Streamline the ADC Path to the Clinic with One-stop Drug Development and Critical Technology Advancements
REDUCING THE TIMELINE FOR ADC DRUG DEVELOPMENT
I began the interview by talking about the greatly reduced timeline that WuXi XDC executed for ADC drug development of only 15 months. We talked about how the normal timeline is 24-30 months and I asked Jimmy how they were able to achieve such a significant time savings. He explained that WuXi XDC can perform all facets and phases of bioconjugate development, and the entire supply chain is within one central geographic region, and lastly the entire project is tightly controlled through intensive project management processes. Another key factor in reducing the timeline is that they perform many of the development activities in parallel. For example, instead of conducting each step in sequence and waiting for the results of each step, they work the process in parallel to further reduce the overall time required.
Next, I asked if he could give me a specific example of how they accomplished this. He said that the monoclonal antibody (mAb) process development and ADC conjugation process development are heavily overlapped. This saves a great deal of time, but requires extensive project coordination and meticulous planning, as well as excellent project execution. Release testing of the mAb and payload-linker intermediates, and the ADC conjugated drug substance also needs to be managed carefully to enable quick turn-around time to the next step of manufacturing.
I followed up by asking if this was a common practice. Jimmy described how these risk-based approaches are difficult to accomplish in a multi-vendor model. For example, what WuXi XDC is doing is very different than the typical approach of waiting for full testing of each of these elements before moving to the next step, and this can only be realized by working within a single quality system, with highly-vetted and well-understood development platforms for the various intermediates. In essence their team knows what risks to take based on the experience they have across their entire development platform.
SINGLE-SOURCE APPROACHES IN DISCOVERY AND LEAD SELECTION PHASES
Then, I asked if WuXi XDC could provide single-source solutions earlier in the process, such as in the discovery phase and during lead selection. He said yes, WuXi XDC has large teams that can generate antibody, payload, and linker libraries. Then, in matrix-like fashion, they perform the engineering, conjugation, and evaluation of a wide-variety of bioconjugated lead candidates. This includes payloads tethered not just to mAbs, but also bispecific and multispecific antibodies, fusion proteins and Fab-fragments, and other complex molecules. They can serve an extension of their clients’ R&D programs and, if required, they can conduct these programs on an FTE-basis with dedicated personnel to really large programs.
I followed up to see if Jimmy could provide an example for listeners. He said that for several organizations, including large pharma, they can conduct large-scale comprehensive conjugation programs. In these programs, they not only perform conjugations on a multitude of different antibodies and payloads, but then they also perform the protein or antibody generation, analytical characterization, and other critical preclinical screens. Thereby, providing evaluation of these various lead candidates for efficacy, biology, DMPK, and toxicity. They can conduct all these activities in-house, which greatly streamlines the lead identification process like how they streamline CMC development.
HANDLING HIGHLY CHALLENGING INTERMEDIATES
We then discussed that ADCs and some of the other new bioconjugate modalities often contain highly potent, or highly toxic payloads. Thereby, requiring development and manufacture of these intermediates and the subsequent conjugation to be done in special facilities equipped to handle these compounds and that they may also require additional oversight from regulatory authorities. I asked if WuXi XDC is equipped to handle these types of intermediates and compounds? Jimmy stated that their chemical payload-linker and bioconjugation manufacturing facilities are purpose-built to handle highly potent and toxic materials and the designs and construction were set to meet U.S. FDA, EMA, and China National Medical Products Administration (NMPA) standards for those compounds. Their GMP bioconjugation manufacturing and drug product fill facility is designed to handle OEB 5 or Safebridge III to IV grade of compounds. In addition, they are using the same WuXi Biologics’ quality system that has passed many inspections from multiple global regulatory agencies in the past couple of years.
ADC EFFICACY CHALLENGES
We then discussed the challenges that ADCs have had historically with efficacy due to control of the drug to antibody ratio, and also product stability, pharmacokinetics, metabolism, and clearance. I asked how WuXi XDC works with developers to overcome these types of challenges. Jimmy explained that collectively the industry has worked diligently to overcome many of these. Specifically, WuXi XDC has now worked with so many different antibodies and other biological molecules, linker and payload chemistries, and combinations thereof, they are uniquely qualified to advise clients on development strategies that will best suit their clinical needs and ensure success.
I asked if there were other areas where WuXi XDC could offer support. Jimmy affirmed their strong manufacturability and developability strategies when evaluating the various technologies and bioconjugation options to provide sound data-driven decisions for lead selection and throughout development, in order to generate a robust GMP process. By looking at many of the challenges and pitfalls of certain linker and bioconjugation schemes, they have continually developed new technology platforms for linkers. In some cases they have made proprietary modifications to enhance the drug to antibody ratio or certain payloads to increase effectiveness for first-in-human trials.
CRITICAL ADVANCEMENTS IN ADC TECHNOLOGY
Next, we discussed controlling drug-to-antibody ratio (DAR) and the proprietary technologies that WuXi XDC has developed to address this issue. Jimmy shared that their R&D team developed a unique DAR enrichment and conjugation technology that provides substantial improvement to generate DAR4 ADC molecules versus standard cysteine-based conjugation methodologies. With their WuXiDAR4TM technology platform, they have seen greater than 70% DAR4 species using standard IgG1 molecules, and over 90% enrichment can be achieved with Ig1 and IgG4 domain switching and engineering. In addition, the WuXiDAR4 technology can put all 4 payloads onto the Fab region and as a result, the molecules show better product stability and pharmacokinetic profiles in vivo.
He went on to share additional technological advancements including the development of a novel linker for Lysine-based conjugation that demonstrates higher reactivity, better solubility, and a more flexible range of conjugation temperatures, plus the ability to conjugate this linker to other molecules beyond IgGs. Their unique payload chemistry involves more homogenous drug loading for cysteine conjugation. They can provide more information under a Confidential Disclosure Agreement (CDA).
I closed the interview by asking if these technologies were scalable. He said that they have designed all the technologies with an eye for ease of conjugation, formulation, and manufacturing – to be able to scale up for clinical trial-scale and beyond. They have a number of experts specialized in scale-up of conjugation, formulation, DP filling, and lyophilization.