LAUSR

In this issue, we present a special section on the use of CHO cell pools to produce material for Investigational New Drug (IND)-enabling Good Laboratory Practice (GLP) toxicology studies and/or other non-clinical early development studies. While the approaches may vary, all have the common goal of making new biotherapeutics available to patients as early as possible while maintaining high standards for product safety. This goal aligns with “fast to clinic” paradigms that are already an integral part of biologics drug development at many companies. In addition, the novel strategy of using “pools for tox” enables earlier regulatory dossier submissions and shorter timelines to first-in-human (FIH) clinical trials than those achieved using traditional approaches. Material for GLP toxicology studies has typically been manufactured using a clonally-derived cell line, and this is usually the same cell line that will be used to manufacture the FIH/ phase I clinical material. This often leads to the toxicology studies being on critical path for moving toward FIH and limiting options for acceleration. The different strategies presented by the articles in this section range from uncloned pools to pooled mixtures of clones for producing early stage material for non-clinical studies. When pool-derived material was indicated for use in GLP toxicology studies, development timelines could be reduced by 3 to 6 months depending on the strategy employed. The potential risk of using pool-derived material for GLP tox studies was mitigated by showing that the product quality of the pool-derived material is representative of the clone-derived material used for the FIH clinical study. The articles in this section all focus on CHO cells for production of mAbs and, in one case, Fc-fusion proteins, yet there is diversity in both the approaches that were evaluated and the decisions taken for future directions. In “Evaluation of PiggyBac-Mediated CHO Pools to Enable Material Generation to Support GLP Toxicology Studies,” pools generated by transposon-mediated gene integration are each shown to be comparable to a pool of the top four clones producing the same mAb, while further reducing the development timeline. The article “Strategic Deployment of CHO Expression Platforms to Deliver Pfizer’s Monoclonal Antibody Portfolio” 2 describes the random integration and site-specific integration platforms for cell line development and evaluation of material produced by pools derived from each platform. In all of the articles, at least one variation of a pool population is compared to clones producing the same mAb (or Fc-fusion protein) and the implications of the data are discussed. In some cases, mixtures of clones are described, while other examples speak to the degree of homogeneity of uncloned pools. While introducing different approaches for achieving the earlier availability of non-clinical material, the articles in this section all touch on these three important considerations for development programs: speed to clinic, productivity requirements, and representative product quality. As noted in the articles, acceleration of early development timelines is a major enabler of a faster path to FIH clinical trials and delivering new biotherapeutics to patients in a more timely manner. It can be noted, though, that if the GLP toxicology study is not on the critical path, acceleration for this study may not always lead to an accelerated FIH study. These manuscripts also highlight the importance of product quality rather than the specific cell source for generation of material for early development. At the same time, it is important to understand the level of risk of the chosen approach on the specific development program and the associated regulatory approval strategy. Taken together, this group of articles demonstrates that there are different strategies that can be employed to produce non-clinical material early in development of biologics, which, in turn, has the potential to significantly reduce the time to entering the clinic. This section represents an atypical sharing of data and approaches across some major players in the biotechnology industry. We are grateful for the editors, Mike Domach and Elizabeth Gilliard, for providing Biotechnology Progress as the platform for this sharing as well as for their reviewing and editing efforts. We would also like to acknowledge Dr. Chetan Goudar as instrumental in coordinating between the authors and the editors. Finally, readers interested in the subject of clonality should remain alert for the next issue. There, articles on the technology of selecting clones and a commentary on the robustness of statistical assumptions will appear.