Antibody-drug conjugates or ADCs, which link an antibody to a potent, small-molecule, cytotoxic, cell-killing, chemotherapeutic agent, use the target-specificity of monoclonal antibodies or antibody fragments, to adhere exclusively to specific membrane receptors that are characteristic of tumor cells. Following internalization, the potent, anti-cancer drugs, are releases and kill the malignant cell.
This approach creates an excellent control mechanism of drug activation, resulting in an increase of the therapeutic window and, thereby, increasing the use attached drug. However, the therapeutic window of antibody-drug conjugates is still quite narrow, making research in developing a more safe and efficacious ADC technology with a wider therapeutic window a viable field of study.
Antibody-drug Conjugates are currently used for the treatment of lymphoma and metastatic breast cancer. Today, four Antibody-drug Conjugates have been approved by the U.S. Food and Drug Administration (FDA). These agents include brentuximab vedotin (Adcetris®; Seattle Genetics) for Hodgkin and anaplastic large cell lymphoma, ado-trastuzumab emtansine (Kadcyla®; Genentech/Roche) for HER2-positive metastatic breast cancer, gemtuzumab ozogamicin (Mylotarg®; Pfizer) for acute myeloid leukemia and inotuzumab ozogamicin (Besponsa®; Pfizer) for the treatment of acute lymphoblastic leukemia.
The unique properties of an antibody-drug conjugate are determined by the balance of its components. One key part is the cytotoxic payload. The efficacy of of the payload are determined by the drug-to-antibody ratio (DAR) – the number of attached drug molecules to the antibody.
Homogeneous DAR = 8 antibody-drug conjugate can be easily prepared by conjugation to the four accessible antibody hinge cystines. And antibody-drug conjugates with higher drug-to-antibody ratios have greater in vitro potency than the current clinically approved ADCs with a DAR of 2 – 4. Furthermore, the higher DAR antibody-drug conjugates are especially effective against cells with low copy numbers of the target antigen. 
However, many clinical programs with higher a DAR have suffered from unwanted toxicity and insufficient efficacy against tumors. In turn, the use of hydrophobic payloads has effectively permitted only DAR = 2–4. This is, in part, due to poor pharmacokinetics and aggregation and systemic exposure. For example, DAR = 8 monomethyl auristatin E (MMAE) antibody-drug conjugates have been shown to be inferior to both ADCs with a drug loading of DAR of 2 and DAR of 4 in vivo. 
Researchers have shown that by reducing hydrophobicity of homogeneous antibody-drug conjugates it is possible to improve the pharmacokinetics and therapeutic index. These researchers demonstrated that by masking the hydrophobic payloads by hydrophilic linker moieties,antibody-drug conjugates with a drug loading of DAR = 8 and improved in vivo biodistribution and efficacy can be achieved .
A novel payload
Tero Satomaa and colleagues at Glykos Finland, in Helsinki, Finland and OcellO, in Leiden, The Netherlands, generated a novel homogeneous antibody-drug conjugate (MC-Val-Cit-PABC-MMAU) with a DAR = 8. Their antibody-drug conjugate includes a novel monomethyl auristatin β-D-glucuronide (MMAU).
Their glycoside payload contributed to overall hydrophilicity of the antibody-drug conjugates, reducing aggregation. Furthermore, compared to standard drug loading of DAR 2 and 4, the cytotoxicity of the homogeneous ADC with a DAR of 8 was improved to low-picomolar IC50 values against cancer cells in vitro.
Although unconjugated MMAU was relatively non-toxic to cells, the bystander efficacy was restored after internalization and subsequent cleavage of the glycoside. The researchers concluded that their novel monomethyl auristatin β-D-glucuronide (MMAU) antibody-drug conjugate with a DAR of 8 was effective against target antigen-expressing xenograft tumors. Furthermore, studied in 3D in vitro patient-derived xenograft (PDX) assays, these antibody-drug conjugates outperformed clinically used ADC.
Overall, the researchers found that MMAU is a promising novel payload and can overcome many challenges of ADC technology. They demonstrated that the increased hydrophilicity of the payload contributed to the hydrophilicity and stability of antibody-drug conjugates as well as the safety to non-target cells, while significantly improving cytotoxicity to malignant cells and enabling bystander efficacy.
The world’s most comprehensive hematology event of the year will provide an opportunity to Network with top minds in the field and a global community of more than 25,000 hematology professionals from every subspecialty.
New developments in antibody-drug conjugates are expected to create excitement.
The landscape of antibody-drug conjugates is rapidly changing. 
In January 2017 only two ADCs were commercially available in the United States. This included brentuximab vedotin (Adcetris®; Seattle Genetics), an anti-CD30 monomethyl auristatin E (MMAE) conjugate indicated for the treatment of patients with relapsed/refractory Hodgkin lymphoma and systemic anaplastic large cell lymphoma, and ado-trastuzumab emtansine (also know as T-DM1; Kadcyla®; Genentech/Roche), an anti-HER2 DM1 conjugate used to treat HER2-metastatic breast cancer. a
For an overview of oral and poster presentations about antibody-drug conjugates (ADCs) to be presented during the annual meeting of the American Society of Hematology, December 9 – 12, 2017, Click here.
Then in the late summer of this year the number of commercially available antibody-drug conjugates approved by the U.S. Food and Drug Administration (FDA) doubles with the approval, inotuzumab ozogamicin (Besponsa®; Pfizer) for treatment of relapsed/refractory acute lymphoblastic leukemia (ALL) and gemtuzumab ozogamicin (Mylotarg®; Pfizer) b, for relapsed/refractory Hodgkin lymphoma and systemic anaplastic large cell lymphoma.
With four commercially available antibody-drug conjugates, the majority of which are for the treatment of liquid cancers, and with a better understanding of cancer biology and many technological advances, this class of novel (anti-cancer) agents is finally beginning to deliver on decades old expectations and hope for better therapeutic outcomes.
Penelope Drake and David Rabuka, in a recent article published in BioDrugs, discuss how our better understanding and advances are based upon a large – and increasing – body of investigational studies which, taken together, offer a deeper knowledge and comprehension of the absorption, distribution, metabolism, and excretion (ADME), drug metabolism and pharmacokinetics (DMPK) fates of the intact conjugate and its small-molecule drug component.
This year, during the annual meeting of the American Society of Hematology a number of companies will again present their latest developments.
IMGN632 and IMGN779 ImmunoGen, will highlight two experimental ADC therapies, IMGN632 and IMGN779, a CD33-targeted ADC for the treatment of acute myeloid leukemia or Acute Myeloid Leukemia currently in Phase I testing.
Both IMGN779 and IMGN632 use ImmunoGen’s novel indolino-benzodiazepine payloads called IGNs. These ultra-potent, DNA-acting IGNs alkylate DNA without crosslinking, which preclinically has resulted in potent anti-leukemia activity with relative sparing of normal hematopoietic progenitor cells.
Acute Myeloid Leukemia is a cancer of the bone marrow cells that produce white blood cells. It causes the marrow to increasingly generate abnormal, immature white blood cells (blasts) that do not mature into effective infection-fighting cells. The blasts quickly fill the bone marrow, impacting the production of normal platelets and red blood cells. The resulting deficiencies in normal blood cells leave the patient vulnerable to infections, bleeding problems and anemia.
It is estimated that, in the U.S. alone, 21,380 patients will be diagnosed with AML this year and 10,590 patients are expected to die from the disease 
IMGN632 is a humanized anti-CD123 antibody-drug conjugate that is a potential treatment for for hematological malignancies, including AML and blastic plasmacytoid dendritic cell neoplasm (BPDCN), myelodysplastic syndrome, B-cell acute lymphocytic leukemia, and other CD123-positive malignancies.
Earlier this year, ImmungGen announced that the Investigational New Drug application for IMGN632 is active and it expects to open a Phase I trial later this year.
IMGN779 is a novel ADC that combines a high-affinity, humanized anti-CD33 antibody, a cleavable disulfide linker, and one of ImmunoGen’s novel indolino-benzodiazepine payloads, called IGNs, which alkylate DNA without crosslinking, resulting in potent preclinical anti-leukemia activity with relative sparing of normal hematopoietic progenitor cells.
IMGN779 is in Phase I clinical testing for the treatment of AML.
“The clinical and preclinical data to be presented at ASH demonstrate the early potential of our novel IGN portfolio,” said Richard Gregory, Ph.D., executive vice president and chief scientific officer of ImmunoGen.
“One of our strategic priorities is to accelerate the development of these unique and highly differentiated assets. IMGN779 and IMGN632 use our IGN payloads, which were designed to meet the dual challenges of achieving high potency against target cells, while having a tolerability profile that enables continued patient treatment,” Gregory added.
In a poster presentation, the ImmunoGen is expected to report updated data evaluating the safety and anti-leukemia activity from the dose escalation phase of the IMGN779 first-in-human trial. In a separate presentation, preclinical data evaluating the mechanism, anti-leukemia efficacy, and tolerability of repeated dosing of IMGN779 and cytarabine in combination using in vitro and in vivo human AML preclinical models will be reported.
Preclinical data reporting the prevalence of CD123 expression in acute lymphoblastic leukemia (ALL), and assessing the anti-leukemia activity of IMGN632 on ALL cells will be presented in a poster presentation.
Novel payloads: Antibody-targeted Amanitin conjugates
Today, most antibody-drug conjugates, both commercially available and in clinical trials, includes just a limited number of cytotoxic payloads, generally limited to microtubuli- or DNA-targeting toxins including auristatins and maytansines or duocarmycins and pyrrolobenzodiazepines (PBDs). These payloads are mainly targeting proliferating cells potentially leading to limited efficacy in diseases with a low proliferation rates such as indolent lymphomas or multiple myeloma.
Researchers at the German Cancer Research Center, Heidelberg, Baden-Württemberg, Germany in collaboration with Heleidelberg Pharma are developing a novel antibody-drug conjugate with amanitin as toxic payload with an alternative toxicity mechanisms that could enhance the therapeutic potential of ADCs.
Amanitin is the most well-known toxin of the amatoxin family and binds to the eukaryotic RNA polymerase II, inhibiting the cellular transcription process at very low concentrations irrespective of the proliferation status of the target cell.
During this year’s annual meeting, researchers from the German Cancer Research Center will present results of a study assessing in vitro and in vivo specificity and efficacy of HDP-101, an ATAC targeting BCMA (B cell maturation antigen; CD269), which is expressed on cells of the B cell lineage, predominantly on plasma blasts and plasma cells. BCMA is highly expressed on malignant plasma cells and therefore considered an ideal target in multiple myeloma, is not expressed on naïve, germinal center, and memory B cells.
The researchers conclude that the mode of action of the amanitin payload led to an efficient anti-tumor response in vitro and in vivo with good tolerability in non-human primate studies yielding a very favorable therapeutic index.
A first-in-human trial with HDP-101 as a potential treatment for multiple myeloma is expected to start in 2018.
This year 18 abstracts will featuring data from the broad brentuximab vedotin (Adcetris®; Seattle Genetics) development program. Brentuximab vedotin, an ADC directed to CD30, which is expressed on the surface of Hodgkin lymphoma cells and several types of non-Hodgkin lymphoma, is being evaluated globally as the foundation of care for CD30-expressing lymphomas in more than 70 corporate- and investigator-sponsored clinical trials.
The presentations during this years annual meeting include data from the phase III ECHELON-1 clinical trial evaluating brentuximab vedotin in combination with chemotherapy in frontline advanced classical Hodgkin lymphoma patients.
Based on the positive results from the ECHELON-1 trial, the U.S. Food and Drug Administration (FDA) granted Breakthrough Therapy Designation to ADCETRIS in combination with chemotherapy for the frontline treatment of patients with advanced classical Hodgkin lymphoma.
During the annual meeting numerous oral and poster presentations will highlight additional progress within the brentuximab vedotin development program including:
Updated durability results from the phase III ALCANZA clinical trial in patients with CD30-expressing mycosis fungoides and primary cutaneous anaplastic large cell lymphoma, the most common subtypes of cutaneous T-cell lymphoma (CTCL). Based on the positive results from the ALCANZA trial, a supplemental BLA for brentuximab vedotin in CTCL was accepted for filing by the FDA. The FDA granted Priority Review for the application and the Prescription Drug User Fee Act (PDUFA) target action date is December 16, 2017. brentuximab vedotin previously received FDA Breakthrough Therapy Designation in this setting;
Updated results from a phase I/II study of brentuximab vedotin in combination with the ahuman programmed death receptor-1 (PD-1) blocking antibody nivolumab (Opdivo®; Bristol-Myers Squibb Company) among patients with relapsed or refractory Hodgkin lymphoma;
Final five-year survival and durability results in patients with CD30-expressing peripheral T-cell lymphomas who received brentuximab vedotin with cyclophosphamide, hydroxydaunorubicin, and prednisone (CHP) as frontline therapy
“At this year’s ASH Annual Meeting, we will present data from 18 abstracts, highlighting several [brentuximab vedotin] clinical program advancements that support our plans to establish ADCETRIS as the foundation of care for CD30-expressing lymphomas,” noted Clay Siegall, Ph.D., President and Chief Executive Officer of Seattle Genetics.
“Importantly, the results of the phase III ECHELON-1 clinical trial evaluating brentuximab vedotin combination therapy in frontline advanced Hodgkin lymphoma patients was selected from over 6,000 abstracts submitted to be featured in the Plenary Scientific Session. These data are the basis for our planned supplemental biologics license application to the FDA requesting approval of brentuximab vedotin in this setting. The breadth of data being presented with brentuximab vedotin in CD30-expressing lymphomas demonstrates the power of antibody-drug conjugates with a goal of improving patient outcomes,” Siegall added
Brentuximab vedotin is currently not approved for the treatment of frontline Hodgkin lymphoma, CTCL, or as combination therapy for Hodgkin lymphoma or non-Hodgkin lymphoma.
For an overview of oral and poster presentations about antibody-drug conjugates, click here.
a Ado-trastuzumab emtansine is currently the only antibody-drug conjugate available for the treatment of solid tumors.
b In 2000 gemtuzumab ozogamicin, a calicheadmicin conjugates, became the first aDC to be approved in the United States. However, the drug, indicated for the treatment of CD33-positive acute myeloid leukemia (AML) was withdrawn from the market in 2010 due to treatment-related toxicity concerns.
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.).
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%.
A report published by Persistence Market Research (PMR), a U.S.-based full-service market intelligence firm specializing in syndicated research, shows that the global market for antibody-drug conjugates or ADC is expected to be driven by the advancement in medical technology.
According to the report, the key drivers of the market are the increasing cases prevalence of cancer, growing ageing population and increase in obese population.
Furthermore, the increasing research activities on antibody therapies, pre-clinical research, more research on advanced drug discoveries and increasing research on oncology diseases and the growing collaboration between research institutes, biotechnology and biopharmaceuticals companies is also acting as a fuel to the market and is expected to drive the market of antibody-drug conjugates within the forecast period of 2016-2024 discussed in the report.
However, the high cost of the procedures and the lack of fund can be the restraint for the growth of this market.
Three parts- an antibody specific to target Antibody-drug conjugates or ADCs are composed of three parts- an antibody specific to the target associated antigen, antigen that has restricted expression on normal cell, a cytotoxic agent designed to kill target cancer cells and a chemical linker to attach cytotoxic agent to the antibody.
The report’s authors conform that there are 243 antibody-drug conjugates in clinical pipeline for the treatment of cancer. Majority of these agents are investigational drugs in pre-clinical development followed by a considerable agents in phase I – III clinical trials.
These unique, targeted, drugs have therapeutic potential and contains both technological and developmental challenges. ADCs are considered to be the new age of therapeutic agent. They combine the targeting ability of monoclonal antibody and the target specific cell killing ability of cytotoxic drugs.
Success as a result of Technological advances
The success of this technology has become possible only with the increasing technological advancements. Antibody drug conjugates is the new class of therapeutic agent that is gaining attention from both large and small pharmaceutical companies.
The potency of the cytotoxic drug in antibody drug conjugate is 100-1000 fold more than the potency of cytotoxic drug when it acts alone.
Though this technology provides presence to maximum large pharmaceuticals companies, the capabilities for the development of ADC still lies with very few companies. There are many products under pipeline. Most development today has been carried out under license agreements.
The major advantage of using antibody-drug conjugates is that it brings together the best characteristics of both antibodies and the cytotoxic potential of chemotherapy. This offers significant opportunity for the market in terms of targeted accumulation of drug in the tumor cell or tissue. Apart from this there are several other benefits of antibody drug conjugates which are driving the market and will be accelerating its share in the upcoming future. 
The first antibody-drug conjugate, gemtuzumab ozogamicin (marketed by Pfizer/Wyeth as Mylotarg®; previously known as CMA-676) was granted accelerated approval by the FDA based on promising phase II data in relapsed older adults with acute myeloid leukemia (AML).
The drug held promise as a new agent that also could be efficacious in newly diagnosed AML with acceptable toxicity. Several phase III studies were designed to test gemtuzumab ozogamicin in this setting.
The results of a randomized study by the Southwest Oncology Group led in 2010 to the voluntary withdrawal by the manufacturer of this agent when improved efficacy could not be demonstrated and toxicity appeared to be excessive.
Since the withdrawal, 4 randomized studies have been completed that, in aggregate, strongly support the efficacy of this agent in newly diagnosed AML with acceptable toxicity. Based on the results of these studies, it seems that there is a very plausible explanation for this discrepancy. When confirmed, researchers believe that there is a compelling case for re-approval of gemtuzumab ozogamicin in the treatment of patients with AML.
In late January 2017 Pfizer’s Biologics License Application (BLA) for gemtuzumab ozogamicin was accepted for filing by the FDA. in addition, a Marketing Authorization Application (MAA) for review by the European Medicines Agency (EMA) was validated in December 2016.
The number of companies developing methods for antibody drug conjugates technology has not significantly changed in recent years. The increasing investment by the pharmaceutical and Biotechnology companies is expected to drive the market. Based on the product type the market is segmented to brentuximab vedotin (Adcertis®; Seattle Genetics/Takeda) and ado-trastuzumab emtansine (Kadcyla®; Genentech/Roche).
Brentuximab vedotin is indicated for patients suffering with classical Hodgkin lymphoma (HL) after failure from at least two multi-agent chemotherapy regimen in patient who are not auto-HSCT candidates or patient with failure of autologous hematopoietic stem cell transplantation, HL patients at high risk of relapse or progression as post- auto- HSCT consolidation and lymphoma patient after failure of at least one prior multi-agent chemotherapy.
Drugs was granted accelerated approval for Biologics License Application (BLA) by the U.S. Food and Drug Administration (FDA) for its usage in relapsed and refractory Hodgkin’s lymphoma and large cell lymphoma.
Ado-trastuzumab emtansine it is the first HER2-targeted treatment of its own kind for metastatic breast cancer. It contains two cancer- fighting drugs in one. It contains monoclonal antibody trastuzumab, which the same monoclonal antibody in Herceptin® (Genentech/Roche) and a chemotherapy called DM1.
Ado-trastuzumab emtansine is indicated as a single agent for treatment of HER2-positive, metastatic breast cancer in patients who previously received trastuzumab and a taxane, separately or in combination.
Unprecedented tumor response and clinical benefit
A different report, Global Cancer Antibody Drug Conjugates Market & Clinical Pipeline Insight 2022, published earlier this year by Kuick Research, shows that for a number of cancers where validated predictive biomarkers are available, administration of targeted therapies such as antibody-drug conjugates, PD-1s and others, have been associated with unprecedented tumor response and clinical benefit. 
The authors of the report confirm that efforts to design tolerable combination therapies involving antibody-drug conjugate, cancer vaccine, immune checkpoint and kinase inhibition are rational means of maximizing clinical benefit in the targeted delivery of anticancer therapies. 
By end user, the global antibody-drug conjugates market has been segmented into Hospitals, Specialized Cancer Centers, Academic Research Institutes, Biotechnology Companies, Biopharmaceutical Companies and others.
By regional presence, antibody drug conjugates market is segmented into five key regions viz. North America, Latin America, Europe, Asia-Pacific, and the Middle East & Africa. North America will continue to dominate the antibody drug conjugates market as it has high experienced professionals and better healthcare facilities. Europe is expected to hold second largest market share in global antibody drug conjugates market.
The growing government initiatives and increasing number of biotechnology and biopharmaceutical companies in the Asia-Pacific region is also driving the market of Antibody-drug Conjugates.
According to Visiongain Ltd, the global next-generation antibody therapies market, which includes antibody-drug conjugates, is expected to grow at a CAGR of 35.9% in the first half of the forecast period. The market is expected to grow at a CAGR of 22.4% from 2016-2027.
The market is estimated at $3.1bn in 2016 and $14.1bn in 2021.
Catalent Pharma Solutions, the leading global provider of advanced delivery technologies and development solutions for drugs, biologics and consumer health products, today announced that David Rabuka, Ph.D, Global Head of Research and Development, Chemical Biology, Catalent Biologics, will be presenting at the upcoming 7th Protein and Antibody Engineering Summit (PEGS Boston), to be held at the Seaport World Trade Center, Boston, Massachusetts, on May 1 – 5, 2017.
In the presentation, Rabuka will examine the growth of antibody-drug conjugates in clinical trials and pre-clinical development following on from the successes of the approved antibody-drug conjugates drugs brentuximab vedotin (Adcetris™; Seattle Genetics/Takeda) and ado-trastuzumab emtansine (Kadcyla™; Genentech/Roche). He will discuss how innovations in conjugation chemistry and linker technologies suggest further opportunities in the development of antibidy-drug conjugates, and review pre-clinical studies using Catalent’s SMARTag technology platform, which enables precise, programmable, site-selective chemical protein modification.
In addition, Anne Marie Rogan, Senior Associate Scientist at Catalent Biologics’ analytical services will be showcasing expert posters on the use of LC-MS to monitor levels of oxidation and deamidation in proteins for release and stability. Finally, Luke Deters, Senior Manager, Large Molecule Analytical Chemistry will present a poster discussing “quantitation and characterization of polysorbate-80 by HPLC and charged aerosol detection.
Catalent’s proprietary SMARTag site-specific protein-modification and linker technologies were originally developed by Redwood Bioscience to enable the generation of homogenous bioconjugates engineered to enhance potency, safety and stability. The technology employs natural post-translational modifications found in human cells to create one or more aldehyde tags at designated sites on protein molecules. These chemical “handles’’ are then stably conjugated to payloads (e.g. cytotoxic or effector) to prevent their systemic release. The SMARTag platform provides precise payload positioning, stable, site-specific conjugation and defined stoichiometry of drug–protein ratios. The control afforded by the technology enables identification of superior drugs from libraries of differentially designed conjugates.
Authors: Andreev J, Thambi N, Perez Bay AE, Delfino FJ, Martin JH, Kelly MP, Kirshner JR, Rafique A, Kunz A, Nittoli T, MacDonald D, Daly C, Olson W, Thurston G. Title: Bispecific Antibodies and Antibody-Drug Conjugates (ADCs) Bridging HER2 and Prolactin Receptor Improve Efficacy of HER2 ADCs. Published in: Mol Cancer Ther. 2017 Jan 20. pii: molcanther.0658.2016. doi: 10.1158/1535-7163.MCT-16-0658. [Epub ahead of print]
In a research article published in the January 20, 2017 edition of Molecular Cancer Therapeutics, a journal published by the American Association for Cancer Research (AACR), Julian Andreev, Nithya Thambi, Andres E Perez Bay and colleagues compared the trafficking of the well characterized oncogene HER2, which is the target of the clinically approved antibody-drug conjugate ado-trastuzumab emtansine (T-DM1; marketed by Genentech/Roche as Kadcyla®), with that of prolactin receptor (PRLR), another potential target in breast cancer.
While ado-trastuzumab-emtansine has shown benefit for breast cancer patients, use of this agent is not indicated for the treatment of patients whose tumors express low or intermediate levels of HER2.
In a previous, unrelated study, the researchers found that low levels of cell-surface PRLR are sufficient to mediate efficient ADC killing of breast ductal carcinoma cells. Based on these findings they confirmed that PRLR is rapidly and constitutively internalized, and traffics efficiently to lysosomes, where it is degraded. 
Results of their original study, presented in 2015, showed that approximately 90% of a PRLR antibody was internalized by T47D cells within 1h after treatment, and the internalized PRLR Ab co-localized with the lysosomal marker, Lysotracker Red, while trastuzumab was restricted to the plasma membrane and did not co-localize.
Enhancing HER2 degradation
The PRLR cytoplasmic domain is necessary to promote rapid internalization and degradation, and when transferred to HER2, it enhances HER2 degradation. Based on these findings, low levels of cell surface PRLR (~30,000 surface receptors per cell) are sufficient to mediate effective killing by a PRLR ADC. In contrast, cell killing by an HER2 ADC requires higher levels of cell surface HER2 (~106 surface receptors per cell).
Noncovalently cross-linking HER2 to PRLR at the cell surface by using a bispecific antibody that binds to both receptors, dramatically enhances the degradation of HER2 as well as the cell killing activity of a non-competing HER2 ADC.
Furthermore, the researchers found that in breast cancer cells that co-express HER2 and PRLR, a HER2xPRLR bispecific ADC kills more effectively than an HER2 ADC.
These results emphasize that intracellular trafficking of ADC targets is a key property for their activity. Furthermore, coupling an ADC target to a rapidly internalizing protein may be a useful approach to enhance internalization and cell killing activity of ADCs.
Over the last 25 years, there has been an explosion of new and vitally important, anticancer drugs.
The development of these promising new therapeutic agents is generally based on preclinical and clinical research. In many cases, this research has become prohibitively expensive. And only a relatively few investigational drugs have reached the market and successfully improved clinical outcomes in the treatment of patients with cancer and hematological malignancies. In the development of new therapies, the traditional clinical trial process of determining which drugs will ultimately benefit patients is long and expensive.
“The I-SPY Trial Program integrates and links Phase I, Phase II and eventually Phase III clinical oncology trials to build a pipeline of novel anticancer agents…”
Over the last few decades scientists have tried to change – and improve – the way clinical trials are conducted. Their purpose… Improving the process and improving the way novel pharmaceutical drugs are being developed. But it still takes many years and huge investments to successfully bring a new drug to market.
But despite their efforts there is still a huge unmet medical need.
While there are many novel drugs being developed to help improve the outcome and improve survival, resources are limited. Optimal use of resources requires better understanding of cancer biology, the identification of novel therapeutic targets, and the ability to address inefficiencies in the cancer clinical trials system. This may especially be so in how we treat women with metastatic, high risk, breast cancer.
Based on the current limitations in how we conduct clinical trials, scientists of The Biomarkers Consortium, at the Foundation for the National Institutes of Health, are changing the way new anticancer drugs are being developed.
The Foundation’s unique and groundbreaking, re-engineered approach to clinical trials is the I-SPY Clinical Trial. This trial represents an unprecedented and streamlined method in developing new anticancer drugs. Using breast cancer treatment as a model – the I-SPY TRIALs are designed to significantly reduce the overall cost, time, and number of patients required to bring innovative anticancer agents to the right patient at the right time – and do this faster.
The I-SPY Trial Program integrates and links Phase I, Phase II and eventually Phase III clinical oncology trials to build a pipeline of novel anticancer agents. As a result, the new trial program accelerates the process of identifying a subset of high risk breast cancer patients that will directly benefit from these novel agents.
Among the targeted drugs being investigated in the I-SPY 2 trail are antibody-drug conjugates or ADCs. Antibody-drug Conjugates are part of a new wave of targeted antibody-based products. They are novel, innovative agents at the cutting edge of oncology and hematology.
During the Annual Meeting of the American Association of Cancer Research, held – April 16 – 20, 2016, in New Orleans, we sat down with Doctor Angela DeMichele, Professor of Medicine and Epi-demi-ology at the Perelman School of Medicine at the University of Pennsylvania.
We asked Doctor DeMichele a number of questions about a specific part of the I-SPY-2 trial in which researchers investigated a particular antibody-drug conjugate and how a combination of drugs, including antibody-drug conjugates, can bring a substantially greater proportion of patients to the primary endpoint of pathological complete response or PCR, an outcome in which, following neoadjuvant therapy, residual invasive cancer is detected in the breast tissue and lymph nodes during surgery.
And we asked her about the benefit of targeted therapy and how novel drugs like antibody-drug conjugates play a role.
Valuable lessons learned from both approved antibody-drug conjugates (brentuximab vedotin /Adcetris®; Seattle Genetics approved in 2011 and ado-trastuzumab emtansine or T-DM-1/Kadcyla® approved in 2013) as well as novel investigational compounds in ongoing clinical trials, have helped scientists, researchers and clinicians to better understand the mechanisms of action of antibody-drug conjugates. These lessons have also helped them to find new ways in overcoming the challenges of poor internalization, tumor non-specificity, off-target toxicity, lack of efficacy, low expression levels and multi-drug resistance.
Much work is being done in developing innovate next generation antibody-drug conjugates by improving target selection, finding new cytotoxic drugs as payload, engineering antibodies or discovering alternative effector moieties to increase half-lives, improve target specificity and improve and optimize linker-payload chemistry.
As an online-only, hybrid open-access, peer reviewed journal designed to serve the needs of a diverse community of individuals including academia, life sciences, pharma, (basic, translational and clinical) research, clinicians/physicians, along with regulatory affairs, government authorities and representatives from payers, and policy makers, we strive to offer a the latest information related to antibody-drug conjugates by publishing news and news features, editorials/Op-Eds, as well as peer reviewed research, commentaries, discussions and blogs on topics relevant to a broad and international readership. Some of this information focuses on (early) preclinical drug development and clinical development. But we also cover articles discussing upstream and downstream processing, characterization and analytics, regulatory affairs, insurance, reimbursement policies, etc.
Planning ahead for 2017
With the fall medical and scientific meetings in full swing and 2017 only two months away, we’re looking ahead to 2017. Each year, as part of our editorial process, we’re looking at the ‘big topics’ for the next 12 months. Some of our planning is dictated by the medical and scientific meetings* and as a media partner of some of the most influential conferences and symposia in the industry, we will cover the news and late breaking updates presented during these meetings. Some is dictated by industry and clinical breakthroughs. And some of our coverage is dictated by business transactions and decisions made by regulatory bodies.
But there is more. Our editorial calendar also depends on you! Our planning starts with the development of a comprehensive editorial calendar. Being a continuously published (online) journal, we then look for the specific, relevant, topics guiding our coverage. As part of this process, we’re inviting subject-matter experts and Key Opinion Leaders/KOLs to contribute. And this is where you come in.
Being a subject-matter expert or KOL, we welcome your manuscripts for peer-review. Generally, articles can be a data-driven novel research, a clinical/therapeutic review, a science-based opinion/Op-Ed, an academic or scientific review, a technical discussion, application note or case study, a policy/legal or regulatory overview/discussion, etc. Each manuscript, submitted for peer-review to our independent editorial review board, needs to be original, properly referenced and offer timely information focusing on antibody-drug conjugates, targeted therapies and precision/personal medicine suitable for our (experienced) readers.**
In addition to manuscripts for peer review, we invite you – as a contributor – to develop and submit news articles and news features and recommend subjects for the ADC University and video projects.
An Exciting Time
With a new wave of dealmaking, scientific developments and medical breakthroughs, this is an exciting time for anyone involved with antibody-drug conjugate.
Industry-wide there are 60 antibody-drug conjugates in clinical development. Today 40 of these investigational compounds are in phase I trials, 16 in phase II and 4 phase III. Currently, there are two licensed ADCs on the market. Many of the ADCs in phase I trials are not identifying a target disease, but are broadly recruiting for solid tumors. With more than 10 ADCs, breast and lung cancer are common diseases for ADCs. Of the 30 different targets for solid tumors 11 target breast cancer and 9 lung cancer.
With more ADCs moving into later-stage clinical trials in 2017 and other trials coming to a close, we’re eagerly anticipating intermin data as well as mature data from pivotal trials with ADCs in both solid tumors and hematological cancers. But we’re also looking for the latest (early) pre-clinical data. Data you develop as part of your early pre-clinical studies, your characterization or analysis of novel ADCs, your work in the clinical, etc.
Questions to Ask – Answers that Matter
So, what are the lessons we have learned. And, how are the lessons from currently approved and marketed antibody-drug conjugates as well as novel investigational compounds in ongoing clinical trials helping scientists, researchers and clinicians to overcome setbacks previously experienced? How do initiatives like the Cancer Moonshot impact research? How do the regulators look at novel ADC-construcs with new payloads and linkers, and outcomes from combination therapies? What about characterization, analytics, environmental risk assessments, upstream and downstream (manufacturing) issues, single-use technologies, containment, reimbursement and insurance? And… how do research outcomes translate to success in the clinic and benefit patients with unmet medical needs?
With a scientific and technological revolutions driving the many advances and radical new opportunities in the treatment of patients with cancer and hematological diseases, novel treatment options, including solutions for currently unmet medically needs, are opening up new possibilities for meeting the challenge.
And that’s why you are important.
We’re eagerly anticipating your contributions!
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Safety and preliminary efficacy data from a phase I study of DS-8201a (Daiichi Sankyo Company), a novel investigational HER2-targeting antibody drug conjugate or ADC, suggest that the investigational drug candidate is well-tolerated with no dose-limiting toxicities.
These results come from the dose escalation part of a two-part phase I study of DS-8201a presented during a late-breaking poster discussion session during the ESMO 2016 Congress, the annual meeting of the European Society for Medical Oncology, being held October 7 – 11, 2016 in Copenhagen, Denmark.
DS-8201a is an investigational antibody drug conjugate comprised of a humanized anti-HER2 antibody attached by a peptide linker to a novel topoisomerase I inhibitor (DXd) payload, utilizing Daiichi Sankyo’s proprietary payload and linker-payload technology.
Unique Mechanism of Action
Preclinical models have demonstrated that DS-8201a has a unique mechanism of action (MOA) where it selectively binds to the HER2 receptor on a tumor cell surface, triggering an antibody-dependent cell cytotoxic or ADCC response.  DS-8201a is then internalized via endocytosis (transportation into cells by an energy-using process) and the intracellular lysosomal enzymes break down the peptide to release the DXd payload, which then inhibits topoisomerase I activity, causing DNA damage and cell death. 
The linker-payload combination of DS-8201a allows for a higher drug-to-antibody ratio or DAR of about 8 compared to a DAR of about 3.5 seen with ado-trastuzumab emtansine (T-DM1; Kadcyla®; Genentech/Roche).  The higher DAR of DS-8201a may help target low expressing HER2 tumors by supplying more payload per antibody to a tumor. 
“…These preliminary results are compelling and warrant further clinical evaluation of DS-8201a in several different patient populations expressing HER2…”
Phase I results
DS-8201a, given as an intravenous infusion every three weeks, is currently being evaluated in an open-label two-part phase I study in patients with advanced/unresectable or metastatic breast cancer, gastric or gastroesophageal junction adenocarcinoma, or other solid tumors that is/are refractory to or intolerable with standard treatment or for which no standard treatment is available.
The primary objective of part I of the study (dose escalation) is to assess the safety and tolerability of DS-8201a and determine the maximum tolerated dose or MTD. Secondary objectives include evaluating the pharmacokinetics, efficacy and human anti-human antibody (HAHA) against DS-8201a.
The second part of the study, the dose expansion, of the ongoing phase I clinical trial is enrolling patients in Japan and the United States into one of four cohorts including patients with HER2+ breast cancer previously treated with ado-trastuzumab emtansine as well as patients with HER2+ gastric or gastroesophageal junction adenocarcinoma previously treated with trastuzumab (Herceptin®; Genentech/Roche), patients with HER2 low expressing breast cancer and patients with other solid cancers that express HER2, also known as human epidermal growth factor receptor 2.
The study enrolled 22 patients. This included 16 (73%) patients with breast cancer, 5 (23%) patients with gastric cancer, 1 (5%) patient gastroesphageal junction adenocarcinoma. All patients were treated in the dose escalation part of the study.
The maximum tolerated dose was not reached (0.8-8.0 mg/kg given every three weeks) and there have been no dose-limiting toxicities at pharmacologically-active exposure and a favorable pharmacokinetic profile. Seven grade 3 adverse events were seen in three patients (1 hypokalemia, 1 anemia, 1 neutrophil count decreased, 2 lymphocyte count decrease, 1 ALP increase and 1 cholangitis). Most common adverse events were mild or moderate gastrointestinal and hematological events.
Preliminary overall efficacy results in 20 evaluable patients demonstrated an objective response rate or ORR of 35% (seven partial responses) and disease control rate of 90%, including 12 patients previously treated with ado-trastuzumab emtansine and five patients with HER2 low expression (IHC2+/FISH- or IHC1+).
In 15 patients with HER2+ disease defined as IHC3+ or IHC2+/FISH+, the disease control rate was 100%. At the time of the analysis, 17 patients remained on treatment, and five of the first 10 patients have been under active treatment (0.8 to 6.4 mg/kg) for more than 24 weeks. The median progression-free survival had not been reached.
Among 12 evaluable patients with HER2-positive breast cancer who had prior T-DM1, the ORR was 42% and the disease control rate was 92%.
Large unmet need
HER2 is a tyrosine kinase receptor growth-promoting protein found on the surface of some cancer cells. About one in five breast cancers overexpress the HER2/neu gene, which causes these cancers to grow more aggressively.  To be considered HER2+, cancer cells are tested by one of two methods: immunohistochemistry (IHC) or fluorescent in situ hybridization (FISH).2 IHC test results are reported as: 0, IHC1+, IHC2+ or IHC3+. A finding of IHC3+ is considered HER2+.2 A finding of IHC2+ is borderline and typically is confirmed by a positive FISH test.
Several unmet needs remain today in HER2+ metastatic breast cancer. Many tumors advance to the point where no currently approved HER2-targeted treatment continues to control the disease. Additionally, there are no existing options indicated for HER2 low expressing tumors (IHC2+/FISH- or IHC1+) as well as HER2 heterogeneously expressing tumors (tumors with some tumor cells having high HER2 expression and some having low HER2 expression), which generally have poor prognosis. 
“Despite recent advances in treating HER2+ breast and gastric cancer, there still remains a large unmet need for patients with HER2+ disease whose tumors are no longer controlled by currently approved targeted HER2 treatments or for tumors that express low HER2,” noted Antoine Yver, MD, MSc, Executive Vice President and Global Head, Oncology Research and Development, Daiichi Sankyo.
“These preliminary results are compelling and warrant further clinical evaluation of DS-8201a in several different patient populations expressing HER2,” Yver added.
“The components that make up DS-8201a are unique from any other antibody drug conjugate currently in clinical development and may explain the clinical activity observed at such an early phase of development,” said José Baselga, MD, PhD, Physician-in-Chief and Chief Medical Officer at Memorial Sloan Kettering Cancer Center, New York, NY.
“While the results of this study provide important preliminary proof-of-concept for the novel mechanism of action of DS-8201a, additional research will be needed to further confirm these findings,” Baselga said.
HER2+ Breast Cancer Subgroup Analyses
A total of 18 patients enrolled in the study received one or more prior anti-HER2 therapies (18 received trastuzumab, 13 ado-trastuzumab emtansine, 5 pertuzumab, 4 lapatinib). In 12 evaluable HER2+ breast cancer patients previously treated with ado-tratuzumab emtansine, the objective response rate was 42% with a disease control rate of 92%.
“It is impressive that DS-8201a showed activity in these patients since many were heavily pre-treated with more than one HER2-targeting agent including T-DM1, and some with very substantial tumor load or large tumors,” said Kenji Tamura, MD, PhD, Chairman, Department of Breast and Medical Oncology, National Cancer Center Hospital, Tokyo, Japan and lead investigator of the study.
“This finding will be further evaluated in the second part of this study where one cohort will include only advanced breast cancer patients previously treated with T-DM1,” Tamura noted.