Interview with Steve Farmer, Senior Director at WuXi Biologics, where he discusses with Bio-Rad approaches to continuous manufacturing and the risks associated with scaling-up biologics manufacturing from clinical scale to commercial scale.
Category Archives: Perspectives
Developing a Novel ADC for Global Market via Innovative Three-party Collaboration
Recently, Dr. Jiawen Han, Vice President of ADC Technology at WuXi Biologics (a wholly owned subsidiary of WuXi AppTec), presented at the 1st DIA China Drug Discovery and Innovation Conference. His presentation provided a brief history of antibody drug conjugates (ADCs) as a therapeutic class, the challenges of designing and developing these complex drugs, new technologies available to drug developers and finished with a successful case study describing a three-party collaboration model to develop a novel ADC for global clinical trials. This week we sat down with Dr. Han to provide a synopsis of his talk and discussion on the various challenges and approaches to developing novel ADCs for the global healthcare markets and to gain further insight on the case study he presented.
To start off, can you tell us a bit about the history of ADCs and current industry status?
Jiawen: Sure. The concept for ADCs can be traced back to a century ago when German physician Paul Ehrlich envisioned a “magic bullet” type of therapy in which a targeting agent could be harnessed to deliver cytotoxic agents directly to the source of disease. However, due to the limitation of available tools at that time, the vision didn’t come true until mid 1970s when monoclonal antibody technology was invented. The early development of ADC in the 1980s and 1990s suffered a lot of setbacks for mainly two reasons: first, the warheads used then were conventional anti-cancer drugs, and when those drugs were linked to antibodies the resulting ADCs didn’t have significant effect to cancer cells; second, the linkers used for coupling of the drugs to antibodies were not stable in the circulation, and the drugs were released before reaching to the tumor targets. As the industry gradually learned the lessons through these failures, in particular, with more potent drugs and stabled linkers used, ADC technology has improved. As of now, three ADC drugs passed FDA scrutiny and were commercialized and many more are in clinical trials.
What are the key considerations in developing an ADC drug?
Jiawen: Compared to traditional drugs, ADCs have higher efficacy because of its specificity, longer half-life, and stronger cytotoxic effect. During the past thirty years the industry has made a lot of progress in ADC technology in terms of the availability of linkers and conjugation methods. Also we gained a deeper understanding of the design of ADCs. For example, we now know that because only very little toxin will eventually enter the cells, the cytotoxin in ADCs must be extremely potent–hundreds to a thousand times more than traditional stand-alone drugs in chemotherapy. Also, the linker used in ADCs has to be very stable in storage and in circulation but cleavable inside the cells. In short, we need to take into consideration the optimization of various parts of an ADC and finding the efficient way to integrate these parts into a final safe product that has higher efficacy than individual part alone.
What is the current landscape of service providers for ADC development?
Jiawen: Right now there are roughly 50 ADCs in clinical development. As more and more big pharma and biotech companies join the race, the list is expected to grow longer in a rapid pace. If we quickly review the various processes needed to develop an ADC drug, for example producing high potency payload, analyzing and characterizing ADC candidates, and managing the supply of antibodies, toxin, linker and final ADC products, there really aren’t many CROs or CMOs that can handle these tasks. Currently, less than a dozen of CMOs can support ADC development all the way through clinical and less than a handful can support commercial supply.
Can you explain this case study of three-party collaboration for ADC development?
Jiawen: Sure. Back in summer 2013 U.S. Ambrx Inc. and China’s Zhejiang Medicine Co. Ltd. (ZMC) formed a collaboration to develop and manufacture a site-directed ADC targeting Her2-positive breast cancer. Under the agreement ZMC would fund the project whereas Ambrx would provide its technology that enables the incorporation of non-natural amino acid into an antibody and conjugation of drugs with site-selective manner. WuXi was selected to provide full CMC support from cell-line optimization, toxin & linker synthesis to ADC conjugation, fill/finish and release. The ADC product would be used in a clinical trial in an industrialized nation. This is also an example of WuXi’s in-China-for-global business model.
What were the challenges associated with this three-party collaboration?
Jiawen: In addition to technical challenges, many parties being involved in the decision-making process for this ADC program made project management and communication more complex. As both communication and project management are key to successful and timely delivery of the project, we quickly assembled a project team bringing in experts from Ambrx, ZMC and also various WuXi business units and implemented efficient communication mechanisms among team members to address this challenge This ensured clear and timely communications of project progress and problems encountered. It also facilitated quick transfer of information and data. In the end, because of effective communication and collaboration, we were able to successfully complete this program within 18 months.
What lessons can the industry learn from this program to help reduce the cost of ADC therapeutics development and get to the clinic faster?
Jiawen: A single-source service provider can greatly reduce the cost and save the time that would have been wasted on vendor-to-vendor transfers. It also simplifies problem-solving when all the technical teams working on the project can be called into trouble shooting quickly. This is one of the key values we bring to our clients. At WuXi we have established a one-stop shop for ADC R&D and manufacturing. We have four sites of the company that are involved in ADC drug development and all of them are located in the Yangtze Delta region, just within hours of drive of each other. Since we do not have to outsource any part of the work and all sites involved in ADC development are located within 1-2 hours drive of each other, we can greatly simplify the supply chain for our clients and help them reduce costs and get to the clinic faster.
Overcoming Challenges in Developing Antibody Drugs Against Immune Check Point Targets
In May, Dr. Jing Li, Vice President of WuXi Biologics, presented to approximately 175 attendees at the Cambridge Healthtech Institute’s (CHI) 11th Annual PEGS Essential Protein Engineering Summit at the Seaport World Trade Center in Boston, MA. This week we sat down with Jing to continue the discussion on the topic of overcoming challenges in developing antibody drugs against immune check point targets.
Can you elaborate on the mechanisms and functions of immune check-point elements?
Jing: The immune system is a very complex way to protect our body from foreign attack caused by bacteria or virus, as well as to monitor and clean our internal system (e.g,. cleaning and removing apoptotic tissue or tumor cells). The delicate balance between activation and inhibition of the immune system is tightly regulated by the communications among various immune cells. One such crucial communication system is the immune check-point system which utilizes multiple receptors and ligands expressed on various immune cells. In order to easily understand the roles or functions of the immune check-point elements, let’s imagine the immune system is like a car. One group of immune check-points elements are the “gas pedals” and the other group of immune check-point elements are the “brakes”. These elements work together to fine-tune immune responses in order to provide an adequate immune response to a target. Meanwhile, the elements also work together to avoid autoimmunity and the destructive effects of an excessive inflammatory response. However, it is also well established that tumors use several mechanisms to avoid elimination by the immune system and one of those involves “hijacking” or controlling these check-point pathways.
Given such complexity to the problem, why is there such a large interest in immune check-point targets?
Jing: Immune check-point therapy utilizes monoclonal antibodies to release the “brakes” or to activate the “gas pedals” on suppressed T cells, allowing them to be activated and recover their antitumor activity. This therapeutic approach has revolutionized cancer immunotherapy. The extraordinary increases in overall survival of human cancer patients have been noted against two immune check-point targets CTLA-4 (cytotoxic T lymphocyte-associated protein 4) and anti-PD-1 (programmed cell death receptor-1) in melanoma and other malignancies. The approval of anti-CTLA-4 antibody, Ipilimumab (BMS), and the recent approvals of two anti-PD-1 antibodies, Pembrolizumab (Merck) and Nivolumab (BMS), have greatly attracted more attention to the immune check-point therapy field.
This is exciting for the field of oncology, are antibodies to these immune check-point inhibitors the answer and if so, how do we generate such drug candidates?
Jing: Antibodies are ideal because they can be engineered to be highly specific, stable, easy to manufacture, well-tolerated in vivo and with high affinity to the target of interest. There are several approaches to generate antibody therapeutic candidates. The classic approach is to immunize rodents to generate rodent hybridoma clones expressing functional antibodies. Since the rodent generated antibodies will not be recognized as “self” in the human body and thus may be cleared quickly from the body or cause immune damage due to its immunogenicity, this approach has to be followed by further antibody engineering called humanization to reduce the immunogenicity of the original parental rodent antibodies. This approach has been successfully run for many projects in our group. Alternatively, we can generate hybridoma cell clones expressing fully human antibodies using OMT rats, which are transgenic rats expressing only the human antibody repertoire. We have formed a strategic partnership with OMT, which de facto gives us the exclusive status of using OMT transgenic rodents in China. The third approach is to screen for therapeutic candidates from human antibody libraries. The candidates from these libraries are fully human antibodies as well. We have established our own internal proprietary human antibody libraries, and they are ready for use in drug discovery.
What would be the special challenge in developing therapeutic antibodies against immune check-point targets?
Jing: One critical step in drug discovery and development is to test your therapeutic candidates in certain disease relevant animal models to verify your therapeutic rational and test the efficacy of your therapeutic candidates. The commonly used preclinical animal models for cancer drug discovery are xenograft mouse models, which are mice implanted with human cancer cells. However, the cancer immune therapy needs to leverage the inherent mouse immune system to exert its anti-tumor activities. The immune system and tumor in the animal models have to be in the same immune background. So the conventional xenograft mouse models may not fit immune therapy drug discovery. The syngenic mouse tumor models, in which the syngenic mouse tumor cells are implanted in mice, have to be used. This will require your therapeutic antibody candidates to cross-react to mouse targets in such syngenic mouse tumor models. The general protein sequence homology between human and mouse species for those known immune check-point targets is pretty low, posing significant challenge on generating such cross-reactive antibody drug candidates for preclinical in vivo testing.
What would be the solution and how easy is that to do?
Jing: We need to carefully design our work flow of antibody generation to maximize our chance to achieve the same human and mouse target cross reactivity. As you can imagine, with such low target protein sequence homology between human and mouse species, to develop a therapeutic monoclonal antibody that has high affinity for both the human and mouse target, is also highly specific, efficacious, soluble, and stable and can be manufactured easily is not trivial. All of these selection criteria I’ve just mentioned make finding the ideal antibody candidate for clinical trials a real challenge. Using these various selection criteria, we must screen thousands of antibodies just in the hope of finding 3-5 ideal therapeutic candidates. In case we cannot find a good candidate which can cross-react with both the human and mouse target with equal activities, we have to initiate a parallel program to generate a surrogate antibody which recognizes the mouse target, for the purpose of verifying the therapeutic rational in preclinical animal models. Both the human therapeutic antibody and the mouse surrogate antibody must be well-characterized and perform similarly in vitro. This requires though a very experienced team like we have at WuXi to generate and characterize these complex biological molecules.
In your talk you mentioned the using multiple discovery platforms – why would you need to do that?
Jing: There are many different antibody discovery platforms and technologies that allow you to screen thousands of antibodies. However, each of those platforms has its own unique strengths and weaknesses. We’ve seen time and time again in the industry that relying on one platform may not generate the ideal antibody candidate that you’d like to take into clinical trials. The strategy of “multiple shots on goal” has been adopted by many big pharma companies when they work on high value targets. Thus, to overcome the challenge, to maximize your chance of success, and to expedite the drug discovery process, we’ve developed multiple different technology platforms to greatly increase the likelihood of finding the best therapeutic candidate. You hopefully will not need to use all of them but I showed data in my talk in Boston how utilizing two of our platforms doubled the number of ideal mAb therapeutic candidates. We were thus able to provide our clients more timely solutions or better candidates to their drug discovery problems.
Can all the work you mentioned be performed at WuXi?
Jing: Yes, that is what makes WuXi so unique. Our large highly trained antibody discovery team has significant industry experience. Many of our senior staff have worked in the biologics discovery field in big pharma for 10-20 years. We also work closely with our colleagues in discovery biology, oncology, cell line engineering and process development to put together unsurpassed capabilities and capacities for our clients. This single-source approach provides one-stop-shop drug discovery and development services with significant time savings and efficient trouble shooting for our clients. Thus all the resources they need for their drug discovery and development efforts are right here in Shanghai.
WuXi Biologics expands its biosafety testing capacities by adding a new facility in Suzhou, China. The 38,000 sq. ft. facility has been operational since December 2014 and provides viral clearance studies, cell line characterization and lot release testing services. We had the opportunity to sit down with Dr. Paul Liu, Vice President and Head of this new biosafety testing facility, to learn more about him and the future of biosafety testing services in China.
What inspired you to join WuXi after over 25 successful years at biotech companies?
Paul: WuXi has built an amazing organization with superb capabilities and a world-class reputation to match. I am proud to support the mission and commitment of WuXi, and eager to contribute to the rapid growth of our industry in China and Asia.
What can you tell us about the new biosafety facilities in Suzhou, China and what goal do you aspire to achieve?
Paul: Our laboratory is the first of its kind in China and Asia, i.e. a non-state affiliated third-party biosafety testing services provider focused on viral safety. We have available the best practices and technologies from the US and we operate to global quality standards. Last year, it was challenging to promote this new paradigm against the status quo, but we have become well established now. That said, we will continue to improve so that we can remain a market leader.
How do these services fit into the product development process for our clients?
Paul: All of our clients are involved in the GMP manufacturing of biotherapeutics, albeit many in early stages of development. Inherent in the use of mammalian cells for the manufacture of biopharmaceuticals is the risk of introducing viral or other microbiological contaminants into the production process. We provide services that screen for viruses and other microorganisms in the cell lines and raw materials used during production. Another critical requirement that we can fulfill for our clients is to ensure that their purification scheme can remove and inactivate virus should it somehow enter the production process. All regulatory drug filings require this validation. Since the biopharmaceutical industry is relatively young here, we can both educate and assist clients to meet these rigorous demands for product safety and quality.
With these services already established in the US, why duplicate the labs in China?
Paul: Our testing lab makes WuXi Biologics unique among contract development and manufacturing organizations (CDMOs) in Asia as we can perform this important task in-house. Coupled with WuXi Biologics’ other comprehensive services and the vast capabilities of our affiliates, we are truly the only single-source service provider in the world for drug development and manufacturing. In addition, our location makes it convenient to serve a potentially huge market, where the industry is developing rapidly. With our familiarity of the local language and culture, we can more readily share our technical expertise and regulatory knowledge to benefit our clients and partners.
Did the US biosafety team assist in the efforts to develop the services in China?
Paul: Our US colleagues did a lot more than assist. They anticipated the market potential and the importance to extend the commercial reach of their industry leading services to China and Asia. Our Suzhou China facility is designed to replicate the services provided in the US, by employing the same test methods, equipment, and critical raw materials including proprietary cell and virus banks. The US biosafety team helped recruit the Suzhou leadership team, provided operational guidance and much of the senior staff training. Moving forward, we expect to continue collaborating with our US colleagues to address the challenges of our ever changing marketplace and to seek advice on some of the more complex projects.
How do you expect to create value for your clients/partners?
Paul: As mentioned earlier, our one-stop service offering is one of the key areas where we can provide value. Reducing the number of vendors provides significant efficiencies and cost savings for our clients. Furthermore, we shall follow the core values of WuXi AppTec – client first, ownership, respect, excellence, and accept every business opportunity as a challenge to prove ourselves and earn our client’s trust and confidence. To us, the client’s best compliment is their repeat business and that we will never forget.