Abstract 922: End-to-end discovery to support the development of safe and efficacious engineered cell therapies

Abstract

Abstract The global market for cell and gene therapies, including T-cell/Natural Killer cell chimeric antigen receptors (CAR-T/NK), is continuing to grow rapidly - with many clinical success stories for B-cell malignancies in particular. However, the path to clinical success has not been smooth - with early reports of organ damage and even deaths following CAR-T therapy highlighting that there are significant risks involved in their development, and a clear requirement to understand and mitigate for the underlying mechanisms that result in unwanted toxicities. Off-target binding and tonic signalling are indicated in many pre-clinical and clinical cell therapy failures, and it is becoming increasingly apparent that CAR design - particularly the selection of the tumor targeting moiety with exquisite specificity, desirable biophysical attributes and appropriate affinity - is key to developing a successful therapy. Distributed Bio's scFv and VHH phage-display libraries (SuperHuman 2.0 and Tungsten) have been designed to be biophysically stable and non-immunogenic. Their size and clonal diversity, coupled with the use of streamlined work-flows, enable the rapid identification of large panels of VH CDR3 sequence-unique binders which can then be assessed for CAR suitability by exploiting the integrated approach offered by DBio's successful partnership with Charles River. Panels of CAR constructs, covering the diversity of sequences and affinities related to the scFv/VHH domains isolated, can be triaged through Charles River efficacy and safety work-streams to identify the best therapeutic candidates. For example, co-culture experiments with target-expressing carcinoma cell lines and non-target expressing cell lines can be utilized to investigate and compare activity, specificity and potency of the various CAR constructs. Ultimately, combining Distributed Bio discovery with Charles River downstream characterization enables identification of the best lead candidate - balancing efficacy and safety of your CAR-T therapy - for optimal therapeutic outcome. Citation Format: Katherine Vousden, Sanne Holt, Sophie Vermond, Monique Hazenoot, Sarah Ives, Sawsan Youssef, Jake Glanville. End-to-end discovery to support the development of safe and efficacious engineered cell therapies [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 922.