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
- Method Development and Qualification / Validation
- QC Release and Stability Testing
- QA and CMC Support
Our Bioconjugation technologies include:
- SteadFastTM Non-Cleavable Linker (Thioether based)
- Site-directed conjugation of radionuclide chelators to antibodies to improve conjugate binding
- In development:
- 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)
Featured image: Bone scintigram of the body showing vertebral bone cancer metastases from prostate cancer, labelled with technetium 99m (Tc 99m), frontal (left) and rear (right) views. Scans are scintigrams showing bone metastases from primary tumors. Photo and Featured Image Courtesy: © Goodwin Biotechnology. Used with permission.
Last Editorial Review: January 29, 2015
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