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?

 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 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?

Han: 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?

Han: 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?

Han: 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 an example of WuXi’s in-China-for-global business model.

What were the challenges associated with this three-party collaboration?

Han: 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?

Han: 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.