We are seeing incredible responses to some of the products utilizing these technologies and the markets are responding accordingly. It is truly a remarkable time to be part of this process.
Personalized and targeted therapies Question: Based on the previous question. In therapeutic areas like oncology and hematology, there is a drive towards personalization/individualization of therapies. How does this change medicine? What role, if any, does Lonza play – and, how may this change the role of CDMOs in general. What can Lonza offer to help their (pharmaceutical) clients to be successful in this unique market?
Answer: That is correct, as I mentioned before, targeted/personalized therapies will become the norm especially in indications like oncology and rare diseases. From a manufacturing perspective, each therapy will bring its own challenges but commitment to quality, peace of mind and product launch experience is something Lonza can uniquely offer in this changing landscape.
Impact of novel payloads and improved linker chemistry Question: Ongoing research points to new developments in ADCs (different linkers, payloads and monoclonal antibodies. How does Lonza expect this to impact the market? And, how does Lonza’s experience benefit industry players. How is this different from other industry players?
Answer: I think we will start to see more and more of these newer generation products hitting later phases and every new wave should bring differentiating advantages. From a development perspective, you need teams that have enough experience to handle these complex and new technologies. As a leader in the ADC business, we can safely say our research and development teams have seen and have had experience with almost all of the novel technologies and methods we see coming down the pipe. We know not many CMOs can say that confidently.
Shaping the future Question: How does Lonza see the future or these novel drugs and what is the role Lonza plays in shaping the future of ADC and other targeted therapies?
Answer: When we are dealing with oncology and rare diseases, what we have learned is that one size-fits-all approach can only provide marginal benefit to patients. We will need novel treatments utilizing newer technologies like cell therapy and ADCs and also we will need to employ combination treatment algorithms. Developing and manufacturing these therapies, some of which may be used concomitantly requires combining several specialized teams of scientists working together. We have these teams ready to be deployed as soon as our customers come to us.
A quantum leap Question: How do those changes impact health policy in the United States and abroad? How does this impact treatment and treatment “value” and, finally, how does this impact medical technology?
Answer: Targeted and combination treatments will have multiple implications from a policy and value perspective. First of all, companies need to think creatively in terms of identifying those patient groups that will benefit from these novel products and providing access to them. Also, for the first time we are seeing almost a “quantum leap” in terms of the potential benefits of these products. “Cure” is often used to describe the patient responses achieved in early clinical trials. Obviously, this brings the question of “value” and payment methods. Also, how you will manufacture, administer, get paid for these combination therapies is an additional challenge. This is where forming a strategic partnership with a powerful CDMO that can tackle the manufacturing challenges and also assist through the approval and reimbursement processes will be crucial for pharma/biotech companies.
There are only a few facilities/companies around the world capable of offering a “one-stop shop” for the development of ADCs (from monoclonal antibody development/production to linker technology, cytotoxins, fill/finish, regulatory services, etc.). How does Lonza support their clients in this important therapeutic area and how does the company help customers seamlessly scale ADC production from preclinical to commercial phases? Given the announcements and media attention to SAFCs expansion, how important is geography? How is an U.S, based competitor facility expected to impact Lonza? What is Lonza doing to counter this?
When you look at the landscape of facilities that manufacture ADCs, we see a disparity between companies in terms of strength in different areas. Some have more mab or cytotoxin experience, some are emphasizing fill/finish capabilities, etc. In my opinion, there is only one company that has the amount of experience in every “piece-of-the-ADC-puzzle”. We have had a good number of successful biologic product launches and a strong track record with ADCs.
For some companies, geography may play a role in their decision to pick a CMO but at the end of the day, most of the customers we work with would eventually target the global market. “Would you prefer proximity over expertise?” is an important question to ask when you make a decision.
Question: Can you describe some of the developments and additional services/updates created by Lonza, and how does this set the company apart? What makes Lonza the industry leader in the ADC market? What is new, unique? What has worked and what did not?
Answer: We are investing in our development capabilities and manufacturing facilities on an ongoing basis. Because of our reputation, companies are eager to bring new technologies like different site specific conjugation methods, novel toxins, etc. to us. Therefore, we have amassed a technology know-how among our scientists that is We have seen every site-specific conjugation method, every major toxin-linker combination available in the pipeline. Our facilities are state-of-the-art. We now have single-use systems available for our customers and we constantly look for ways to improve both product efficacy, safety and manufacturing methods.
A competitive field Question: In a recent conversation with representatives from Merck KgaA, it was made clear that Merck is expanding its offerings in targeted therapies. In 2014 Merck took over SAFCs parent company (Sigma Aldrich). How important is this development? How does Lonza view this? Is there a benefit to be part of large pharmaceutical company or are there more benefits to operate independently (like Lonza is doing today)? How does Lonza feel, will this ‘merger’ change the (CDMO) industry?
Answer: It is an important development and we are watching their strategy closely. The benefit for Merck is obvious, however, we are working in a very competitive field where manufacturing details could set one product apart from another. Having that sensitive information in the hands of an independent company like Lonza vs. the subsidiary of another pharma company is something to think about. We have already heard our customers voice that reluctance.
The ultimate cancer toolbox Question: What are some other changes (industry and market developments) that will impact the industry and market in the (near) future – 2015 – 2020 – 2025?
Answer: Nano technologies, T-cells, different payloads are all being tested and while it is hard to predict a clear winner, it is clear the pipelines will not be homogeneous and the ultimate cancer toolbox will look very different than what we have today.
Biopharmaceutical contract development and manufacturing organization (CDMO) Ajinomoto Althea earlier today announced that it is expanding its existing biological drug product manufacturing operations to include highly active materials such as Antibody-drug Conjugates or ADCs. The new facility is located in close proximity to existing Althea operations in San Diego, CA.
Oncology therapeutics including Antibody-drug Conjugates and Highly Potent Active Pharmaceutical Ingredients (HPAPIs) represent one of the fastest growing segments of the pharmaceutical industry requiring specialized manufacturing facilities and infrastructure to ensure safe handling, manufacture, and delivery. Althea’s new state-of-the-art manufacturing facility will include areas dedicated to bioconjugation, formulation, purification, quality control, and aseptic fill finish including lyophilization. The 57,000 square foot facility enables the company to offer clients a simplified manufacturing supply chain service from a single United States based location.
Very low Occupational Exposure Limit The facility has been designed for safe handling and manipulation of very low Occupational Exposure Limit (OEL) compounds while maintaining aseptic conditions and GMP compliance. Client projects from early clinical phase through commercial launch and supply will be accommodated at this new facility. Althea is working with Environmental Health & Safety (EHS) and regulatory agencies to address topics specific to high containment manufacturing in the design, construction, and operation of the new facility.
“Currently, there is limited capacity of high containment manufacturing in the United States. Althea is excited to make this significant expansion of our service offerings to address the needs of the ADC market as well as other highly potent products. Given our existing core capabilities in complex biologics formulation and aseptic filling, this investment in ADC and HPAPI fill finish manufacturing is a natural progression and logical step for Althea,” noted Jason Brady, Ph.D., Althea’s Senior Director and Business Head for Antibody-drug Conjugates.
Althea took occupancy of the new facility on May 1, 2015. Construction and retrofitting has already commenced. The company will be executing services from the new facility as soon as Q2 2016 with full manufacturing activities coming online the first half of 2017.
Althea’s expansion is one of many projects by global CDMOs, including Lonza, Novasep, Priamal and SAFC to add to ADC and HPAPI manufacturing capabilities and capacity around the world.